Title of Invention	METHODS FOR PRODUCING PHENYLALANINE DERIVATIVES HAVING A QUINAZOLINEDIONE SKELETON AND INTERMEDIATES FOR PRODUCTION THEREOF
Abstract	The present invention provides a method for producing a phenylalanine derivative(s) having a quinazolinedione ring of formula (5), including steps 5 comprising of: reacting an acylphenylalanine derivative(s) of formula (1) with a carbonyl group-introducing reagent(s) and a derivative(s) of anthranilic acid to form an asymmetric urea intermediate(s); making the asymmetric urea intermediate(s) into a quinazolinedione 10 compound(s) of formula (4) in the presence of a base(s); and N-alkylating quinazolinedione ring amide of the obtained quinazolinedione compounds with N-alkylation agents. This production method is an industrially applicable method for producing phenylalanine derivatives having a quinazolinedione skeleton, which are compounds highly useful as drugs having 15 a 4 integrin inhibiting activity. In the formulae (1) and (5), R1 represents a phenyl group having a substituent(s) and the like, R2 represents an alkyl group and the like, R3 represents a dialkylamino group and the like, and R4 represents an alkyl group and the like.

Title of Invention

METHODS FOR PRODUCING PHENYLALANINE DERIVATIVES HAVING A QUINAZOLINEDIONE SKELETON AND INTERMEDIATES FOR PRODUCTION THEREOF

Abstract

The present invention provides a method for producing a phenylalanine derivative(s) having a quinazolinedione ring of formula (5), including steps 5 comprising of: reacting an acylphenylalanine derivative(s) of formula (1) with a carbonyl group-introducing reagent(s) and a derivative(s) of anthranilic acid to form an asymmetric urea intermediate(s); making the asymmetric urea intermediate(s) into a quinazolinedione 10 compound(s) of formula (4) in the presence of a base(s); and N-alkylating quinazolinedione ring amide of the obtained quinazolinedione compounds with N-alkylation agents. This production method is an industrially applicable method for producing phenylalanine derivatives having a quinazolinedione skeleton, which are compounds highly useful as drugs having 15 a 4 integrin inhibiting activity. In the formulae (1) and (5), R1 represents a phenyl group having a substituent(s) and the like, R2 represents an alkyl group and the like, R3 represents a dialkylamino group and the like, and R4 represents an alkyl group and the like.

Full Text	SPECIFICATION Methods for producing phenylalanine derivatives having a quinazolinedione Skeleton and intermediates for production thereof Background of the Invention The present invention relates to methods for producing phenylalanine derivatives having a quinazohnedione skeleton, which are compounds highly useful as drugs having 4 integrin inhibiting activity, and intermediates thereof. Recently, research on inflammatory diseases in which Of 4 integrin-depending adhesion process participates in the pathology such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Jorgen’s syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplantation rejection has been advanced, and application to treating or preventing agents of the compounds having a 4 integrin inhibiting activity has been expected. The applicant has already invented new phenylalanine derivatives having a 4 integrin inhibiting activity, which are highly useful as treating or preventing agents for inflammatory diseases in which a 4 integrin-depending adhesion process participates in the pathology and filed a patent appKcations (WO2002-16329). Conventionally, as the method for producing the phenylalanine derivatives having a quinazolinedione skeleton, it has been reported such as that a quinazolinedione skeleton is constructed via amide intermediates by supporting phenylalanine derivatives on a solid-phase resin (WO2002-16329 and Synlett, 3, 333-336, 2001). However, though the solid-phase synthesis method has excellent advantages as synthesis of a wide range of derivatives, generally it is not a method suitable for industriahzation because the amount of derivatives which can be supported on a sohd-phase resin has limitations and, as a result, the amount of the object substance which can be prepared at one time is extremely small. Further, in the soKd-phase synthesis, a reaction reagent(s) is generally excessively used, and this is inappropriate from the point of industriahzation. In addition, by substituting the solid-phase synthesis method with a Hquid-phase method based on the sohd-phase synthesis method, for example, in accordance with well-known examples of reports (S.M.Gadekar, et al., J. Am. Chem. Soc. 4666-4667, 1964, and L.GouiUex, et al., Tetrahedron lett, 37(39), 7031, 1996), a quinazohnedione skeleton can be constructed by a synthesizing method comprising steps of reacting amine with carboxylic acid of anthracitic acid to form an amide, and reacting an amino group of anthranihc acid with ethyl chloroform ate, l,l'-carbonyldiimidazole or the Kke to make it in carbamate or carbonyHmidazolyl form and then forming a quinazolinedione ring with a base(s). However, when the compound is synthesized, it has problems in that the number of reaction processes are large and therefore the jelled is low. On the other hand, as the method via urea intermediates, it has been known such as that amine is reacted with isocyanate to form an urea and a quinazohnedione ring is formed with a base (for example, WO2002-16329 and B.Taub, J. Org. Chem., 26, 5238-5239, 1961). However, isocyanate is typically a Hquid with a pungent odor and highly toxic, and it is known that isocyanate sometimes induces self-polymerization to produce isocyanurate or reacts with water in the air to disintegrate. Thus, isocyanate is typically low in chemical stability and has toxicity. From these mentioned above, it is needed to find methods for producing phenylalanine derivatives having a quinazohnedione skeleton suitable for industrialization, Disclosure of the Invention The object of the present invention is to provide industrially apical methods for producing phenylalanine derivatives having a quinazohnedione skeleton, which are compounds highly useful as drug products having Oi 4 integrin inhibiting activity The present invention also intends to provide intermediates for production of the phenylalanine derivatives having a quinazohnedione skeleton. The inventors studied the above problems to be solved and they found industrially apical production methods in which phenylalanine derivatives having a quinazohnedione skeleton are conducted in high yield by a synthesizing method using a carbonyl group-introducing reagent(s) via urea intermediates, which is concise operation in mild reaction temperature without compacted solvent extraction and concentration. The present invention has been completed on the basis of this finding. [l] Namely, the present invention provides methods for producing phenylalanine derivatives having a quinazohnedione ring of following formula (5), comprising steps of: reacting an acyl phenylalanine derivative(s) of formula (l)' R1 N C00R2 H wherein Rl represents a phenyl group which may have a substituent(s) or a pyridyl group which may have a substituent(s), R2 represents an alkyl group which may have a substituent(s), and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s), with a carbonyl group-introducing reagent(s) and an anthracic acid derivative(s) of formula (2): wherein R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group; R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s); and R5 represents an alkyl group or an alkylcarbonyl group, and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s), to form an asymmetric urea intermediate(s) of formula (3): wherein Rl to R5 are defined above; making the asymmetric urea intermediate(s) into a quinazolinedione compound(s) of formula (4) in the presence of a base(s): wherein Rl to R4 are defined above; and when R4 represents a hydrogen atom in the obtained quinazolinedione compound(s) of the formula (4), N-alkylating a quinazolinedione ring amide of the quinazolinedione compound(s) with an N-alkylation agent(s) to form the phenylalanine derivative(s) having a quinazolinedione skeleton of formula (5)' wherein Rl to R3 are defined above, R4 represents an alkyl group or a benzyl group which may have a substituent(s). The present invention also provides the following compounds of (l) to (5), which are intermediates for production of the phenylalanine derivative(s) having a quinazolinedione ring of formula (5). (1) Methylester of N"-(2,6'dichlorobenzoyl)-4-amino-L-phenylalanine wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group, and salts thereof with chemically acceptable acids. (2) Methylester of 5-dimethylamino-2-aminobenzoic acid wherein, in the formula (2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids. (3) Methylester of 2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonyl ethyl]phenyl}ureide)-5-dimethylaminobenzoic acid wherein, in the formula (3), Rl represents a 2,6-dichlorophenyl group, R2 represents a methyl group, R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids. (4) The compound wherein, in the formula (2), R3 represents a dialkylamuio group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids. (5) The compound wherein, in the formula (3), Rl represents a 2,6-dichlorophenyl group, R2 represents a methyl group, R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alchemy group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids. Best Mode for Carrying out the Invention The following embodiments are preferable in the present invention. [2] The production method according to above [l], wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an alkynyl group. [3] The production method according to above [l], wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group or a nitro group. [4] The production method according to above [l], wherein, in the formulae (2) to (5), R3 represents a dialkylamino group. [5] The production method according to any one of above [l] to [4], wherein the carbonyl group-introducing reagent(s) is l,l'-carbonyldiimidazole or chloroform ate. [6] The production method according to any one of above [l] to [5], wherein the base is potassium carbonate or sodium methoxide. [7] The production method according to any one of above [l] to [6], wherein the N-alkylation agent is methyl p-toluenesulfonate. [8] The production method according to above [l], comprising steps of reacting a carbonyl group-introducing reagent selected from the group consisting of l,r-carbonyldiimidazole and chloroformate and the compound of the formula (2) wherein R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group with the compound of the formula (l) wherein Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to obtain methylester of 2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl}ureide)-5-di methylaminobenzoic acid; converting it in the presence of potassium carbonate or sodium methoxide into methylester of N°'-(2,6-dichlorobenzoyl)-4-(6-dimethylamino-2,4[lH,3Hl-quinazolinedione-3-yl)-L -phenylalanine of the formula (4); and then N-alkylating the resultant with methyl p-toluenesulfonate to obtain methylester of N«"(2,6-dichlorobenzoyl)"4-(l-methyl-6-dimethylamino'2,4[lH,3H]-quinazolinedione ne-3-yl)-L-phenylalanine. [9] The production method according to above [ll, comprising steps of reacting a carbonyl group-introducing reagent selected from the group consisting of l,l'carbonyldiimidazole and chloroformate and the compound of the formula (2) wherein R3 represents a dimethylamino group, R4 represents a methyl group and R5 represents a methyl group with the compound of the formula (l) wherein Rl represents a 2,6-diclilorophenyl group and R2 represents a methyl group to obtain the compound of the formula (3); converting it in the presence of potassium carbonate or sodium methoxide into methylester of N° ■(2,6"dichloro-benzoyD "4-(l-methyl-6-dimethylamino"2,4[lH,3H]-quinazolinedione-3-yl)"L'Phenylalanin e. Next, the compounds in the present invention are described as follows. Rl represents a phenyl group which may have a substituent(s) or a pyridyl group which may have a substituent(s). In this connection, examples of the substituents are a halogen atom, an alkyl group, a halogenoalkyl group including a perfluoroalkyl group, an alkoxy group, a halogenoalkoxy group including a perfluoroalkoxy group, an alkylthio group, a nitro group, an alkylsulfonylamino group and a tetrazolyl group. Here, an alkyl group as a component preferably has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms, and they may be same or different from each other. Rl is preferably a phenyl group substituted with a halogen atom and/or an alkyl group, and, for example, they are preferably 2,6-dichlorophenyl group, 2,6" dimethylphenyl group, 2-chloro-6-methylphenyl group, 2-chlorophenyl group, 2-methylphenyl group, 2,4,6-trichlorophenyl group, 2,4,6-trimethylphenyl group and 2,6-dichloro-4-methylphenyl group. R2 is an alkyl group which may have a substituent(s). In this connection, an alkyl group preferably has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms. When R2 has a substituent(s), such substituent(s) include a substituted or unsubstituted lower alkylcarbonyl group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted amino group, a lower alkoxy group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group and a substituted or unsubstituted carbamoyl group. Here, when the substituent(s) of R2 is a lower alkylcarbonyloxy group, a lower alkoxycarbonyloxy group or a lower alkoxy group, alkyl and alkoxy thereof preferably have 1 to 6 carbon atoms, and include chain, cithc, linear and branched ones. Further, when the substituent(s) of R2 is an aryl group, it represents a mono-or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. For example, it includes a phenyl group and a naphthyl group. When the substituent(s) of R2 is a heteroaryl group, it represents a 5 to 8 membered mono-, hi" or tricycUc aromatic heterocyclic group including 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as a cyclic atom. For example, they include a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, an isoxazolyl group, an oxazolyl group, an isothiazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a tetrazolyl group, an indolyl group, a benzimidazolyl group, a quinolyl group and an isoquinolyl group. Here, a substituent(s) of the aryl group and the hetero aryl group is, for example, a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group. Among these, a pyridyl group, a furyl group and a thienyl group are preferred. Meanwhile, when the substituent(s) of R2 is a lower alkylcarbonyloxy group or a lower alkoxycarbonyloxy group, the substituent(s) thereof include a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a hydroxy group, an amino group and an amino group substituted with a lower alkyl group including monosubstitution or trisubstitution thereof, A methyl group and an ethyl group are preferred among these. When the substituent(s) of R2 is an amino group, the substituent(s) thereof include a lower alkyl group, a lower alkoxycarbonyl group and a lower alkylsulfornyl group. Among these, a methyl group and an ethyl group are preferable. Here, two substituents may bond together to form a ring and, when forming a ring, they may also sandwich an oxygen, nitrogen or sulfur atom between them. For example, a substituted amino group includes a cyclic amino group such as 1-piperidinyl group and 4-morphonyl group, a cyclic amide group such as 2-oxo-l-pyrroUdinyl group and a cyclic urea group such as 2-oxoimidazoline-l-yl group and 2-oxoimidazolidine-l-yl group. Further, when the substituent(s) of R2 is an aryl group or a heteroaryl group, the substituent(s) thereof include a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group. When the substituent(s) of R2 is a carbamoyl group, the substituent(s) thereof include a lower alkyl group and a phenyl group, and mono- and di-substitutions thereof are also included. When R2 has a substituent(s), the substituent(s) thereof is preferably a lower alkylcarbonyloxy group, a chlorine atom, a pyridyl group, a furyl group, a thienyl group and a lower dialkylcarbamoyl group. In the formula (l), an amino group is preferably in the para position among ortho, meta and para positions on a benzene ring. R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group, and R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s). While R5 may be whatever 0R5 is removed from C00R5 by a base, an alkyl group and an alkylcarbonyl group are preferable. In R3 to R5, an alkyl group as a component preferably has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms. R3 are preferably a dialkylamino group, a hydrogen atom, a halogen atom, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group. Particularly preferred ones are a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group and an alkylthio group. A dialkylamino group represents an amino group disubstituted with an alkyl group having 1 to 6 carbon atoms, including a cithc one. Preferably it is an amino group disubstituted with an alkyl group having 1 to 3 carbon atoms or a cyclic amino group having 2 to 6 carbon atoms. For example, it includes a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group, a piperidyl group, a di propylamino group, a methylpropylamino group and an ethylpropylamino group. A monoalkylamino group represents an amino group monosubstituted with an alkyl group having 1 to 6 carbon atoms, including alkylamino group with a cyclic alkyl group (s). Preferably it is an amino group monosubstituted with an alkyl group having 1 to 4 carbon atoms such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group and a cyclopropylmethylamino group. An alkyl group substituted with a dialkylamino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with the same substituent(s) as those of the dialkylamino group. Preferably it is an alkyl group having 1 to 3 carbon atoms, which is substituted with the same substituent(s) as those of the dialkylamino group. For example, it includes either of a methyl group, an ethyl group or a propyl group substituted with a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group, a piperidyl group, a dipropylamino group, a methylpropylamino group or an ethylpropylamino group. Particularly preferable ones are a dimethyl aminomethyl group, a Dimethylaminoethyl group, a methylethylaminomethyl group and the like. An alkyl group substituted with a monoalkylamino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with the same substituent(s) as those of the monoalkylamino group. Preferably it is an alkyl group having 1 to 3 carbon atoms, which is substituted with the same substituent(s) as those of the monoalkylamino group. For example, it includes either of a methyl group, an ethyl group or a propyl group substituted with a methylamino group, an ethylamino group, a propylamino group, isopropylamino group, a butylamino group or a cyclopropylmethylamino group. Particularly preferable ones are a methylaminomethyl group, an methylamJnomethyl group, a methylamJnomethyl group, an methylamJnomethyl group and the hake. An alkyl group substituted with an amino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an amino group, and preferably an alkyl group having 1 to 3 carbon atoms, which is substituted with an amino group. For example, it includes an aminomethyl group, an aminomethyl group, an iminopropyl group and the like. An alkyl group substituted with an alkenyl group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an alkenyl group having 2 to 6 carbon atoms, and preferably an alkyl group having 1 to 3 carbon atoms, which is substituted with an alkenyl group having 2 to 4 carbon atoms. For example, it includes -CH2CH=CH2, -CH2CH2CH=CH2 and the like. An alkyl group substituted with an alkynyl group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an alkynyl group having 2 to 6 carbon atoms, and preferably an alkyl group having 1 to 3 carbon atoms, which is substituted with an alkynyl group having 2 to 4 carbon atoms. For example, it includes -CH2CECH, -CH2CH2C = CH and the Hke. An alkoxycarbonyl group represents an alkoxycarbonyl group having 2 to 7 carbon atoms and preferably having 2 to 4 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group and a propyloxycarbonyl group. An alkylthio group represents a thio group substituted with an alkyl group having 1 to 6 carbon atoms and preferably a thio group substituted with an alkyl group having 1 to 3 carbon atoms, such as a methylthio group, an ethylthio group and a propylthio group. An arylthio group represents a phenylthio group and a naphthylthio group. Particularly, R3 is preferably a a dimethylamino group, a diethylamino group, a methylethylamino group, a l group, a piperidyl group, a methylamino group, an ethylamino group, a propylamine group, a cyclopropylmethylamino group, a dimethylaminomethyl group, a diethylaminomethyl group, a dimethylaminoethyl group, a diethylaminoethyl group, a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, a methylaminoethyl group, an ethylaminoethyl group, a propylaminoethyl group, HC = CCH2 group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylthio group or an ethylthio group. R4 is preferably a hydrogen atom or an alkyl group. In the formula (2), (S) and (4), a hydrogen atom is further preferable and, in the formula (5), an alkyl group is further preferable. While a substituent(s) of a benzyl group includes an alkyl group, an aikoxy group, a halogen atom and the hke, an unsubstituted benzyl group is preferable. R5 is particularly preferably an alkyl group. In the formula (2), it is preferable that R3 is in the para position to an amino group. The synthetic intermediates of the formula (l) are synthesized as follows. A phenylalanine having a nitro group on an aromatic ring and acid chloride are condensed under the conditions of the well-known method, Schotten-Baumann reaction (such as N. 0, V, Sonntag, Chem. Rev. 52, 272, 1953) to produce acylphenylalanine derivatives. Then, said carboxyhc acid is esterified using the well known method (such as R.C.Larock’ Comprehensive Organic Transformations (2nd Ed.), p.1932-1941, Wiley-VCH, New York) to synthesize alkylester of acylphenylalanine. The conventional method, catalytic reduction with a transition metal catalyst(s) (such as R. C. Larock ‘ Comprehensive Organic Transformations (2nd Ed.), p.821-828, Wiley-VCH, New York) is applied to the synthesized substance in the presence of hydrogen gas to obtain the corresponding compounds of the formula (l). For example, as the method for producing methylester of N’ -(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine which is a new synthetic intermediate wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group, said compound can be synthesized by following processes' condensing a publicly-known and commercially available 4"nitro-L"phenylalanine and a similarly pubhcly-known and commercially available 2,6-dichlorobenzoylchloride; subjecting the resultant to methyl esterification ; and reduction of a nitro group. Concretely, 4-nitro-L"phenylalanine and 2,6-dichlorobenzoylchloride are condensed in a mixed solvent of a sodium hydroxide aqueous solution and acetone with keeping the reaction temperature at 5 to 15 °C, and then crystallization is conducted to obtain a corresponding condensed substance, N° -(2,6-dichlorobenzoyl)-4-nitro-L"phenylalanine almost quantitatively. Subsequently, the condensed substance is suspended into methanol, and methyl esterification is conducted by heating with adding concentrated sulfuric acid. Then, crystallization is conducted to obtain a corresponding methyl esterified substance, methylester of N° -(2,6-dichloro benzoyl)-4-nitro-L-phenylalanine almost quantitatively. Then, catalytic reduction reaction is conducted to the methyl esterified substance using a transition metal catalyst(s) of a nitro group which is a well-known method (such as F. S. DoveU et al., J. Am. Chem. Soc, 87, 2767, 1965) and preferably using a platinum carbon catalyst poisoned with sulfur, and hydrogen gas. Thereafter, crystaUization is conducted to obtain methylester of N’-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine in high yield, wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group. The yield in case of going through the three steps from 4-nitro"L-phenylalanine is about 90%. Meanwhile, the above-mentioned synthesizing method is not a sole method for producing the compound of the formula (l) and does not hmit the method of the present invention. Similarly, the jield indicates an average value thereof and doe not limit the value. On the other hand, as the method for producing the compound of the formula (2), said compound can be obtained by well-known methods from commercially available trisubstituted benzene derivatives. For example, as the method for producing methylester of 5-dimethylamino-2-aminobenzoic acid which is a new synthetic intermediate wherein, in the formula (2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represent a methyl group, said compound can be synthesized by following processes: dimethyl amination, methyl esterification and reduction of a nitro group from a pubhcly-known and commercially available 5-chloro-2-nitrobenzoic acid. Concretely, 5-chloro-2-nitrobenzoic acid is dissolved in a dimethylamine aqueous solution and heated to produce 5-dimethylamino’2-nitrobenzoic acid. Hydrochloric acid is added to the reaction solution to precipitate out the product as a solid material. The sohd material is separated to obtain 5-dimethylamno-2-nitrobenzoic acid almost quantitatively. Next, the 5-dimethylamno-2-nitrobenzoic acid is dissolved in concentrated sulfuric acid/methanol and heated to conduct methyl esterification in order to produce methylester of 5-dimethylamino -2-nitrobenzoic acid, which is a well"known method. Toluene and water are added to the reaction solution, and the obtained product is extracted to an organic layer, concentrated, and crystallized to obtain 5-dimethylamino-2-nitrobenzoic acid in high yield. Next, catalytic reduction is conducted to a nitro group of methylester of 5-dimethylamino-2-nitrobenzoic acid under the acidic condition by hydrochloric acid, using transition metal catalysts such as palladium carbon and hydrogen gas in a methanol solvent. Crystallization is conducted to obtain methylester of 5-dimethylamino-2-aminobenzoic acid / dihydrochloride in high yield. The yield via the three processes from 5-chloro-2-nitrobenzoic acid is about 80%, Further, thus obtained methylester of 5-dimethylamino-2-amino benzoic acid of the formula (2) can be obtained stably as salts with acidic substances, e.g., hydrochloride. However, the above-mentioned synthesizing method is not a sole method for producing the compound of the formula (2) and does not limit the production method of the present invention. Similarly, the jdeld indicates an average value thereof and does not Hmit the value. The step 1 of the production method of the present invention is explained below. The method for producing phenylalanine derivatives having a quinazohnedione ring of the formula (5) in the present invention is as follows. The compound of the formula (l) which is the important intermediate and the compound of the formula (2) are converted into asymmetric urea intermediates by using a carbonyl group-introducing reagent(s), preferably l,l'-carbonyldiimidazole or chloroformate, and then the compound of the formula (3) is converted to the compound of the formula (4) under mild basic condition. In case of the compound wherein R4 in the formula (4) represents a hydrogen atom, the compound can be prepared without isolating the compound of the formula (4), by successively conducting N-alkylation reaction with N-alkylation agents under basic condition. It may be also possible to isolate the compound of the formula (4) and then conduct N-alkylation reaction. For example, an amino group of methylester of N ‘‘ -(2,6-dichlorobenzoyl)"4-amino-L-phenylalanine of the formula (l) is converted into carbonylimidazolyl by l,l'-carbonyldiimidazole using an organic solvent(s) having suitable solubility such as, particularly preferably, acetonitrile. Without isolating the intermediates thereof, methylester of 5-dimethylamino-2-aminobenzoic acid of the formula (2) is put into the reaction solvent to be able to obtain methylester of 2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl}ureide)-5-di methylaminobenzoic acid of the formula (S), which is asymmetric urea intermediates, in high yield. In the present specification, "a carbonyl group-introducing reagent(s)" indicates those wherein only a carbonyl group in atomic groups of a quinazolinedione ring is derived from the present reagent. For instance, they include l,l'-carbonyldiimidazole (Organic syntheses collective volume V, R201-204, Wiley, New York, 1973, as a synthetic example thereof), chloroformate and the hke. These are publicly known and commercially available. Further, it is also possible to use reagents wherein an imidazolyl group of l,l'-carbonyldiimidazole is substituted with other heteroaryl removing group(s), such as l,r-carbonyldi(l,2,4-triazole) (an imidazolyl group in this reagent is substituted with a triazoyl group and the reagent is commercially available). The substituents thereof are not hmited to only an imidazolyl group and a triazoyl group. It is also possible to use other heteroaryl removing groups as the substituents. It is further possible to use N,N'-disuccinimidyl carbonate (DSC) (N"hydroxysuccinimide in this reagent is a removing group and the reagent is commercially available). Chloroformate includes reagents having 2 to 10 carbon atoms, such as phenyl chloroformate, nitrophenyl chloroformate, methoxjrphenyl chloroformate, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, octyl chloroformate and benzyl chloroformate, though they are not hmited to these examples. Similarly, it is also possible to use phosgene and phosgene analogues such as triphosgene as the carbonyl group-introducing reagents. These are gas or Uquid and highly toxic (Reference: RTECS SY 5600000) as compared with the above reagents and therefore difficult to deal with. Further, since a particular kind of facilities is usually required and distribution thereof is limited, these reagents are not very favorable in the carbonyl group-introducing reagents. l,l'-carbonyldiimida2ole is particularly preferred as a carbonyl group-introducing reagents. When l,r-carbonyldiimidazole is used, it is superior in that the amount of produced by-products is small and the objective asymmetric urea intermediates are obtained in high yield. A carbonyl group-introducing reagents is preferably used in 0.8 to 1.2 mol equivalent weight to 1 mol of the compound of the formula (l). The compound of the formula (2) is preferably used in 0.8 to 1.2 mol equivalent weight to 1 mol of the compound of the formula (l). The solvents of the present reaction include organic solvents having suitable solubihty to the compounds of the formula (l) such as methylester of N" -(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine. For example, it is possible to use acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), halogenated carbon hydride such as methylene chloride, pyridine, pyrroHdone, N-methylpjn:rohdone, or mixed solvents thereof. Above aU, when acetonitrile is used, products can be easily separated from the reaction solvent by filtration. Therefore, it is possible to isolate very pure asymmetric urea intermediates of the formula (3) by only a simple separation with filtration. Since it does not require any cumbersome operations such as extraction and concentration of solvents, it is useful as industriahzed process. Similarly, it is also possible to obtain crystals of the objective compound by the steps of the reaction with N,N-dimethylformamide (DMF); adding poor solvents such as alcohols having 1 to 10 carbon atoms or water to precipitate asymmetric urea intermediates as a sohd substance; and then separation by filtration thereof. As a result, acetonitrile and N,N-dimethylformamide are particularly preferable as the solvents of the present reaction. The concentration of the above reaction is preferably that apphcable as industriahzed process. For example, when acetonitrile is used as a reaction solvent, the reaction should be conducted in 1 to 0.0IM and particularly preferably around 0.2M, from the point of flowabihty in stirring the reaction solution or crystallizing solution. When the compound of the formula (l) is converted into carbonylimidazolyl by carbonyl group-introducing reagents such as l,r-carbonyldiimidazole, the reaction temperature thereof is preferably within the range of around 0°C to not above the boiling point of the reaction solvent. To conduct the reaction around 0°C to not above 10°C is more industrially preferable in that it is useful for inhibiting side reactions and improving the yield. The reaction time is preferable around 1 to 5 hours. In the condensation reaction of the compound of the formula (l) converted into carbonyhmidazolyl with methylester of 5-dimethylamino-2-aminobenzoic acid of the formula (2), the reaction temperature thereof is preferably within the range of around 0°C to not above the boihng point of the appHed solvent. Particularly, the reaction is more preferably conducted at the reaction temperature of around 50°C since urea bond formation reaction is completed in around 2 to 3 hours and the asymmetric urea intermediates of the formula (3) can be obtained in high yield. However, the reaction temperature and time are not Umited to the above and the reaction time is determined by the balance with the reaction temperature. It is desirable from the industrial point of view that the reaction solution is controlled by analytical methods such as HPLC. In the above reaction, input order of raw materials and reagents is not particularly hmited. However, the method wherein the compound of the formula (l) is first reacted with a carbonyl group-introducing reagent(s) to convert into carbonyhmidazolyl and then reacted with the compound of the formula (2) is more preferable from the point of the high yield and side reactions as compared with the method wherein the compound of the formula (2) is first converted into carbonylimidazolyl. While, in the production method of the present invention, the compound of the formula (2) may be first converted into carbonylimidazolyl, and the compound of the formula (l), a carbonyl group-introducing reagent(s) and the compound of the formula (2) may be reacted simultaneously. Next, described herein is the step 2. The asymmetric urea intermediates of the formula (3) form a quinazoLLnedione ring in the presence of a base in a sviitable reaction solvent to give the quinazoUnedione compounds of the formula (4). The 'T’ase" herein includes an inorganic base and organic base. Inorganic bases include salts with alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and the hke; and salts with alkahne earth metals such as calcium carbonate and magnesium carbonate. Organic bases include triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine, l,8-diazabicyclo[5.4.0]undec"7-ene (DBU) and N,N-diisopropyl-N-ethylamine (DIPEA). Inorganic bases are preferable and particularly potassium carbonate and sodium methoxide are preferable. The base is preferably used in 0,1 to 2.0 mol equivalent weight to 1 mol of the compound of the formula (3), and it is more preferable that 1 mol equivalent weight or less of a catalyst is used. The reaction time is preferably 1 to 6 hours. For example, when potassium carbonate is used as a base, 0.1 to 2 mol equivalent weight thereof is preferable and 0.2 to 0.4 mol equivalent weight is more preferable. When sodium methoxide is used as a base, 0.1 to 1.0 mol equivalent weight thereof is preferable and 0.2 to 0.4 mol equivalent weight is more preferable. 1 to 2 hours of the reaction time are enough at that time. The solvents in the above reactions may be those in which the compound of the formula (3) is dissolved and the reaction proceeds smoothly. For example, they include dimethylformamide (DMF) and a mixed solvent with alcohols containing dimethylformamide as a main ingredient, though the solvents are not Hmited to these. Meanwhile, when potassium carbonate is used as a base, it is preferable to use a mixed solvent of DMF and methanol from the point of shortening of the reaction time. As the relative proportions of the mixed solvent of DMF and methanol, around 10 to 1 is suitable, though the proportions are not hmited to this. As the reaction concentration of the above reactions, it is preferable that the reaction is conducted in the concentration apphcable as industrialized process of within 0.01 to 2M and, for example, around 0.25M in case of the mixed solvent of DMF and methanol, though the concentration thereof is not Hmited to these. As the reaction temperature, 0°C to not above the boiling point of the solvent, and preferably around 25'C is suitable. The quinazohnedione compounds of the formula (4) produced by the above reactions can be precipitated as solid substance by adding water or an aqueous solution of hydrochloric acid dropwise to the reaction solution, or by adding the reaction solution to water or an aqueous solution of hydrochloric acid, and then precipitated substance can be isolated by the typical separating methods. When potassium carbonate is used as a base, the quinazohnedione ring formation reaction is conducted to the asymmetric urea intermediates of the formula (3) and then N-methylation reaction can be soon hnked after that without isolating the compound of the formula (4) and, therefore, one process in the reaction processes can be skipped. When taking account of improvement in production efficiency from the point of industriahzation, this method is particularly useful as industriahzed process since the isolating process of the compound of the formula (4) can be simplified. Finally, described herein is the step 3, In the formula (4), when R4 is a hydrogen atom, the compound can be derived into quinazohnedione compounds of the formula (5) with N- alkylation agents in the presence of a base. Meanwhile, it is also possible to isolate the quinazohnedione compounds of the formula (4), which is produced in the step 2, and then N-alkylate. However, it is preferable from the point of industriahzation to N-alkylate without isolation. In the present specification, "N-alkylation agents" indicate reagents which can introduce an alkyl group on a nitrogen atom, and haloalkane, alkyl sulfonate and benzyl hahde which may be substituted are included, for example. Here, haloalkane and alkyl sulfonate are preferably those having 1 to 10 carbon atoms. Those having 1 to 6 carbon atoms are further preferable and those having 1 to 3 carton atoms are particularly preferable. Haloalkane includes, for example, methyl iodide and ethyl iodide, and alkyl sulfonate includes, for example, methyl methanesulphonate, ethyl methanesulphonate, methyl ethanesulphonate, ethyl ethanesulphonate, methyl p-toluenesulphonate and ethyl p-toluenesulphonate. Benzyl halide includes benzylchloride, benzylbromide and the like, and the substituents thereof are an alkyl group, an alkoxy group, a halogen atom and the like. For example, in the production of the compound wherein R4 in the formula (5) is a methyl group, methyl p-toluenesulphonate is suitable from the point of industrialization. Namely, methyl p-toluenesulphonate has the higher boiling point as compared with methyl iodide and is easy to deal with under room temperature. Further, methyl p-toluenesulphonate has the favorable flowabiUty of the reaction solution and is suitable for the industrialized process with solution sending. As the usage amount of N-alkylation agents, the range of 1 to 10 mol eqxuvalent weight thereof and preferably around 1.2 to 2.0 mol equivalent weight is suitable to the compound of the formula (3) or (4). The amount of the reagents can be increased or decreased in accordance with progress of the reaction. A base includes inorganic bases and organic bases. Here, examples of inorganic bases are salts with alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and the like; and salts with alkaline earth metals such as calcium carbonate and magnesium carbonate. Organic bases include triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-dusopropyl-N-ethylamine (DIPEA). Inorganic bases are preferable and particularly potassium carbonate is preferable. The base is preferably used in 1.5 to 2 mol equivalent weight to the compound of the formula (3) or (4) and more preferably around 1.8 mol equivalent weight, while the amount is not limited to these and can be increased or decreased in accordance with progress of the reaction. The reaction solvents may be those in which the compound of the formula (3) or (4) is dissolved and the reaction proceeds smoothly. For example, they include dimethylformamide (DMF) and a mixed solvent with alcohols containing dimethylformamide as a main ingredient, though the solvents are not limited to these. Meanwhile, when potassium carbonate is used as a base, it is preferable to use a mixed solvent of DMF and methanol from the point of shortening of the reaction time. As the relative proportions of the mixed solvent of DMF and methanol, around 10 to 1 is suitable, though the proportions are not Hmited to this. As the reaction concentration of the above reactions, it is preferable that the reaction is conducted in the concentration apphcable as industriahzed process of within 0.01 to 2M and, for example, around 0.25M in case of the mixed solvent of DMF and methanol, though the concentration thereof is not Hmited to these. As the reaction temperature, 0°C to not above the boiling point of the reaction solvent, and preferably around 40°C is suitable, though the temperature thereof is not Hmited to these. The reaction time may be 3 to 18 hours, and it is desirable from the industrial point of view that the reaction solution is administered by analytical methods such as HPLC. For example, an asymmetric urea intermediate wherein, in the formula (4), Rl is 2,6-dihlorophenyl group, R2 is a methyl group and R3 is a dimethylamino group is dissolved at 25 ‘C in a mixed solvent of DMF and methanol. The quinazolinedione ring formation reaction is conducted by stirring for 2 hours using 0.2 mol equivalent weight of potassium carbonate to the compound of the formula (4). Then, 1.5 mol equivalent weight of methyl p-toluenesulphonate and 1.8 mol equivalent weight of potassium carbonate are added to conduct N-methylation reaction. Two processes are gone through from the formula (4) to be able to obtain methylester of N ‘‘ -(2,6-dichlorobenzoyl)-4-(l-methyl-6-dimethylamino-2,4 [lH,3H]-quinazolinedione-3-yl)-L-phenylalanine of the formula (5) in the yield of 80 to 90%. The compound of the formula (5) can be precipitated as solid substance by adding water to the reaction solvent and isolated by the typical separating methods such as jSltration, though the method is not limited to this. The above production methods describe the case using the compound wherein, in the formula (2), R4 is a hydrogen atom. As for the compounds wherein, in the formula (2), R4 is an alkyl group or a benzyl group which may have a substituent(s), as the reaction process with N-alkylation agents is not necessary, the compound of the formula (l) and the compound of the formula (2) are derived into asymmetric urea intermediates of the formula (3) by using a carbonyl group-introducing reagent(s) and preferably l,r-carbonyldiimidazole; the compound of the formula (3) is converted to the compound of the formula (4) under mild basic condition; and then the compound of the formula (4) is isolated to obtain the objective compound of the formula (5) (because the formula (4) and the formula (5) are identical in this case). From the above production methods, herein provided is the industrially appHcable method for producing phenylalanine derivatives having a quinazolinedione ring of the formula (5) via the crucial intermediate (3) from crucial intermediates of the formulae (l) and (2). Meanwhile, when R3 is a monoalkylamino group, an amino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an amino group, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be protected in advance by a proper protecting group(s) and then the protection thereof may be removed by suitable methods of removal of protection. The methods for protection and removal of protection are described in, for example, "Protecting group in organic synthesis" by Theodora W. Greene, Peter G. M. Wuts, Second edition, John Wiley & Sons Inc., New York, 1991, 309-385. For example, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted, by using acylation agents in ordinary acylation methods, with an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a trifluoroacetyl group and the like; an arylcarbonyl group which may have a substituent(s) such as a benzoyl group; an arylalkylcarbonyl group which may have a substituent(s) such as a benzylcarbonyl group; an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a butoxycarbonyl group, a tertiarybutoxycarbonyl group, a trifluoromethoxy carbonyl group and the like; an aryloxycarbonyl group which may have a substituent(s) such as a phenoxycarbonyl group; and an arylalkyloxycarbonyl group which may have a substituent(s) such as a benzyloxycarbonyl group. In this case, after completion of the reaction of the first, second or third step in the present invention, particularly after the completion of the N-alkylation reaction in the third step of the present invention, a protecting group(s) can be removed under the acidic condition or the basic condition and the hke in case of an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s), an arylcarbonyl group which may have a substituent(s) and an arylalkylcarbonyl group which may have a substituent(s); under the basic condition and the like in case of an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) and an aryloxycarbonyl group which may have a substituent(s); under the acidic condition and the like in case of a tertiarybutoxycarbonyl group; and under the catalytic reduction condition (hydrogenating reaction) and the hke. Further, for instance, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted, by using benzylation reagents in ordinary benzylation methods, with an arylalkyl group which may have a substituent(s) such as a benzyl group, a phenethyl group, a methylbenzyl group, a methoxybenzyl group and a halobenzyl group, and the Uke. In this case, after completion of the reaction of the first, second or third step in the present invention, particularly after the completion of the N-alkylation reaction in the third step of the present invention, a protecting group(s) can be removed under the catalytic reduction condition (hydrogenating reaction) and the hke. Meanwhile, the substituents in case of the above protecting groups "which may have a substituent(s)" include, for example, a halogen atom, an alkoxy group, an aUcyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group. The 'Tialogen atom" in the present specification indicates a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The 'lialogeno"" as the component in a substituent indicates fluoro-, chloro-, bromo- and iodo-. The "chemically acceptable acids" in the formula (l) or (2) include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid; organic carboxylic acid such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, trifluoroacetic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teochc acid, salicylic acid, lactic acid, oxahc acid, mandehc acid and malic acid; and organic sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid. The free forms are particularly preferable in the compound of the formula (l) and the hydrochloride is particularly preferable in the compound of the formula (2), They may be hydrates or solvates thereof. In the present invention, when R3 in the formula (5) is a dialkylamino group, the resulting compound is therapeutically superior, and therefore, R3 in the formulae (2) and (3) are preferably dialkylamino groups. Among dialkylamino groups, a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group and a piperidinyl group are preferable. Particularly, it is preferable that R3 is a dimethylamino group. Similarly, it is also preferable that R3 in the formulae (2) and (3) are a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group. Particularly preferred ones are a methylamino group, an ethylamino group, a propylamino group, a cyclopropylmethylamino group, a dimethylaminometyl group, a diethylaminomethyl group, a dimethylaminoethyl group, a diethylaminoethyl group, a methylaminom ethyl group, an ethylaminomethyl group, a propylaminomethyl group, methylaminoethyl group, ethylaminoethyl group, a propylaminoethyl group, HC = CCH2 group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylthio group and an ethylthio group. Among these, when R3 in the formulae (2) and (3) are a monoalkylamino group or an alkyl group substituted with a monoalkylamino group, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted with an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a trifluoroacetyl group and the like; an arylcarbonyl group which may have a substituent(s) such as a benzoyl group; an arylalkylcarbonyl group which may have a substituent(s) such as a benzylcarbonyl group; an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a butoxycarbonyl group, a tertiary-butoxycarbonyl group, a triQuoromethoxy carbonyl group and the like; an aryloxycarbonyl group which may have a substituent(s) such as a phenoxycarbonyl group; and an arylaUcyloxycarbonyl group which may have a substituent(s) such as a benzyloxycarbonyl group. A hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted with an arylalkyl group which may have a substituent(s) such as a benzyl group, a phenethyl group, a methylbenzyl group, a methoxybenzyl group and a halobenzyl group, and the like. The substituents in case of the above protecting groups "which may have a substituent(s)" include a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group. Examples Next, Examples will further illustrate the present invention in detail. The following Examples only explain the present invention and do not particularly limit the invention. TMS was used as an internal reference material in ‘ H and ‘ ‘ C NMR, and measurement was conducted with AVANCE 400mHz NMR of Bruker BioSpin GmbH. As DMSO-de, the product (containing 0.03% TMS) of Eurisotop CEA Group was used. As an HPLC apparatus, LClO series (Pump: LC-IOAT, Controller' SCL-IGA and Detector: SPD-lGAvp) of Shimadzu Corporation was used. As an autosampler, KMT-IGOX of Kyowaseimitsu Corporation ( was used (the injection volume is 10/il as long as it is not particularly described). As an column oven, U-620 of Sugai Chemical Industry Co.,LTD was used. As a chromato waveform processing, C-R7A of Shimadzu Corporation was used. As raw materials and reagents in the present Examples, commercial items thereof are used themselves without purification. Compositions of eluting solvents: Solution A 0.1% TEA aqueous solution Synthesis of methylester of N" -(2,6-dichlorobenzoyl)-4-aniino-L-phenylalanine 200mL of water and 91mL of acetone were mixed and 72.4g (344mmol) of 4-nitro-L-phenylalanine was added thereto and cooled down to 10°C or lower. 68niL of 6M sodium hydroxide aqueous solution was added dropwise to the solution so that the temperature thereof did not exceed 15°C. Keeping around pH 14, 73.58g (344mmol) of 2,6-dichlorobenzoyl chloride was slowly added dropwise thereto. In order to keep around pH 14, if needed, a sodium hydroxide aqueous solution was added dropwise. 2 hours later of completion of drop, 86mL of 6M hydrochloric acid was added with keeping the temperature of the reaction solution at 15°C or lower to precipitate white crystals. After maturing at 10°C or lower, the crystals were separated, dried under reduced pressure at 60°C to obtain 128.5gof N" -(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine. (Yield-' 97%) iH NMR (400MHz, DMSO-de): 9.12 (d, IH, J=8.42 Hz), 8.16 (d, 2H, J=8.78 Hz), 7.59 (d, J=8.77Hz), 7.42 (m, 3H), 3.29 (m), 3.07 (dd, IH, J=3.64 and 10.42 Hz). 13C NMR (lOOMHz, DMSO-de): 172.25, 163.74, 146.68, 146.18, 131.51, 131.37, 131.05, 128.37, 123.55, 53.17, 36.74. MS (FAB) : m/z 383.1 (M+H)+ HRMS (FAB) : m/z 383.0219 (M+H)+ Next, 117.3g(306mmol) ofN" -(2,6-dichlorobenzoyl) -4-nitro-L-phenylalanine was added to 592mL of methanol and dissolved. 31.6g of 95% concentrated sulfuric acid was added dropwise being careful of heating. After the drop, the reaction was conducted for 3 hours at the reaction temperature of 40°C. After confirming completion of the reaction with HPLC, the reaction solution was cooled down to 30°C or lower. 395mL of water cooled down to around 10°C in advance was added dropwise in 1 hour so that the temperature of the reaction solution did not exceed 30°C. After crystallizing out, the reaction solution was matured for 5 hours with keeping a crystallizing solution at 10°C or lower. The crystals were separated by filtration, and then dried under reduced pressure at 60 °C to obtain 117.8g of methylester of N " -(2,6-dichlorobenzoyl) -4-nitro-L-phenylalanine. (5deld 97%) iH NMR (400MHz, DMSO-de )•- 9.23 (d, IH, J=8.2 Hz), 8.18 (d, 2H, J=8.8 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.38-7.46 (m, 3H), 4.88 (ddd, IH, J=6.4, 8.2 and 11 Hz), 3.69 (s, 3H), 3.31 (dd, IH, J=6.4 and 14 Hz), 3.10 (dd, IH, J=ll and 14 Hz). 13C NMR (lOOMHz, DMSO-de): 171.27, 163.83, 146.74, 145.80, 136.15, 131.49, 131.05, 128.42, 123.58, 53.07, 52.40, 36.39. MS (FAB) : m/z 397.2 (M-HH)+ HRMS (FAB) : m/z 397.0345 (M+B.> Further, 115.94g (290mmol) of methylester of N ‘ ■(2,6-dichlorobenzoyD-4-nitro"L-phenylalanine and 28.37g (0.5mol% to substrate) of 3% platinum carbon powder (wet) were suspended to 825mL of methanol. Nitro groups in the suspended solution were reduced under hydrogen gas atmosphere at 30°C for 5 hours. After confirming completion of the reaction with HPLC, the platinum catalyst was filtered out and the concentration of the reaction solution was adjusted. 539mL of water was added dropwise thereto at the liquid temperature of around 30 °C, and crystallization by cooling was conducted at 10°C or lower. The crystals were filtered out and dried under reduced pressure at 60 °C to obtain 84.6 Ig of methylester of N ‘ -(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine. (yield 80%) iH NMR (400MHz, DMSO-de): 9.23 (d, IH, J=7.8 Hz), 7.38-7.47 (m, 3H), 6.90 (d, 2H, J=7.0 Hz), 6.47 (d, 2H, J=7.0 Hz), 4.57 (ddd, IH, J=5.8, 7.8 and 9.1 Hz), 3.62 (s, 3H), 2.90 (dd, IH, J=5.8 and 14 Hz), 2.79 (dd, IH, J=9.1 and 14 Hz). 13C NMR (lOOMHz, DMSO-de)'- 171.87, 163.88, 147.52, 136.43, 131.65, 131.34, 129.90, 128.34, 124,01, 114.14, 54.57, 52.07, 36.40. MS (FAB) : m/z 367.2 (M+H)+ HRMS (FAB) : m/z 367.0585 (M+H)+ Synthetic example of the compound of formula (7) H.N '2' r’ (7) H3COOC’’’N(CH3)2 Synthesis of methylester of 2-amino-5-(dimethylamino) benzoic acid / dihydrochloride 30.0g (l48mmol) of 5-chloro'-2-nitrobenzoic acid was dissolved by stirring in 78mL (744mmol) of 50% dimethylamine aqueous solution under cooHng in the ice bath. After the solution was put into a pressure-resistant container and sealed, the solution was stirred by heating in the oil bath for 23 hours at 60°C. The reaction solution was sufficiently cooled down and the inner pressure thereof was released. After confirming completion of the reaction by HPLC analysis, the reaction solution was put into another container (using 50mL of water), 49.6mL of concentrated hydrochloric acid, and then 200mL of water were added thereto. Yellow crystals were precipitated by addition of hydrochloric acid. The crystallizing solution was matured at 10°C overnight, separated by filtration and dried under reduced pressure to obtain 30.95g of 5-dimethylamino-2-nitrobenzoic acid, (yield 99%) iH NMR (400MHz, DMSO-de): 8.88 (bs, IH), 7,97 (d, IH, J=9.4 Hz, aryl coupling=1.76 Hz), 6.78 (d, IH, J=9.4 Hz, aryl coupling=2.84 and 1.92 Hz), 6,71 (s, IH, aryl coupling=2.88 and 1.60 Hz), 3.08 (s, 6H), 13C NMR (lOOMHz, DMSO-de): 168.58, 153.86, 133.94, 132.85, 127.03, 111.44, 109.69, 40.24. MS(ESI): m/z 211.17 (M+H)+, 209.27 (M-H)' Next, 40.0g (l90.30mmol) of 5-dimethylamino-2-nitrobenzoic acid was suspended in 160mL of methanol at 25’C. This suspension was under cooled down in the ice bath and 53.6mL of concentrated sulfuric acid was added thereto. After adding the concentrated sulfuric acid, the temperature of the solution rose up to about 30°C. The solution was directly soaked in the bath of 60°C and stirred by heating for 20 hours. The progress of the reaction was confirmed by HPLC, and after confirming disappearance of a raw material, 400mL of toluene was added thereto to dilute. Then, 200mL of water and an aqueous solution of sodium hydroxide (wherein 38.06g of sodium hydroxide was dissolved in 200mL of water) were added thereto. The aqueous layer was extracted with 200mL of toluene and a toluene solvent(s) was mixed together. The toluene layer was washed with 300mL of saturated sodium bicarbonate water. The toluene layer was further concentrated under reduced pressure (bath temperature; 50°C) and adjusted so that the objective substance becomes about 20wt%. After distilling under reduced pressure, crystals of the objective substance precipitated. After maturing them at room temperature for about one hour, 220mL of n-heptane was added and further stirred at 5°C overnight. The crystals were separated by suction filtration and washed with lOOmL of n-heptane. These wet crystals were dried under reduced pressure for 3 hours at 65°C to obtain 34.82g of methylseter of 5-dimethylamino ■2-nitrobenzoic acid as yellow crystaUized powder, (yield 82%) iH NMR (400MHz, DMSO-de): 8.02 (d, IH, J=9,4 Hz), 6.82 (d, IH, J=9.36 Hz, aryl coupHng=2.56 Hz), 6.78 (s, IH, aryl coupling=2.4 Hz), 3.83 (s, 3H), 3.10 (s, 6H). 13C NMR (lOOMHz, DMSO-de)-' 167.70, 153.92, 132.71, 132.34, 127.24, 111.87, 110.07, 53.21, 40.28. MS (FAB): m/z 224.24 (M> HR MS (FAB): m/z 224.0830 (M)+ Further, 10.06g (44.9mmol) of methylester of 5-dimethylamino-2-nitrobenzoic acid was added to 50mL of methanol and suspended. 9.0mL of lOM hydrochloric acid and 1.96g (wet, lmol% to substrate) of 5% palladium carbon were added thereto. The reaction container was substituted with hydrogen gas and stirred at room temperature overnight. A palladium catalyst was filtered out with Cehte and the filtrate was concentrated under reduced pressure by about a half amount thereof. Then, 80mL of acetone was added to the solution and concentrated under reduced pressure three times to precipitate the compound of the formula (12). The compound was further matured at 10°C or lower and dried under reduced pressure to 11.16g of methylester of 2-amino-5-(dimethylamino) benzoic acid / dihydrochloride. (yield 93%) iH NMR (400MHz, DMSO-de): 8.09 (s, IH), 7.72 (d, IH, J=9.0 Hz), 6.96 (d, IH, 9.08 Hz), 5.50 (bs), 3.83 (s, 3H), 3.04 (s, 6H). 13C NMR (lOOMHz, DMSO-de): 167.12, 131.64, 126.66, 123.29, 118.7, 108.88, 52.18,45.84. MS (FAB): m/z 195.3 (M+H)+ HR MS (FAB): m/z 195.1122 (M+H)+ Synthesis of methylester of 2-(3-{4-[2-(2,6-diclilorobenzoylamino) - 2 -methoxycarbonylethyllphenyllureide) ■ 5 ■ dimethylaminobenzoic acid Method i: In case of using l,l'-carbonyldiimidazole (GDI) as a carbonyl group-introducing reagent 9.73g (59.41mmol) of l,r"carbonyldiiinidazole was added to 310mL of acetonitrile and dissolved. The solution was cooled down to 10°C or lower and 20.78g (56.58mmol) of methylester of N ‘ ■(2,6-dichlorobenzoyl)"4-amino-L-phenylalanine of the formula (6) was added thereto and stirred. 2 hours later, 15.06g (54.50mmol) of methylester of 2-amino-5-(dimethylamino) benzoic acid / dihydrochloride of the formula (7) was added, heated up to 50°C and stirred for 2 hours. After completion of the reaction, 62mL of methanol was added to the reaction solution, and the solution was cooled down to 10°C or lower. After maturing 10 hours or more, the crystals were separated by filtration and dried under reduced pressure to obtain 30.03g of objective methylester of 2-(3-{4-[2-(2,6"dichlorobenzoylaniino)-2-niethoxycarbonylethyl]phenyl}ureide)-5"di methylaminobenzoic acid of formula (8). (yield 88%) iH NMR (400 MHz, DMSO-d6):5 9.56 (s, IH), 9.46 (s, IH), 9.22 (d, IH, J=8.0 Hz), 8.07 (d, IH, J:=9.24 Hz), 7.47-7.38 (m, 5H), 7.19 (m, 3H), 7.06 (m, IH), 4.69 (m, IH), 3.88 (s, 3H), 3.66 (s, 3H), 3.06 (dd, IH, J=14.1 and 5.3 Hz), 2.93-2.88 (m, IH), 2.88(s, 6H) i3CNMR(l00MHz, DMSO-d6):5 171.72, 168.20, 163.88, 152.87, 145.63, 138.89, 136.38, 131.80, 131.64, 131.37, 130.46, 129.78, 128.36, 122.83, 119.31, 118.54, 117.18, 112.99, 54.09, 52.59, 52.18, 40.80, 36.34. MS (FAB): m/z 586.3 (M)+ HR MS (FAB): 586.1407 (M)+ Method 2: In case of using phenyl chloroformate as a carbonyl group-introducing reagent 2.08g (5.45mmol) of methylester of N "" -(2,6-dichlorobenzoyl) ■4-amino-L-phenylalanine of the formula (6) was added to 30mL of acetonitrile and stirred at room temperature and dissolved. After under coohng in the ice bath, 0.83mL of triethylamiae and 0.72mL (5.72mmol) of phenyl chloroformate were added thereto. After warming the reaction solution to room temperature and stirring for 1.5 hours, 1.46g(5.45mmol) of methylester of 2-amino-5"dimethylamino benzoic acid / dihydrochloride and 1.5 ImL of triethylamine were added thereto and stirred at room temperature for 3 days. Precipitated crystals were filtered out, washed with methanol and dried under reduced pressure to obtain 2.55g of a crystalline sohd substance containing objective methylester of 2-(3-{4-[2-(2,6-dichlorobenzoylamino)"2-methoxycarbonylethyl]phenyl}ureide)-5-di methylaminobenzoic acid of formula (8). (content 61.3wt%, yield 49%) Meanwhile, analytical data of the compound conformed to those of the above mentioned Method 1. Methods: In case of using N,N'"disuccinimidyl carbonate (DSC) as a carbonyl group-introducing reagent 1.32g (3.60mmol) of methylester of N "‘ -(2,6-dichlorobenzoyl) -4-amino-L-phenylalanine of the formula (6) was added to 15mL of acetonitrile and stirred at room temperature and dissolved. l.Og (3.90mmol) of N,N'-disuccinimidyl carbonate (DSC) was added to the solution and stirred at room temperature. 0.98g (3.68mmol) of methylester of 2-amino-5-dimethylamino benzoic acid / dihydrochloride and 1.92g of N,N"diisopropyl-N-ethylamine (DIPEA) were added to the reaction solution and stirred at 50°C for 2.5 hours. The objective substance precipitated as a soUd material as the reaction proceeded, and the suspension was cooled down to 10°C or lower. The crystals were filtered out, washed with methanol and dried under reduced pressure to obtain 1.16g of objective methylester of 2"(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxy carbonylethyl]phenyl}ureide)-5"dimethylaminobenzoic acid of formula (8). (sdeld 55%) Meanwhile, analytical data of the compound conformed to those of the above mentioned Method 1. Synthetic example of the compound of formula (9) Z'2 CI O N' 'COOCH H 3 N(CH,) (9) Synthesis of methylester of N*’ -(2,6-dichlorobenzoyl)-4"(6-dimethylamino -2,4[lH,3H]-quinazoluiedione-3"yl)-L-phenylalanine 40.0g (68.14mmol) of methylester of 2-(3-{4-[2-(2,6"dichlorobenzoyl ainino)-2-methoxycarbonylethyl]phenyl}ureide)-5-dimethylaminobenzoic acid of the formula (8) was added to 200inL of N,N-dimethylformainide and stirred and dissolved at 25°C. 5.4mL of 28% sodium methoxide/methanol solution was added thereto and stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was added dropwise to 210mL of an aqueous solution of hydrochloric acid to precipitate the compound of formula (14). The compound was separated and dried under reduced pressure to obtain 36.74g of the title compound, (yield 97.2%) iH NMR (400 MHz, DMSO-d6):5 11.20 (bs, IH), 9.29 (d, IH, J=8.12 Hz), 7.47-7.38 (m, 5H), 7.29-7.26 (m, IH), 7.18 (d, 2H, J=8.3 Hz), 7.12 (m, 2H), 4.81 (m, IH), 3.69 (s, 3H), 3.22 (dd, IH, J=14.1 and 4.8 Hz), 3.02 (dd, IH, J=14.0 and 3.8 Hz), 2.91 (s, 6H). 13C NMR (100 MHz, DMSO-d6):5 171.70, 163.99, 162.75, 150.18, 146.80, 137.15, 136.34, 134.80, 131.78, 131.36, 131.15, 129.84, 129.18, 128.32, 122.05, 116.48, 115.03, 108.50, 53.70, 52.29, 40.93, 36.36. MS (FAB): m/z 555.2 (M-HH)+ HR MS (FAB): m/z 555.1172 (M+H)+ Synthetic example of the compound of formula (lO) N COOCH., N(CH3)2 (10) (Method l) Synthesis of methylester of N°-(2,6-dichlorobenzoyl) ■4-(l-methyl-6-dimethylamino-2,4[lH,3H]-quinazohnedione-3-yl)-L-phenylalanine e by N-methylation of the formula (9) [A production method in case of isolating the compound of the formula (9)] 30.Og (54.0mmol) of methylester of N’ ■(2,6-dichlorobenzoyl)-4-(6-dimethylamino-2,4[lH,3H]-quinazolinedione-3yl)-L-phenylalanine of the formula (9) was added to a solution containing 180mL of N,N-dimethylformamide (DMF) and 20mL of methanol and stirred and dissolved at 25 °C. A DMF solution (20mL as DMF) containing 15.3g (Sl.lmmol) of methyl of p-toluenesulfonic acid and 15.0g (lOS.lmmol) of potassium carbonate were added thereto. After addition thereof, the reaction solution was stirred at the reaction temperature of 40°C for 6 hours. Then, the solution was added dropwise being careful of exothermic heating to an aqueous solution of hydrochloric acid (l.SmL of 6M hydrochloric acid and 250mL of water) which was cooled down in advance at 10°C or lower. The precipitated substance was filtered out and dried at 60°C under reduced pressure to obtain 25.3g of the title compound of the formula (lO). (yield 82%) (Method 2) Synthesis of methylester of N’ -(2,6-dichlorobenzoyl)-4- (l-methyl-6-dimethylamino-2,4[lH,3H]-quinazolinedione-3"yl)-L-phenylalanine [A production method in case of not isolating the compound of the formula (9)] 20g (34.07mmol) of methylester of 2-(3-{4-[2-(2,6"dichlorobenzoylamino) ■2-methoxycarbonylethyl]phenyl}ureide)-5-dimethylaminobenzoic acid of the formula (8) was stirred and dissolved in llOmL of N,N-dimethylformamide (DMF) at 20°C. llmL of methanol and 0,94g (6.81mmol) of potassium carbonate were added thereto and stirred at 25'C for 1 hour. After confirming completion of the quinazolinedione ring formation reaction with HPLC, without isolating the compound of the formula (9), a DMF solution (l4mL of DMF) containing 7.74mL (Llmmol) of methyl of p-toluenesulfonic acid and 8.46g (61.33mmol) of potassium carbonate were added to the reaction solution. N-methylation reaction was conducted to the solution at 40°C. After completion of the reaction, the reaction solution was added to water to precipitate the title compound of the formula (lO) as a solid substance. Tlie precipitated substance was filtered out and dried under reduced pressure to obtain 16.7 Ig thereof, (yield 86.2%) iH NMR (400 MHz, DMSO-d6):5 9.29 (d, IH, J=8.12 Hz), 7.47-7.36 (m, 6H), 7.32-7.29 (m, IH), 7.24 (d, IH, J=2.84 Hz), 7.18 (d, 2H, J=8.28 Hz), 4.82 (m, IH), 3.69 (s, 3H), 3.49 (s, 3H), 3.23 (dd, IH, J=14.1 and 4.6 Hz), 3.02 (dd, IH, J=13.9 and 3.5 Hz), 2.94 (s, 6H). 13C NMR (100 MHz, DMSO-d6):5 171.73, 163.99, 161.88, 150.37, 146.73, 137.20, 136.34, 135.34, 132.06, 131.78, 131.36, 129.89, 128.99, 128.32, 121.34, 116.21, 116.00, 109.15, 53.65, 52.29, 40.75, 36.35, 30.88. MS (ESI): m/z 569.33 (M-fH)+ Anal. Calcd for C28H26N4O5CI2 : C, 59.06; H, 4.60; N, 9.84; CI, 12.45. Found: C, 59.08; H, 4.64; N, 9.82; CI, 12.43. 1. A method for producing a phenylalanine derivative(s) having a quinazolinedione ring of the following formula (5), comprising steps of reacting an acyl phenylalanine derivative(s) of formula (l): wherein Rl represents a phenyl group which may have a substituent(s) or a pyridyl group which may have a substituent(s), R2 represents an alkyl group which may have a substituent(s), and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s), with a carbonyl group-introducing reagent(s) and an anthranilic acid derivative (s) of formula (2): wherein R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alk5niyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group; R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s); and R5 represents an alkyl group or an alkylcarbonyl group, and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s). to form an asymmetric urea intermediate(s) of formula (3): wherein Rl to R5 are dej5ned above; making the asymmetric urea intermediate(s) into a quinazolinedione compound(s) of formula (4) in the presence of a base(s): wherein Rl to R4 are defined above; and when R4 represents a hydrogen atom in the obtained quinazolinedione compound(s) of the formula (4), N-alkylating a quinazolinedione ring amide of the quinazolinedione compound(s) with an N-alkylation agent(s) to form the phenylalanine derivative(s) having a quinazolinedione skeleton of formula (5)^ wherein Rl to R3 are defined above, R4 represents an alkyl group or a benzyl group which may have a substituent(s). 2. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an alkynyl group. 3. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group or a nitro group. 4. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group. 5. The production method according to any one of claims 1 to 4, wherein the carbonyl group-introducing reagent is l,l'-carbonyldiimidazole or chloroformate. 6. The production method according to any one of claims 1 to 5, wherein the base(s) represents a potassium carbonate or a sodium methoxide. 7. The production method according to any one of claims 1 to 6, wherein the N-alkylation agent is methyl p-toluenesulfonate. 8. The production method according to claim 1, comprising steps of reacting a carbonyl group-introducing reagent selected from the group consisting of l,l'-carbonyldiimida2ole and chloroformate and the compound of the formula (2) wherein R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group with the compound of the formula (l) wherein Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to obtain methylester of 2-(3-{4-[2-(2,6"dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl methylaminobenzoic acid; converting it in the presence of potassium carbonate or sodium methoxide into methylester of N^-(2,6-dichlorobenzoyl)-4"(6-dimethylamino-2,4[lH,3H]-quina2olinedione-3"yl)-L -phenylalanine of the formula (4); and then N-alkylating it with methyl p-toluenesulfonate" to obtain methylester of N°-(2,6-dichlorobenzoyl)-4-(l-methyl-6"dimethylamino-2,4[lH,3H]-quinazolinedione ne-3-yl)-L-phenylalanine. 9. The production method according to claim 1 comprising steps of reacting a carbonyl group-introducing reagent selected from the group consisting of l,r'carbonyldiimidazole and chloroformate and the compound of the formula (2) wherein R3 represents a dimethylamino group, R4 represents a methyl group and R5 represents a methyl group with the compound of the formula (l) wherein Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to obtain the compound of the formula (3); converting it in the presence of potassium carbonate or sodium methoxide into methylester of N^ ■(2,6-dichlorobenzoyl) "4-(l-methyl-6-dimethylamino-2,4[lH,3H]-quinazolinedione-3-yl)-L-phenylalanine 10. Methylester of N°-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine according to claim 1, wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group, and salts thereof with chemically acceptable acids. 11. Methylester of 5-dimethylamino-2-aminobenzoic acid according to claim 1, wherein, in the formula (2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids. 12. Methylester of 2-(3"{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonyl ethyl]phenyl}reside)"5-dimethylaminobenzoic acid according to claim 1, wherein, in the formula (3), Rl represents a 2,6-dichlorophenyl group, R2 represents a methyl group, R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group.

Full Text

SPECIFICATION
Methods for producing phenylalanine derivatives having a quinazolinedione
Skeleton and intermediates for production thereof
Background of the Invention
The present invention relates to methods for producing phenylalanine derivatives having a quinazohnedione skeleton, which are compounds highly useful as drugs having 4 integrin inhibiting activity, and intermediates thereof.
Recently, research on inflammatory diseases in which Of 4 integrin-depending adhesion process participates in the pathology such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Jorgen’s syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplantation rejection has been advanced, and application to treating or preventing agents of the compounds having a 4 integrin inhibiting activity has been expected.
The applicant has already invented new phenylalanine derivatives having a 4 integrin inhibiting activity, which are highly useful as treating or preventing agents for inflammatory diseases in which a 4 integrin-depending adhesion process participates in the pathology and filed a patent appKcations (WO2002-16329).
Conventionally, as the method for producing the phenylalanine derivatives having a quinazolinedione skeleton, it has been reported such as that a quinazolinedione skeleton is constructed via amide intermediates by supporting phenylalanine derivatives on a solid-phase resin (WO2002-16329 and Synlett, 3, 333-336, 2001).

However, though the solid-phase synthesis method has excellent advantages as synthesis of a wide range of derivatives, generally it is not a method suitable for industriahzation because the amount of derivatives which can be supported on a sohd-phase resin has limitations and, as a result, the amount of the object substance which can be prepared at one time is extremely small. Further, in the soKd-phase synthesis, a reaction reagent(s) is generally excessively used, and this is inappropriate from the point of industriahzation.
In addition, by substituting the solid-phase synthesis method with a Hquid-phase method based on the sohd-phase synthesis method, for example, in accordance with well-known examples of reports (S.M.Gadekar, et al., J. Am. Chem. Soc. 4666-4667, 1964, and L.GouiUex, et al., Tetrahedron lett, 37(39), 7031, 1996), a quinazohnedione skeleton can be constructed by a synthesizing method comprising steps of reacting amine with carboxylic acid of anthracitic acid to form an amide, and reacting an amino group of anthranihc acid with ethyl chloroform ate, l,l'-carbonyldiimidazole or the Kke to make it in carbamate or carbonyHmidazolyl form and then forming a quinazolinedione ring with a base(s). However, when the compound is synthesized, it has problems in that the number of reaction processes are large and therefore the jelled is low.
On the other hand, as the method via urea intermediates, it has been known such as that amine is reacted with isocyanate to form an urea and a quinazohnedione ring is formed with a base (for example, WO2002-16329 and B.Taub, J. Org. Chem., 26, 5238-5239, 1961).
However, isocyanate is typically a Hquid with a pungent odor and highly toxic, and it is known that isocyanate sometimes induces self-polymerization to produce isocyanurate or reacts with water in the air to disintegrate. Thus, isocyanate is typically low in chemical stability and has toxicity.
From these mentioned above, it is needed to find methods for producing phenylalanine derivatives having a quinazohnedione skeleton suitable for

industrialization,
Disclosure of the Invention
The object of the present invention is to provide industrially apical methods for producing phenylalanine derivatives having a quinazohnedione skeleton, which are compounds highly useful as drug products having Oi 4 integrin inhibiting activity
The present invention also intends to provide intermediates for production of the phenylalanine derivatives having a quinazohnedione skeleton.
The inventors studied the above problems to be solved and they found industrially apical production methods in which phenylalanine derivatives having a quinazohnedione skeleton are conducted in high yield by a synthesizing method using a carbonyl group-introducing reagent(s) via urea intermediates, which is concise operation in mild reaction temperature without compacted solvent extraction and concentration. The present invention has been completed on the basis of this finding.
[l] Namely, the present invention provides methods for producing phenylalanine derivatives having a quinazohnedione ring of following formula (5), comprising steps of: reacting an acyl phenylalanine derivative(s) of formula (l)'

R1 N C00R2
H
wherein Rl represents a phenyl group which may have a substituent(s) or a pyridyl group which may have a substituent(s), R2 represents an alkyl group which may have a substituent(s), and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s),

with a carbonyl group-introducing reagent(s) and an anthracic acid derivative(s) of formula (2):

wherein R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group; R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s); and R5 represents an alkyl group or an alkylcarbonyl group, and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s), to form an asymmetric urea intermediate(s) of formula (3):

wherein Rl to R5 are defined above;
making the asymmetric urea intermediate(s) into a quinazolinedione
compound(s) of formula (4) in the presence of a base(s):

wherein Rl to R4 are defined above; and
when R4 represents a hydrogen atom in the obtained quinazolinedione compound(s) of the formula (4), N-alkylating a quinazolinedione ring amide of the quinazolinedione compound(s) with an N-alkylation agent(s) to form the phenylalanine derivative(s) having a quinazolinedione skeleton of formula (5)'

wherein Rl to R3 are defined above, R4 represents an alkyl group or a benzyl group which may have a substituent(s).
The present invention also provides the following compounds of (l) to (5), which are intermediates for production of the phenylalanine derivative(s) having a quinazolinedione ring of formula (5).
(1) Methylester of N"-(2,6'dichlorobenzoyl)-4-amino-L-phenylalanine wherein,
in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a
methyl group, and salts thereof with chemically acceptable acids.
(2) Methylester of 5-dimethylamino-2-aminobenzoic acid wherein, in the formula
(2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and
R5 represents a methyl group, and salts thereof with chemically acceptable acids.
(3) Methylester of 2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonyl
ethyl]phenyl}ureide)-5-dimethylaminobenzoic acid wherein, in the formula (3),

Rl represents a 2,6-dichlorophenyl group, R2 represents a methyl group, R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids.
(4) The compound wherein, in the formula (2), R3 represents a dialkylamuio group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids.
(5) The compound wherein, in the formula (3), Rl represents a 2,6-dichlorophenyl group, R2 represents a methyl group, R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alchemy group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids.
Best Mode for Carrying out the Invention
The following embodiments are preferable in the present invention. [2] The production method according to above [l], wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an alkynyl group. [3] The production method according to above [l], wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group or a nitro group. [4] The production method according to above [l], wherein, in the formulae (2) to

(5), R3 represents a dialkylamino group.
[5] The production method according to any one of above [l] to [4], wherein the
carbonyl group-introducing reagent(s) is l,l'-carbonyldiimidazole or
chloroform ate.
[6] The production method according to any one of above [l] to [5], wherein the
base is potassium carbonate or sodium methoxide.
[7] The production method according to any one of above [l] to [6], wherein the
N-alkylation agent is methyl p-toluenesulfonate.
[8] The production method according to above [l], comprising steps of reacting a
carbonyl group-introducing reagent selected from the group consisting of
l,r-carbonyldiimidazole and chloroformate and the compound of the formula (2)
wherein R3 represents a dimethylamino group, R4 represents a hydrogen atom
and R5 represents a methyl group with the compound of the formula (l) wherein
Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to
obtain methylester of
2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl}ureide)-5-di
methylaminobenzoic acid; converting it in the presence of potassium carbonate or
sodium methoxide into methylester of
N°'-(2,6-dichlorobenzoyl)-4-(6-dimethylamino-2,4[lH,3Hl-quinazolinedione-3-yl)-L
-phenylalanine of the formula (4); and then N-alkylating the resultant with
methyl p-toluenesulfonate to obtain methylester of
N«"(2,6-dichlorobenzoyl)"4-(l-methyl-6-dimethylamino'2,4[lH,3H]-quinazolinedione
ne-3-yl)-L-phenylalanine.
[9] The production method according to above [ll, comprising steps of reacting a
carbonyl group-introducing reagent selected from the group consisting of
l,l'carbonyldiimidazole and chloroformate and the compound of the formula (2)
wherein R3 represents a dimethylamino group, R4 represents a methyl group
and R5 represents a methyl group with the compound of the formula (l) wherein

Rl represents a 2,6-diclilorophenyl group and R2 represents a methyl group to
obtain the compound of the formula (3); converting it in the presence of
potassium carbonate or sodium methoxide into methylester of
N° ■(2,6"dichloro-benzoyD "4-(l-methyl-6-dimethylamino"2,4[lH,3H]-quinazolinedione-3-yl)"L'Phenylalanin
e.
Next, the compounds in the present invention are described as follows.
Rl represents a phenyl group which may have a substituent(s) or a pyridyl
group which may have a substituent(s). In this connection, examples of the
substituents are a halogen atom, an alkyl group, a halogenoalkyl group including
a perfluoroalkyl group, an alkoxy group, a halogenoalkoxy group including a
perfluoroalkoxy group, an alkylthio group, a nitro group, an alkylsulfonylamino
group and a tetrazolyl group. Here, an alkyl group as a component preferably
has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms, and they
may be same or different from each other. Rl is preferably a phenyl group
substituted with a halogen atom and/or an alkyl group, and, for example, they
are preferably 2,6-dichlorophenyl group, 2,6" dimethylphenyl group,
2-chloro-6-methylphenyl group, 2-chlorophenyl group, 2-methylphenyl group,
2,4,6-trichlorophenyl group, 2,4,6-trimethylphenyl group and
2,6-dichloro-4-methylphenyl group.
R2 is an alkyl group which may have a substituent(s). In this connection, an alkyl group preferably has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms.
When R2 has a substituent(s), such substituent(s) include a substituted or unsubstituted lower alkylcarbonyl group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted amino group, a lower alkoxy group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group and a substituted or unsubstituted

carbamoyl group.
Here, when the substituent(s) of R2 is a lower alkylcarbonyloxy group, a lower alkoxycarbonyloxy group or a lower alkoxy group, alkyl and alkoxy thereof preferably have 1 to 6 carbon atoms, and include chain, cithc, linear and branched ones.
Further, when the substituent(s) of R2 is an aryl group, it represents a mono-or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. For example, it includes a phenyl group and a naphthyl group. When the substituent(s) of R2 is a heteroaryl group, it represents a 5 to 8 membered mono-, hi" or tricycUc aromatic heterocyclic group including 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as a cyclic atom. For example, they include a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, an isoxazolyl group, an oxazolyl group, an isothiazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a tetrazolyl group, an indolyl group, a benzimidazolyl group, a quinolyl group and an isoquinolyl group. Here, a substituent(s) of the aryl group and the hetero aryl group is, for example, a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group. Among these, a pyridyl group, a furyl group and a thienyl group are preferred.
Meanwhile, when the substituent(s) of R2 is a lower alkylcarbonyloxy group or a lower alkoxycarbonyloxy group, the substituent(s) thereof include a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a hydroxy group, an amino group and an amino group substituted with a lower alkyl group including monosubstitution or trisubstitution thereof, A methyl group and an ethyl group are preferred among these.
When the substituent(s) of R2 is an amino group, the substituent(s) thereof include a lower alkyl group, a lower alkoxycarbonyl group and a lower

alkylsulfornyl group. Among these, a methyl group and an ethyl group are preferable. Here, two substituents may bond together to form a ring and, when forming a ring, they may also sandwich an oxygen, nitrogen or sulfur atom between them. For example, a substituted amino group includes a cyclic amino group such as 1-piperidinyl group and 4-morphonyl group, a cyclic amide group such as 2-oxo-l-pyrroUdinyl group and a cyclic urea group such as 2-oxoimidazoline-l-yl group and 2-oxoimidazolidine-l-yl group.
Further, when the substituent(s) of R2 is an aryl group or a heteroaryl group, the substituent(s) thereof include a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group.
When the substituent(s) of R2 is a carbamoyl group, the substituent(s) thereof include a lower alkyl group and a phenyl group, and mono- and di-substitutions thereof are also included.
When R2 has a substituent(s), the substituent(s) thereof is preferably a lower alkylcarbonyloxy group, a chlorine atom, a pyridyl group, a furyl group, a thienyl group and a lower dialkylcarbamoyl group.
In the formula (l), an amino group is preferably in the para position among ortho, meta and para positions on a benzene ring.
R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group, and R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s). While R5 may be whatever 0R5 is removed from C00R5 by a base, an alkyl group and an alkylcarbonyl group are preferable. In R3 to R5, an

alkyl group as a component preferably has 1 to 6 carbon atoms and particularly preferably 1 to 3 carbon atoms.
R3 are preferably a dialkylamino group, a hydrogen atom, a halogen atom, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group. Particularly preferred ones are a dialkylamino group, a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group and an alkylthio group.
A dialkylamino group represents an amino group disubstituted with an alkyl group having 1 to 6 carbon atoms, including a cithc one. Preferably it is an amino group disubstituted with an alkyl group having 1 to 3 carbon atoms or a cyclic amino group having 2 to 6 carbon atoms. For example, it includes a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group, a piperidyl group, a di propylamino group, a methylpropylamino group and an ethylpropylamino group.
A monoalkylamino group represents an amino group monosubstituted with an alkyl group having 1 to 6 carbon atoms, including alkylamino group with a cyclic alkyl group (s). Preferably it is an amino group monosubstituted with an alkyl group having 1 to 4 carbon atoms such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group and a cyclopropylmethylamino group.
An alkyl group substituted with a dialkylamino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with the same substituent(s) as those of the dialkylamino group. Preferably it is an alkyl group having 1 to 3 carbon atoms, which is substituted with the same substituent(s) as those of the dialkylamino group. For example, it includes either of a methyl group, an ethyl

group or a propyl group substituted with a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group, a piperidyl group, a dipropylamino group, a methylpropylamino group or an ethylpropylamino group. Particularly preferable ones are a dimethyl aminomethyl group, a Dimethylaminoethyl group, a methylethylaminomethyl group and the like.
An alkyl group substituted with a monoalkylamino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with the same substituent(s) as those of the monoalkylamino group. Preferably it is an alkyl group having 1 to 3 carbon atoms, which is substituted with the same substituent(s) as those of the monoalkylamino group. For example, it includes either of a methyl group, an ethyl group or a propyl group substituted with a methylamino group, an ethylamino group, a propylamino group, isopropylamino group, a butylamino group or a cyclopropylmethylamino group. Particularly preferable ones are a methylaminomethyl group, an methylamJnomethyl group, a methylamJnomethyl group, an methylamJnomethyl group and the hake.
An alkyl group substituted with an amino group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an amino group, and preferably an alkyl group having 1 to 3 carbon atoms, which is substituted with an amino group. For example, it includes an aminomethyl group, an aminomethyl group, an iminopropyl group and the like.
An alkyl group substituted with an alkenyl group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an alkenyl group having 2 to 6 carbon atoms, and preferably an alkyl group having 1 to 3 carbon atoms, which is substituted with an alkenyl group having 2 to 4 carbon atoms. For example, it includes -CH2CH=CH2, -CH2CH2CH=CH2 and the like.
An alkyl group substituted with an alkynyl group is an alkyl group having 1 to 6 carbon atoms, which is substituted with an alkynyl group having 2 to 6 carbon atoms, and preferably an alkyl group having 1 to 3 carbon atoms, which is

substituted with an alkynyl group having 2 to 4 carbon atoms. For example, it includes -CH2CECH, -CH2CH2C = CH and the Hke.
An alkoxycarbonyl group represents an alkoxycarbonyl group having 2 to 7 carbon atoms and preferably having 2 to 4 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group and a propyloxycarbonyl group.
An alkylthio group represents a thio group substituted with an alkyl group having 1 to 6 carbon atoms and preferably a thio group substituted with an alkyl group having 1 to 3 carbon atoms, such as a methylthio group, an ethylthio group and a propylthio group.
An arylthio group represents a phenylthio group and a naphthylthio group. Particularly, R3 is preferably a a dimethylamino group, a diethylamino group, a methylethylamino group, a l group, a piperidyl group, a methylamino group, an ethylamino group, a propylamine group, a cyclopropylmethylamino group, a dimethylaminomethyl group, a diethylaminomethyl group, a dimethylaminoethyl group, a diethylaminoethyl group, a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, a methylaminoethyl group, an ethylaminoethyl group, a propylaminoethyl group, HC = CCH2 group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylthio group or an ethylthio group.
R4 is preferably a hydrogen atom or an alkyl group. In the formula (2), (S) and (4), a hydrogen atom is further preferable and, in the formula (5), an alkyl group is further preferable. While a substituent(s) of a benzyl group includes an alkyl group, an aikoxy group, a halogen atom and the hke, an unsubstituted benzyl group is preferable.
R5 is particularly preferably an alkyl group.
In the formula (2), it is preferable that R3 is in the para position to an amino group.

The synthetic intermediates of the formula (l) are synthesized as follows.
A phenylalanine having a nitro group on an aromatic ring and acid chloride are condensed under the conditions of the well-known method, Schotten-Baumann reaction (such as N. 0, V, Sonntag, Chem. Rev. 52, 272, 1953) to produce acylphenylalanine derivatives. Then, said carboxyhc acid is esterified using the well known method (such as R.C.Larock’ Comprehensive Organic Transformations (2nd Ed.), p.1932-1941, Wiley-VCH, New York) to synthesize alkylester of acylphenylalanine. The conventional method, catalytic reduction with a transition metal catalyst(s) (such as R. C. Larock ‘ Comprehensive Organic Transformations (2nd Ed.), p.821-828, Wiley-VCH, New York) is applied to the synthesized substance in the presence of hydrogen gas to obtain the corresponding compounds of the formula (l).
For example, as the method for producing methylester of N’ -(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine which is a new synthetic intermediate wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group, said compound can be synthesized by following processes' condensing a publicly-known and commercially available 4"nitro-L"phenylalanine and a similarly pubhcly-known and commercially available 2,6-dichlorobenzoylchloride; subjecting the resultant to methyl esterification ; and reduction of a nitro group.
Concretely, 4-nitro-L"phenylalanine and 2,6-dichlorobenzoylchloride are condensed in a mixed solvent of a sodium hydroxide aqueous solution and acetone with keeping the reaction temperature at 5 to 15 °C, and then crystallization is conducted to obtain a corresponding condensed substance, N° -(2,6-dichlorobenzoyl)-4-nitro-L"phenylalanine almost quantitatively.
Subsequently, the condensed substance is suspended into methanol, and methyl esterification is conducted by heating with adding concentrated sulfuric acid. Then, crystallization is conducted to obtain a corresponding methyl

esterified substance, methylester of N° -(2,6-dichloro
benzoyl)-4-nitro-L-phenylalanine almost quantitatively.
Then, catalytic reduction reaction is conducted to the methyl esterified substance using a transition metal catalyst(s) of a nitro group which is a well-known method (such as F. S. DoveU et al., J. Am. Chem. Soc, 87, 2767, 1965) and preferably using a platinum carbon catalyst poisoned with sulfur, and hydrogen gas. Thereafter, crystaUization is conducted to obtain methylester of N’-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine in high yield, wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group.
The yield in case of going through the three steps from 4-nitro"L-phenylalanine is about 90%.
Meanwhile, the above-mentioned synthesizing method is not a sole method for producing the compound of the formula (l) and does not hmit the method of the present invention. Similarly, the jield indicates an average value thereof and doe not limit the value.
On the other hand, as the method for producing the compound of the formula (2), said compound can be obtained by well-known methods from commercially available trisubstituted benzene derivatives.
For example, as the method for producing methylester of 5-dimethylamino-2-aminobenzoic acid which is a new synthetic intermediate wherein, in the formula (2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represent a methyl group, said compound can be synthesized by following processes: dimethyl amination, methyl esterification and reduction of a nitro group from a pubhcly-known and commercially available 5-chloro-2-nitrobenzoic acid.
Concretely, 5-chloro-2-nitrobenzoic acid is dissolved in a dimethylamine aqueous solution and heated to produce 5-dimethylamino’2-nitrobenzoic acid.

Hydrochloric acid is added to the reaction solution to precipitate out the product as a solid material. The sohd material is separated to obtain 5-dimethylamno-2-nitrobenzoic acid almost quantitatively.
Next, the 5-dimethylamno-2-nitrobenzoic acid is dissolved in concentrated sulfuric acid/methanol and heated to conduct methyl esterification in order to produce methylester of 5-dimethylamino -2-nitrobenzoic acid, which is a well"known method. Toluene and water are added to the reaction solution, and the obtained product is extracted to an organic layer, concentrated, and crystallized to obtain 5-dimethylamino-2-nitrobenzoic acid in high yield.
Next, catalytic reduction is conducted to a nitro group of methylester of 5-dimethylamino-2-nitrobenzoic acid under the acidic condition by hydrochloric acid, using transition metal catalysts such as palladium carbon and hydrogen gas in a methanol solvent. Crystallization is conducted to obtain methylester of 5-dimethylamino-2-aminobenzoic acid / dihydrochloride in high yield.
The yield via the three processes from 5-chloro-2-nitrobenzoic acid is about 80%,
Further, thus obtained methylester of 5-dimethylamino-2-amino benzoic acid of the formula (2) can be obtained stably as salts with acidic substances, e.g., hydrochloride.
However, the above-mentioned synthesizing method is not a sole method for producing the compound of the formula (2) and does not limit the production method of the present invention. Similarly, the jdeld indicates an average value thereof and does not Hmit the value.
The step 1 of the production method of the present invention is explained below.
The method for producing phenylalanine derivatives having a quinazohnedione ring of the formula (5) in the present invention is as follows. The compound of the formula (l) which is the important intermediate and the

compound of the formula (2) are converted into asymmetric urea intermediates by using a carbonyl group-introducing reagent(s), preferably l,l'-carbonyldiimidazole or chloroformate, and then the compound of the formula (3) is converted to the compound of the formula (4) under mild basic condition.
In case of the compound wherein R4 in the formula (4) represents a hydrogen atom, the compound can be prepared without isolating the compound of the formula (4), by successively conducting N-alkylation reaction with N-alkylation agents under basic condition. It may be also possible to isolate the compound of the formula (4) and then conduct N-alkylation reaction.
For example, an amino group of methylester of N ‘‘
-(2,6-dichlorobenzoyl)"4-amino-L-phenylalanine of the formula (l) is converted
into carbonylimidazolyl by l,l'-carbonyldiimidazole using an organic solvent(s)
having suitable solubility such as, particularly preferably, acetonitrile. Without
isolating the intermediates thereof, methylester of
5-dimethylamino-2-aminobenzoic acid of the formula (2) is put into the reaction
solvent to be able to obtain methylester of
2-(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl}ureide)-5-di methylaminobenzoic acid of the formula (S), which is asymmetric urea intermediates, in high yield.
In the present specification, "a carbonyl group-introducing reagent(s)" indicates those wherein only a carbonyl group in atomic groups of a quinazolinedione ring is derived from the present reagent. For instance, they include l,l'-carbonyldiimidazole (Organic syntheses collective volume V, R201-204, Wiley, New York, 1973, as a synthetic example thereof), chloroformate and the hke. These are publicly known and commercially available.
Further, it is also possible to use reagents wherein an imidazolyl group of l,l'-carbonyldiimidazole is substituted with other heteroaryl removing group(s), such as l,r-carbonyldi(l,2,4-triazole) (an imidazolyl group in this reagent is

substituted with a triazoyl group and the reagent is commercially available). The substituents thereof are not hmited to only an imidazolyl group and a triazoyl group. It is also possible to use other heteroaryl removing groups as the substituents.
It is further possible to use N,N'-disuccinimidyl carbonate (DSC) (N"hydroxysuccinimide in this reagent is a removing group and the reagent is commercially available).
Chloroformate includes reagents having 2 to 10 carbon atoms, such as phenyl chloroformate, nitrophenyl chloroformate, methoxjrphenyl chloroformate, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, octyl chloroformate and benzyl chloroformate, though they are not hmited to these examples.
Similarly, it is also possible to use phosgene and phosgene analogues such as triphosgene as the carbonyl group-introducing reagents. These are gas or Uquid and highly toxic (Reference: RTECS SY 5600000) as compared with the above reagents and therefore difficult to deal with. Further, since a particular kind of facilities is usually required and distribution thereof is limited, these reagents are not very favorable in the carbonyl group-introducing reagents.
l,l'-carbonyldiimida2ole is particularly preferred as a carbonyl group-introducing reagents. When l,r-carbonyldiimidazole is used, it is superior in that the amount of produced by-products is small and the objective asymmetric urea intermediates are obtained in high yield.
A carbonyl group-introducing reagents is preferably used in 0.8 to 1.2 mol equivalent weight to 1 mol of the compound of the formula (l).
The compound of the formula (2) is preferably used in 0.8 to 1.2 mol equivalent weight to 1 mol of the compound of the formula (l).
The solvents of the present reaction include organic solvents having suitable solubihty to the compounds of the formula (l) such as methylester of N"

-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine. For example, it is possible to use acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), halogenated carbon hydride such as methylene chloride, pyridine, pyrroHdone, N-methylpjn:rohdone, or mixed solvents thereof.
Above aU, when acetonitrile is used, products can be easily separated from the reaction solvent by filtration. Therefore, it is possible to isolate very pure asymmetric urea intermediates of the formula (3) by only a simple separation with filtration. Since it does not require any cumbersome operations such as extraction and concentration of solvents, it is useful as industriahzed process. Similarly, it is also possible to obtain crystals of the objective compound by the steps of the reaction with N,N-dimethylformamide (DMF); adding poor solvents such as alcohols having 1 to 10 carbon atoms or water to precipitate asymmetric urea intermediates as a sohd substance; and then separation by filtration thereof. As a result, acetonitrile and N,N-dimethylformamide are particularly preferable as the solvents of the present reaction.
The concentration of the above reaction is preferably that apphcable as industriahzed process. For example, when acetonitrile is used as a reaction solvent, the reaction should be conducted in 1 to 0.0IM and particularly preferably around 0.2M, from the point of flowabihty in stirring the reaction solution or crystallizing solution.
When the compound of the formula (l) is converted into carbonylimidazolyl by carbonyl group-introducing reagents such as l,r-carbonyldiimidazole, the reaction temperature thereof is preferably within the range of around 0°C to not above the boiling point of the reaction solvent. To conduct the reaction around 0°C to not above 10°C is more industrially preferable in that it is useful for inhibiting side reactions and improving the yield. The reaction time is preferable around 1 to 5 hours.
In the condensation reaction of the compound of the formula (l) converted

into carbonyhmidazolyl with methylester of 5-dimethylamino-2-aminobenzoic acid of the formula (2), the reaction temperature thereof is preferably within the range of around 0°C to not above the boihng point of the appHed solvent. Particularly, the reaction is more preferably conducted at the reaction temperature of around 50°C since urea bond formation reaction is completed in around 2 to 3 hours and the asymmetric urea intermediates of the formula (3) can be obtained in high yield.
However, the reaction temperature and time are not Umited to the above and the reaction time is determined by the balance with the reaction temperature. It is desirable from the industrial point of view that the reaction solution is controlled by analytical methods such as HPLC.
In the above reaction, input order of raw materials and reagents is not particularly hmited. However, the method wherein the compound of the formula (l) is first reacted with a carbonyl group-introducing reagent(s) to convert into carbonyhmidazolyl and then reacted with the compound of the formula (2) is more preferable from the point of the high yield and side reactions as compared with the method wherein the compound of the formula (2) is first converted into carbonylimidazolyl. While, in the production method of the present invention, the compound of the formula (2) may be first converted into carbonylimidazolyl, and the compound of the formula (l), a carbonyl group-introducing reagent(s) and the compound of the formula (2) may be reacted simultaneously.
Next, described herein is the step 2.
The asymmetric urea intermediates of the formula (3) form a quinazoLLnedione ring in the presence of a base in a sviitable reaction solvent to give the quinazoUnedione compounds of the formula (4).
The 'T’ase" herein includes an inorganic base and organic base. Inorganic bases include salts with alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and the hke;

and salts with alkahne earth metals such as calcium carbonate and magnesium carbonate. Organic bases include triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine, l,8-diazabicyclo[5.4.0]undec"7-ene (DBU) and N,N-diisopropyl-N-ethylamine (DIPEA). Inorganic bases are preferable and particularly potassium carbonate and sodium methoxide are preferable.
The base is preferably used in 0,1 to 2.0 mol equivalent weight to 1 mol of the compound of the formula (3), and it is more preferable that 1 mol equivalent weight or less of a catalyst is used. The reaction time is preferably 1 to 6 hours.
For example, when potassium carbonate is used as a base, 0.1 to 2 mol equivalent weight thereof is preferable and 0.2 to 0.4 mol equivalent weight is more preferable. When sodium methoxide is used as a base, 0.1 to 1.0 mol equivalent weight thereof is preferable and 0.2 to 0.4 mol equivalent weight is more preferable. 1 to 2 hours of the reaction time are enough at that time.
The solvents in the above reactions may be those in which the compound of the formula (3) is dissolved and the reaction proceeds smoothly. For example, they include dimethylformamide (DMF) and a mixed solvent with alcohols containing dimethylformamide as a main ingredient, though the solvents are not Hmited to these.
Meanwhile, when potassium carbonate is used as a base, it is preferable to use a mixed solvent of DMF and methanol from the point of shortening of the reaction time. As the relative proportions of the mixed solvent of DMF and methanol, around 10 to 1 is suitable, though the proportions are not hmited to this.
As the reaction concentration of the above reactions, it is preferable that the reaction is conducted in the concentration apphcable as industrialized process of within 0.01 to 2M and, for example, around 0.25M in case of the mixed solvent of DMF and methanol, though the concentration thereof is not Hmited to these.
As the reaction temperature, 0°C to not above the boiling point of the solvent,

and preferably around 25'C is suitable.
The quinazohnedione compounds of the formula (4) produced by the above reactions can be precipitated as solid substance by adding water or an aqueous solution of hydrochloric acid dropwise to the reaction solution, or by adding the reaction solution to water or an aqueous solution of hydrochloric acid, and then precipitated substance can be isolated by the typical separating methods.
When potassium carbonate is used as a base, the quinazohnedione ring formation reaction is conducted to the asymmetric urea intermediates of the formula (3) and then N-methylation reaction can be soon hnked after that without isolating the compound of the formula (4) and, therefore, one process in the reaction processes can be skipped. When taking account of improvement in production efficiency from the point of industriahzation, this method is particularly useful as industriahzed process since the isolating process of the compound of the formula (4) can be simplified.
Finally, described herein is the step 3,
In the formula (4), when R4 is a hydrogen atom, the compound can be derived into quinazohnedione compounds of the formula (5) with N- alkylation agents in the presence of a base.
Meanwhile, it is also possible to isolate the quinazohnedione compounds of the formula (4), which is produced in the step 2, and then N-alkylate. However, it is preferable from the point of industriahzation to N-alkylate without isolation.
In the present specification, "N-alkylation agents" indicate reagents which can introduce an alkyl group on a nitrogen atom, and haloalkane, alkyl sulfonate and benzyl hahde which may be substituted are included, for example.
Here, haloalkane and alkyl sulfonate are preferably those having 1 to 10 carbon atoms. Those having 1 to 6 carbon atoms are further preferable and those having 1 to 3 carton atoms are particularly preferable. Haloalkane includes, for example, methyl iodide and ethyl iodide, and alkyl sulfonate

includes, for example, methyl methanesulphonate, ethyl methanesulphonate, methyl ethanesulphonate, ethyl ethanesulphonate, methyl p-toluenesulphonate and ethyl p-toluenesulphonate. Benzyl halide includes benzylchloride, benzylbromide and the like, and the substituents thereof are an alkyl group, an alkoxy group, a halogen atom and the like.
For example, in the production of the compound wherein R4 in the formula (5) is a methyl group, methyl p-toluenesulphonate is suitable from the point of industrialization. Namely, methyl p-toluenesulphonate has the higher boiling point as compared with methyl iodide and is easy to deal with under room temperature. Further, methyl p-toluenesulphonate has the favorable flowabiUty of the reaction solution and is suitable for the industrialized process with solution sending.
As the usage amount of N-alkylation agents, the range of 1 to 10 mol eqxuvalent weight thereof and preferably around 1.2 to 2.0 mol equivalent weight is suitable to the compound of the formula (3) or (4). The amount of the reagents can be increased or decreased in accordance with progress of the reaction.
A base includes inorganic bases and organic bases. Here, examples of inorganic bases are salts with alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and the like; and salts with alkaline earth metals such as calcium carbonate and magnesium carbonate. Organic bases include triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-dusopropyl-N-ethylamine (DIPEA). Inorganic bases are preferable and particularly potassium carbonate is preferable.
The base is preferably used in 1.5 to 2 mol equivalent weight to the compound of the formula (3) or (4) and more preferably around 1.8 mol equivalent weight, while the amount is not limited to these and can be increased or decreased in accordance with progress of the reaction.

The reaction solvents may be those in which the compound of the formula (3) or (4) is dissolved and the reaction proceeds smoothly. For example, they include dimethylformamide (DMF) and a mixed solvent with alcohols containing dimethylformamide as a main ingredient, though the solvents are not limited to these. Meanwhile, when potassium carbonate is used as a base, it is preferable to use a mixed solvent of DMF and methanol from the point of shortening of the reaction time. As the relative proportions of the mixed solvent of DMF and methanol, around 10 to 1 is suitable, though the proportions are not Hmited to this. As the reaction concentration of the above reactions, it is preferable that the reaction is conducted in the concentration apphcable as industriahzed process of within 0.01 to 2M and, for example, around 0.25M in case of the mixed solvent of DMF and methanol, though the concentration thereof is not Hmited to these.
As the reaction temperature, 0°C to not above the boiling point of the reaction solvent, and preferably around 40°C is suitable, though the temperature thereof is not Hmited to these. The reaction time may be 3 to 18 hours, and it is desirable from the industrial point of view that the reaction solution is administered by analytical methods such as HPLC.
For example, an asymmetric urea intermediate wherein, in the formula (4),
Rl is 2,6-dihlorophenyl group, R2 is a methyl group and R3 is a dimethylamino
group is dissolved at 25 ‘C in a mixed solvent of DMF and methanol. The
quinazolinedione ring formation reaction is conducted by stirring for 2 hours
using 0.2 mol equivalent weight of potassium carbonate to the compound of the
formula (4). Then, 1.5 mol equivalent weight of methyl p-toluenesulphonate and
1.8 mol equivalent weight of potassium carbonate are added to conduct
N-methylation reaction. Two processes are gone through from the formula (4) to
be able to obtain methylester of N ‘‘
-(2,6-dichlorobenzoyl)-4-(l-methyl-6-dimethylamino-2,4 [lH,3H]-quinazolinedione-3-yl)-L-phenylalanine of the formula (5) in the yield of

80 to 90%.
The compound of the formula (5) can be precipitated as solid substance by adding water to the reaction solvent and isolated by the typical separating methods such as jSltration, though the method is not limited to this.
The above production methods describe the case using the compound wherein, in the formula (2), R4 is a hydrogen atom. As for the compounds wherein, in the formula (2), R4 is an alkyl group or a benzyl group which may have a substituent(s), as the reaction process with N-alkylation agents is not necessary, the compound of the formula (l) and the compound of the formula (2) are derived into asymmetric urea intermediates of the formula (3) by using a carbonyl group-introducing reagent(s) and preferably l,r-carbonyldiimidazole; the compound of the formula (3) is converted to the compound of the formula (4) under mild basic condition; and then the compound of the formula (4) is isolated to obtain the objective compound of the formula (5) (because the formula (4) and the formula (5) are identical in this case).
From the above production methods, herein provided is the industrially appHcable method for producing phenylalanine derivatives having a quinazolinedione ring of the formula (5) via the crucial intermediate (3) from crucial intermediates of the formulae (l) and (2).
Meanwhile, when R3 is a monoalkylamino group, an amino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an amino group, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be protected in advance by a proper protecting group(s) and then the protection thereof may be removed by suitable methods of removal of protection. The methods for protection and removal of protection are described in, for example, "Protecting group in organic synthesis" by Theodora W. Greene, Peter G. M. Wuts, Second edition, John Wiley & Sons Inc., New York, 1991, 309-385.

For example, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted, by using acylation agents in ordinary acylation methods, with an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a trifluoroacetyl group and the like; an arylcarbonyl group which may have a substituent(s) such as a benzoyl group; an arylalkylcarbonyl group which may have a substituent(s) such as a benzylcarbonyl group; an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a butoxycarbonyl group, a tertiarybutoxycarbonyl group, a trifluoromethoxy carbonyl group and the like; an aryloxycarbonyl group which may have a substituent(s) such as a phenoxycarbonyl group; and an arylalkyloxycarbonyl group which may have a substituent(s) such as a benzyloxycarbonyl group.
In this case, after completion of the reaction of the first, second or third step in the present invention, particularly after the completion of the N-alkylation reaction in the third step of the present invention, a protecting group(s) can be removed under the acidic condition or the basic condition and the hke in case of an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s), an arylcarbonyl group which may have a substituent(s) and an arylalkylcarbonyl group which may have a substituent(s); under the basic condition and the like in case of an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) and an aryloxycarbonyl group which may have a substituent(s); under the acidic condition and the like in case of a tertiarybutoxycarbonyl group; and under the catalytic reduction condition (hydrogenating reaction) and the hke.
Further, for instance, a hydrogen atom(s) directly bonding to a nitrogen atom

constituting the amino group may be substituted, by using benzylation reagents in ordinary benzylation methods, with an arylalkyl group which may have a substituent(s) such as a benzyl group, a phenethyl group, a methylbenzyl group, a methoxybenzyl group and a halobenzyl group, and the Uke. In this case, after completion of the reaction of the first, second or third step in the present invention, particularly after the completion of the N-alkylation reaction in the third step of the present invention, a protecting group(s) can be removed under the catalytic reduction condition (hydrogenating reaction) and the hke.
Meanwhile, the substituents in case of the above protecting groups "which may have a substituent(s)" include, for example, a halogen atom, an alkoxy group, an aUcyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group.
The 'Tialogen atom" in the present specification indicates a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The 'lialogeno"" as the component in a substituent indicates fluoro-, chloro-, bromo- and iodo-.
The "chemically acceptable acids" in the formula (l) or (2) include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid; organic carboxylic acid such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, trifluoroacetic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teochc acid, salicylic acid, lactic acid, oxahc acid, mandehc acid and malic acid; and organic sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid. The free forms are particularly preferable in the compound of the formula (l) and the hydrochloride is particularly preferable in the compound of the formula (2), They may be hydrates or solvates thereof.
In the present invention, when R3 in the formula (5) is a dialkylamino group, the resulting compound is therapeutically superior, and therefore, R3 in the formulae (2) and (3) are preferably dialkylamino groups. Among dialkylamino

groups, a dimethylamino group, a diethylamino group, a methylethylamino group, a pyrrolidinyl group and a piperidinyl group are preferable. Particularly, it is preferable that R3 is a dimethylamino group.
Similarly, it is also preferable that R3 in the formulae (2) and (3) are a monoalkylamino group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an alkynyl group, a carboxyl group, an alkoxycarbonyl group or an alkylthio group. Particularly preferred ones are a methylamino group, an ethylamino group, a propylamino group, a cyclopropylmethylamino group, a dimethylaminometyl group, a diethylaminomethyl group, a dimethylaminoethyl group, a diethylaminoethyl group, a methylaminom ethyl group, an ethylaminomethyl group, a propylaminomethyl group, methylaminoethyl group, ethylaminoethyl group, a propylaminoethyl group, HC = CCH2 group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylthio group and an ethylthio group.
Among these, when R3 in the formulae (2) and (3) are a monoalkylamino group or an alkyl group substituted with a monoalkylamino group, a hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted with an alkylcarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a trifluoroacetyl group and the like; an arylcarbonyl group which may have a substituent(s) such as a benzoyl group; an arylalkylcarbonyl group which may have a substituent(s) such as a benzylcarbonyl group; an alkoxycarbonyl group having 2 to 7 carbon atoms which may have a substituent(s) such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a butoxycarbonyl group, a tertiary-butoxycarbonyl group, a triQuoromethoxy carbonyl group and the like; an aryloxycarbonyl group which may have a

substituent(s) such as a phenoxycarbonyl group; and an arylaUcyloxycarbonyl group which may have a substituent(s) such as a benzyloxycarbonyl group. A hydrogen atom(s) directly bonding to a nitrogen atom constituting the amino group may be substituted with an arylalkyl group which may have a substituent(s) such as a benzyl group, a phenethyl group, a methylbenzyl group, a methoxybenzyl group and a halobenzyl group, and the like. The substituents in case of the above protecting groups "which may have a substituent(s)" include a halogen atom, an alkoxy group, an alkyl group, a hydroxy group, a halogenoalkyl group and a halogenoalkoxy group.
Examples
Next, Examples will further illustrate the present invention in detail. The following Examples only explain the present invention and do not particularly limit the invention.
TMS was used as an internal reference material in ‘ H and ‘ ‘ C NMR, and measurement was conducted with AVANCE 400mHz NMR of Bruker BioSpin GmbH. As DMSO-de, the product (containing 0.03% TMS) of Eurisotop CEA Group was used. As an HPLC apparatus, LClO series (Pump: LC-IOAT, Controller' SCL-IGA and Detector: SPD-lGAvp) of Shimadzu Corporation was used. As an autosampler, KMT-IGOX of Kyowaseimitsu Corporation ( was used (the injection volume is 10/il as long as it is not particularly described). As an column oven, U-620 of Sugai Chemical Industry Co.,LTD was used. As a chromato waveform processing, C-R7A of Shimadzu Corporation was used. As raw materials and reagents in the present Examples, commercial items thereof are used themselves without purification. Compositions of eluting solvents: Solution A 0.1% TEA aqueous solution

Synthesis of methylester of N" -(2,6-dichlorobenzoyl)-4-aniino-L-phenylalanine
200mL of water and 91mL of acetone were mixed and 72.4g (344mmol) of 4-nitro-L-phenylalanine was added thereto and cooled down to 10°C or lower. 68niL of 6M sodium hydroxide aqueous solution was added dropwise to the solution so that the temperature thereof did not exceed 15°C. Keeping around pH 14, 73.58g (344mmol) of 2,6-dichlorobenzoyl chloride was slowly added dropwise thereto. In order to keep around pH 14, if needed, a sodium hydroxide aqueous solution was added dropwise. 2 hours later of completion of drop, 86mL of 6M hydrochloric acid was added with keeping the temperature of the reaction

solution at 15°C or lower to precipitate white crystals. After maturing at 10°C or lower, the crystals were separated, dried under reduced pressure at 60°C to obtain 128.5gof N" -(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine. (Yield-' 97%) iH NMR (400MHz, DMSO-de): 9.12 (d, IH, J=8.42 Hz), 8.16 (d, 2H, J=8.78 Hz), 7.59 (d, J=8.77Hz), 7.42 (m, 3H), 3.29 (m), 3.07 (dd, IH, J=3.64 and 10.42 Hz). 13C NMR (lOOMHz, DMSO-de): 172.25, 163.74, 146.68, 146.18, 131.51, 131.37, 131.05, 128.37, 123.55, 53.17, 36.74. MS (FAB) : m/z 383.1 (M+H)+ HRMS (FAB) : m/z 383.0219 (M+H)+
Next, 117.3g(306mmol) ofN" -(2,6-dichlorobenzoyl) -4-nitro-L-phenylalanine was added to 592mL of methanol and dissolved. 31.6g of 95% concentrated sulfuric acid was added dropwise being careful of heating. After the drop, the reaction was conducted for 3 hours at the reaction temperature of 40°C. After confirming completion of the reaction with HPLC, the reaction solution was cooled down to 30°C or lower. 395mL of water cooled down to around 10°C in advance was added dropwise in 1 hour so that the temperature of the reaction solution did not exceed 30°C. After crystallizing out, the reaction solution was matured for 5 hours with keeping a crystallizing solution at 10°C or lower. The crystals were separated by filtration, and then dried under reduced pressure at 60 °C to obtain 117.8g of methylester of N " -(2,6-dichlorobenzoyl) -4-nitro-L-phenylalanine. (5deld 97%)
iH NMR (400MHz, DMSO-de )•- 9.23 (d, IH, J=8.2 Hz), 8.18 (d, 2H, J=8.8 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.38-7.46 (m, 3H), 4.88 (ddd, IH, J=6.4, 8.2 and 11 Hz), 3.69 (s, 3H), 3.31 (dd, IH, J=6.4 and 14 Hz), 3.10 (dd, IH, J=ll and 14 Hz). 13C NMR (lOOMHz, DMSO-de): 171.27, 163.83, 146.74, 145.80, 136.15, 131.49, 131.05, 128.42, 123.58, 53.07, 52.40, 36.39. MS (FAB) : m/z 397.2 (M-HH)+ HRMS (FAB) : m/z 397.0345 (M+B.>

Further, 115.94g (290mmol) of methylester of N ‘ ■(2,6-dichlorobenzoyD-4-nitro"L-phenylalanine and 28.37g (0.5mol% to substrate) of 3% platinum carbon powder (wet) were suspended to 825mL of methanol. Nitro groups in the suspended solution were reduced under hydrogen gas atmosphere at 30°C for 5 hours. After confirming completion of the reaction with HPLC, the platinum catalyst was filtered out and the concentration of the reaction solution was adjusted. 539mL of water was added dropwise thereto at the liquid temperature of around 30 °C, and crystallization by cooling was conducted at 10°C or lower. The crystals were filtered out and dried under reduced pressure at 60 °C to obtain 84.6 Ig of methylester of N ‘ -(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine. (yield 80%)
iH NMR (400MHz, DMSO-de): 9.23 (d, IH, J=7.8 Hz), 7.38-7.47 (m, 3H), 6.90 (d, 2H, J=7.0 Hz), 6.47 (d, 2H, J=7.0 Hz), 4.57 (ddd, IH, J=5.8, 7.8 and 9.1 Hz), 3.62 (s, 3H), 2.90 (dd, IH, J=5.8 and 14 Hz), 2.79 (dd, IH, J=9.1 and 14 Hz). 13C NMR (lOOMHz, DMSO-de)'- 171.87, 163.88, 147.52, 136.43, 131.65, 131.34, 129.90, 128.34, 124,01, 114.14, 54.57, 52.07, 36.40. MS (FAB) : m/z 367.2 (M+H)+ HRMS (FAB) : m/z 367.0585 (M+H)+
Synthetic example of the compound of formula (7)

H.N
'2'
r’ (7)
H3COOC’’’N(CH3)2
Synthesis of methylester of 2-amino-5-(dimethylamino) benzoic acid / dihydrochloride
30.0g (l48mmol) of 5-chloro'-2-nitrobenzoic acid was dissolved by stirring in 78mL (744mmol) of 50% dimethylamine aqueous solution under cooHng in the ice

bath. After the solution was put into a pressure-resistant container and sealed, the solution was stirred by heating in the oil bath for 23 hours at 60°C. The reaction solution was sufficiently cooled down and the inner pressure thereof was released. After confirming completion of the reaction by HPLC analysis, the reaction solution was put into another container (using 50mL of water), 49.6mL of concentrated hydrochloric acid, and then 200mL of water were added thereto. Yellow crystals were precipitated by addition of hydrochloric acid. The crystallizing solution was matured at 10°C overnight, separated by filtration and dried under reduced pressure to obtain 30.95g of 5-dimethylamino-2-nitrobenzoic acid, (yield 99%)
iH NMR (400MHz, DMSO-de): 8.88 (bs, IH), 7,97 (d, IH, J=9.4 Hz, aryl coupling=1.76 Hz), 6.78 (d, IH, J=9.4 Hz, aryl coupling=2.84 and 1.92 Hz), 6,71 (s, IH, aryl coupling=2.88 and 1.60 Hz), 3.08 (s, 6H),
13C NMR (lOOMHz, DMSO-de): 168.58, 153.86, 133.94, 132.85, 127.03, 111.44, 109.69, 40.24. MS(ESI): m/z 211.17 (M+H)+, 209.27 (M-H)'
Next, 40.0g (l90.30mmol) of 5-dimethylamino-2-nitrobenzoic acid was suspended in 160mL of methanol at 25’C. This suspension was under cooled down in the ice bath and 53.6mL of concentrated sulfuric acid was added thereto. After adding the concentrated sulfuric acid, the temperature of the solution rose up to about 30°C. The solution was directly soaked in the bath of 60°C and stirred by heating for 20 hours. The progress of the reaction was confirmed by HPLC, and after confirming disappearance of a raw material, 400mL of toluene was added thereto to dilute. Then, 200mL of water and an aqueous solution of sodium hydroxide (wherein 38.06g of sodium hydroxide was dissolved in 200mL of water) were added thereto. The aqueous layer was extracted with 200mL of toluene and a toluene solvent(s) was mixed together. The toluene layer was washed with 300mL of saturated sodium bicarbonate water. The toluene layer

was further concentrated under reduced pressure (bath temperature; 50°C) and
adjusted so that the objective substance becomes about 20wt%. After distilling
under reduced pressure, crystals of the objective substance precipitated. After
maturing them at room temperature for about one hour, 220mL of n-heptane was
added and further stirred at 5°C overnight. The crystals were separated by
suction filtration and washed with lOOmL of n-heptane. These wet crystals
were dried under reduced pressure for 3 hours at 65°C to obtain 34.82g of
methylseter of 5-dimethylamino ■2-nitrobenzoic acid as yellow crystaUized
powder, (yield 82%)
iH NMR (400MHz, DMSO-de): 8.02 (d, IH, J=9,4 Hz), 6.82 (d, IH, J=9.36 Hz,
aryl coupHng=2.56 Hz), 6.78 (s, IH, aryl coupling=2.4 Hz), 3.83 (s, 3H), 3.10 (s,
6H).
13C NMR (lOOMHz, DMSO-de)-' 167.70, 153.92, 132.71, 132.34, 127.24, 111.87,
110.07, 53.21, 40.28.
MS (FAB): m/z 224.24 (M>
HR MS (FAB): m/z 224.0830 (M)+
Further, 10.06g (44.9mmol) of methylester of 5-dimethylamino-2-nitrobenzoic acid was added to 50mL of methanol and suspended. 9.0mL of lOM hydrochloric acid and 1.96g (wet, lmol% to substrate) of 5% palladium carbon were added thereto. The reaction container was substituted with hydrogen gas and stirred at room temperature overnight. A palladium catalyst was filtered out with Cehte and the filtrate was concentrated under reduced pressure by about a half amount thereof. Then, 80mL of acetone was added to the solution and concentrated under reduced pressure three times to precipitate the compound of the formula (12). The compound was further matured at 10°C or lower and dried under reduced pressure to 11.16g of methylester of 2-amino-5-(dimethylamino) benzoic acid / dihydrochloride. (yield 93%) iH NMR (400MHz, DMSO-de): 8.09 (s, IH), 7.72 (d, IH, J=9.0 Hz), 6.96 (d, IH,

9.08 Hz), 5.50 (bs), 3.83 (s, 3H), 3.04 (s, 6H).
13C NMR (lOOMHz, DMSO-de): 167.12, 131.64, 126.66, 123.29, 118.7, 108.88,
52.18,45.84.
MS (FAB): m/z 195.3 (M+H)+
HR MS (FAB): m/z 195.1122 (M+H)+

Synthesis of methylester of 2-(3-{4-[2-(2,6-diclilorobenzoylamino) - 2 -methoxycarbonylethyllphenyllureide) ■ 5 ■ dimethylaminobenzoic acid
Method i: In case of using l,l'-carbonyldiimidazole (GDI) as a carbonyl group-introducing reagent
9.73g (59.41mmol) of l,r"carbonyldiiinidazole was added to 310mL of
acetonitrile and dissolved. The solution was cooled down to 10°C or lower and
20.78g (56.58mmol) of methylester of N ‘
■(2,6-dichlorobenzoyl)"4-amino-L-phenylalanine of the formula (6) was added
thereto and stirred. 2 hours later, 15.06g (54.50mmol) of methylester of
2-amino-5-(dimethylamino) benzoic acid / dihydrochloride of the formula (7) was
added, heated up to 50°C and stirred for 2 hours. After completion of the
reaction, 62mL of methanol was added to the reaction solution, and the solution
was cooled down to 10°C or lower. After maturing 10 hours or more, the crystals
were separated by filtration and dried under reduced pressure to obtain 30.03g of
objective methylester of

2-(3-{4-[2-(2,6"dichlorobenzoylaniino)-2-niethoxycarbonylethyl]phenyl}ureide)-5"di
methylaminobenzoic acid of formula (8). (yield 88%)
iH NMR (400 MHz, DMSO-d6):5 9.56 (s, IH), 9.46 (s, IH), 9.22 (d, IH, J=8.0 Hz),
8.07 (d, IH, J:=9.24 Hz), 7.47-7.38 (m, 5H), 7.19 (m, 3H), 7.06 (m, IH), 4.69 (m,
IH), 3.88 (s, 3H), 3.66 (s, 3H), 3.06 (dd, IH, J=14.1 and 5.3 Hz), 2.93-2.88 (m, IH),
2.88(s, 6H)
i3CNMR(l00MHz, DMSO-d6):5 171.72, 168.20, 163.88, 152.87, 145.63, 138.89,
136.38, 131.80, 131.64, 131.37, 130.46, 129.78, 128.36, 122.83, 119.31, 118.54,
117.18, 112.99, 54.09, 52.59, 52.18, 40.80, 36.34.
MS (FAB): m/z 586.3 (M)+
HR MS (FAB): 586.1407 (M)+
Method 2: In case of using phenyl chloroformate as a carbonyl group-introducing reagent
2.08g (5.45mmol) of methylester of N "" -(2,6-dichlorobenzoyl)
■4-amino-L-phenylalanine of the formula (6) was added to 30mL of acetonitrile
and stirred at room temperature and dissolved. After under coohng in the ice
bath, 0.83mL of triethylamiae and 0.72mL (5.72mmol) of phenyl chloroformate
were added thereto. After warming the reaction solution to room temperature
and stirring for 1.5 hours, 1.46g(5.45mmol) of methylester of
2-amino-5"dimethylamino benzoic acid / dihydrochloride and 1.5 ImL of
triethylamine were added thereto and stirred at room temperature for 3 days.
Precipitated crystals were filtered out, washed with methanol and dried under
reduced pressure to obtain 2.55g of a crystalline sohd substance containing
objective methylester of
2-(3-{4-[2-(2,6-dichlorobenzoylamino)"2-methoxycarbonylethyl]phenyl}ureide)-5-di methylaminobenzoic acid of formula (8). (content 61.3wt%, yield 49%)
Meanwhile, analytical data of the compound conformed to those of the above mentioned Method 1.

Methods: In case of using N,N'"disuccinimidyl carbonate (DSC) as a carbonyl group-introducing reagent
1.32g (3.60mmol) of methylester of N "‘ -(2,6-dichlorobenzoyl)
-4-amino-L-phenylalanine of the formula (6) was added to 15mL of acetonitrile
and stirred at room temperature and dissolved. l.Og (3.90mmol) of
N,N'-disuccinimidyl carbonate (DSC) was added to the solution and stirred at
room temperature. 0.98g (3.68mmol) of methylester of
2-amino-5-dimethylamino benzoic acid / dihydrochloride and 1.92g of N,N"diisopropyl-N-ethylamine (DIPEA) were added to the reaction solution and stirred at 50°C for 2.5 hours. The objective substance precipitated as a soUd material as the reaction proceeded, and the suspension was cooled down to 10°C or lower. The crystals were filtered out, washed with methanol and dried under reduced pressure to obtain 1.16g of objective methylester of 2"(3-{4-[2-(2,6-dichlorobenzoylamino)-2-methoxy
carbonylethyl]phenyl}ureide)-5"dimethylaminobenzoic acid of formula (8). (sdeld 55%) Meanwhile, analytical data of the compound conformed to those of the above mentioned Method 1. Synthetic example of the compound of formula (9)

Z'2

CI O
N' 'COOCH H

3

N(CH,)

(9)

Synthesis of methylester of N*’ -(2,6-dichlorobenzoyl)-4"(6-dimethylamino -2,4[lH,3H]-quinazoluiedione-3"yl)-L-phenylalanine
40.0g (68.14mmol) of methylester of 2-(3-{4-[2-(2,6"dichlorobenzoyl

ainino)-2-methoxycarbonylethyl]phenyl}ureide)-5-dimethylaminobenzoic acid of
the formula (8) was added to 200inL of N,N-dimethylformainide and stirred and
dissolved at 25°C. 5.4mL of 28% sodium methoxide/methanol solution was
added thereto and stirred at 25°C for 2 hours. After completion of the reaction,
the reaction solution was added dropwise to 210mL of an aqueous solution of
hydrochloric acid to precipitate the compound of formula (14). The compound
was separated and dried under reduced pressure to obtain 36.74g of the title
compound, (yield 97.2%)
iH NMR (400 MHz, DMSO-d6):5 11.20 (bs, IH), 9.29 (d, IH, J=8.12 Hz), 7.47-7.38
(m, 5H), 7.29-7.26 (m, IH), 7.18 (d, 2H, J=8.3 Hz), 7.12 (m, 2H), 4.81 (m, IH), 3.69
(s, 3H), 3.22 (dd, IH, J=14.1 and 4.8 Hz), 3.02 (dd, IH, J=14.0 and 3.8 Hz), 2.91 (s,
6H).
13C NMR (100 MHz, DMSO-d6):5 171.70, 163.99, 162.75, 150.18, 146.80, 137.15,
136.34, 134.80, 131.78, 131.36, 131.15, 129.84, 129.18, 128.32, 122.05, 116.48,
115.03, 108.50, 53.70, 52.29, 40.93, 36.36.
MS (FAB): m/z 555.2 (M-HH)+
HR MS (FAB): m/z 555.1172 (M+H)+

Synthetic example of the compound of formula (lO)

N COOCH.,

N(CH3)2
(10)

(Method l) Synthesis of methylester of N°-(2,6-dichlorobenzoyl)
■4-(l-methyl-6-dimethylamino-2,4[lH,3H]-quinazohnedione-3-yl)-L-phenylalanine e by N-methylation of the formula (9) [A production method in case of isolating

the compound of the formula (9)]
30.Og (54.0mmol) of methylester of N’ ■(2,6-dichlorobenzoyl)-4-(6-dimethylamino-2,4[lH,3H]-quinazolinedione-3yl)-L-phenylalanine of the formula (9) was added to a solution containing 180mL of N,N-dimethylformamide (DMF) and 20mL of methanol and stirred and dissolved at 25 °C. A DMF solution (20mL as DMF) containing 15.3g (Sl.lmmol) of methyl of p-toluenesulfonic acid and 15.0g (lOS.lmmol) of potassium carbonate were added thereto. After addition thereof, the reaction solution was stirred at the reaction temperature of 40°C for 6 hours. Then, the solution was added dropwise being careful of exothermic heating to an aqueous solution of hydrochloric acid (l.SmL of 6M hydrochloric acid and 250mL of water) which was cooled down in advance at 10°C or lower. The precipitated substance was filtered out and dried at 60°C under reduced pressure to obtain 25.3g of the title compound of the formula (lO). (yield 82%)
(Method 2) Synthesis of methylester of N’ -(2,6-dichlorobenzoyl)-4-
(l-methyl-6-dimethylamino-2,4[lH,3H]-quinazolinedione-3"yl)-L-phenylalanine [A production method in case of not isolating the compound of the formula (9)]
20g (34.07mmol) of methylester of 2-(3-{4-[2-(2,6"dichlorobenzoylamino) ■2-methoxycarbonylethyl]phenyl}ureide)-5-dimethylaminobenzoic acid of the formula (8) was stirred and dissolved in llOmL of N,N-dimethylformamide (DMF) at 20°C. llmL of methanol and 0,94g (6.81mmol) of potassium carbonate were added thereto and stirred at 25'C for 1 hour. After confirming completion of the quinazolinedione ring formation reaction with HPLC, without isolating the compound of the formula (9), a DMF solution (l4mL of DMF) containing 7.74mL (Llmmol) of methyl of p-toluenesulfonic acid and 8.46g (61.33mmol) of potassium carbonate were added to the reaction solution. N-methylation reaction was conducted to the solution at 40°C. After completion of the reaction, the reaction solution was added to water to precipitate the title compound of the

formula (lO) as a solid substance. Tlie precipitated substance was filtered out
and dried under reduced pressure to obtain 16.7 Ig thereof, (yield 86.2%)
iH NMR (400 MHz, DMSO-d6):5 9.29 (d, IH, J=8.12 Hz), 7.47-7.36 (m, 6H),
7.32-7.29 (m, IH), 7.24 (d, IH, J=2.84 Hz), 7.18 (d, 2H, J=8.28 Hz), 4.82 (m, IH),
3.69 (s, 3H), 3.49 (s, 3H), 3.23 (dd, IH, J=14.1 and 4.6 Hz), 3.02 (dd, IH, J=13.9
and 3.5 Hz), 2.94 (s, 6H).
13C NMR (100 MHz, DMSO-d6):5 171.73, 163.99, 161.88, 150.37, 146.73, 137.20,
136.34, 135.34, 132.06, 131.78, 131.36, 129.89, 128.99, 128.32, 121.34, 116.21,
116.00, 109.15, 53.65, 52.29, 40.75, 36.35, 30.88.
MS (ESI): m/z 569.33 (M-fH)+
Anal. Calcd for C28H26N4O5CI2 : C, 59.06; H, 4.60; N, 9.84; CI, 12.45. Found: C,
59.08; H, 4.64; N, 9.82; CI, 12.43.

1. A method for producing a phenylalanine derivative(s) having a quinazolinedione ring of the following formula (5), comprising steps of reacting an acyl phenylalanine derivative(s) of formula (l):

wherein Rl represents a phenyl group which may have a substituent(s) or a pyridyl group which may have a substituent(s), R2 represents an alkyl group which may have a substituent(s), and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s),
with a carbonyl group-introducing reagent(s) and an anthranilic acid derivative (s) of formula (2):

wherein R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, perfluoroalkyl group, an alkoxy group, a nitro group, an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group, an alkyl group substituted with an amino group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alk5niyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group or an arylthio group; R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent(s); and R5 represents an alkyl group or an alkylcarbonyl group, and the derivative(s) is in a salt(s) with chemically acceptable acid(s) or free form(s).

to form an asymmetric urea intermediate(s) of formula (3):

wherein Rl to R5 are dej5ned above;
making the asymmetric urea intermediate(s) into a quinazolinedione
compound(s) of formula (4) in the presence of a base(s):

wherein Rl to R4 are defined above; and
when R4 represents a hydrogen atom in the obtained quinazolinedione compound(s) of the formula (4), N-alkylating a quinazolinedione ring amide of the quinazolinedione compound(s) with an N-alkylation agent(s) to form the phenylalanine derivative(s) having a quinazolinedione skeleton of formula (5)^

wherein Rl to R3 are defined above, R4 represents an alkyl group or a benzyl group which may have a substituent(s).
2. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an alkyl group

substituted with a dialkylamino group, an alkyl group substituted with a monoalkylamino group or an alkyl group substituted with an alkynyl group.
3. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group, a monoalkylamino group, an amino group, a hydrogen atom, a halogen atom, an alkyl group, a perfluoroalkyl group, an alkoxy group or a nitro group.
4. The production method according to claim 1, wherein, in the formulae (2) to (5), R3 represents a dialkylamino group.
5. The production method according to any one of claims 1 to 4, wherein the carbonyl group-introducing reagent is l,l'-carbonyldiimidazole or chloroformate.
6. The production method according to any one of claims 1 to 5, wherein the base(s) represents a potassium carbonate or a sodium methoxide.
7. The production method according to any one of claims 1 to 6, wherein the N-alkylation agent is methyl p-toluenesulfonate.
8. The production method according to claim 1, comprising steps of reacting a carbonyl group-introducing reagent selected from the group consisting of l,l'-carbonyldiimida2ole and chloroformate and the compound of the formula (2) wherein R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group with the compound of the formula (l) wherein Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to obtain methylester of 2-(3-{4-[2-(2,6"dichlorobenzoylamino)-2-methoxycarbonylethyl]phenyl methylaminobenzoic acid; converting it in the presence of potassium carbonate or sodium methoxide into methylester of N^-(2,6-dichlorobenzoyl)-4"(6-dimethylamino-2,4[lH,3H]-quina2olinedione-3"yl)-L -phenylalanine of the formula (4); and then N-alkylating it with methyl p-toluenesulfonate" to obtain methylester of N°-(2,6-dichlorobenzoyl)-4-(l-methyl-6"dimethylamino-2,4[lH,3H]-quinazolinedione

ne-3-yl)-L-phenylalanine.
9. The production method according to claim 1 comprising steps of reacting a
carbonyl group-introducing reagent selected from the group consisting of
l,r'carbonyldiimidazole and chloroformate and the compound of the formula (2)
wherein R3 represents a dimethylamino group, R4 represents a methyl group
and R5 represents a methyl group with the compound of the formula (l) wherein
Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group to
obtain the compound of the formula (3); converting it in the presence of
potassium carbonate or sodium methoxide into methylester of
N^ ■(2,6-dichlorobenzoyl)
"4-(l-methyl-6-dimethylamino-2,4[lH,3H]-quinazolinedione-3-yl)-L-phenylalanine
10. Methylester of N°-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine according to claim 1, wherein, in the formula (l), Rl represents a 2,6-dichlorophenyl group and R2 represents a methyl group, and salts thereof with chemically acceptable acids.
11. Methylester of 5-dimethylamino-2-aminobenzoic acid according to claim 1, wherein, in the formula (2), R3 represents a dimethylamino group, R4 represents a hydrogen atom and R5 represents a methyl group, and salts thereof with chemically acceptable acids.
12. Methylester of 2-(3"{4-[2-(2,6-dichlorobenzoylamino)-2-methoxycarbonyl
ethyl]phenyl}reside)"5-dimethylaminobenzoic acid according to claim 1, wherein,
in the formula (3), Rl represents a 2,6-dichlorophenyl group, R2 represents a
methyl group, R3 represents a dimethylamino group, R4 represents a hydrogen
atom and R5 represents a methyl group.

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Patent Number

229562

Indian Patent Application Number

1977/CHENP/2005

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

18-Feb-2009

Date of Filing

19-Aug-2005

Name of Patentee

AJINOMOTO CO., INC.

Applicant Address

15-1, Kyobashi 1-chome, Chuo-ku, Tokyo 104-0031,

Inventors:

#	Inventor's Name	Inventor's Address
1	KATAOKA, Noriyasu	c/o Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681,
2	TATARA, Akinori	c/o Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681,
3	YATAGAI, Masanobu	c/o Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681,
4	YAMANAKA, Junko	c/o Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681,

PCT International Classification Number

C07C 233/87

PCT International Application Number

PCT/JP04/01982

PCT International Filing date

2004-02-20

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2003-042560	2003-02-20	Japan