Indian Patents. 252195:"PROCESS FOR PRODUCING 2, 3, 6-TRIALKYL-8-FLUORO-4-QUINOLINE DERIVATIVES"

Title of Invention	"PROCESS FOR PRODUCING 2, 3, 6-TRIALKYL-8-FLUORO-4-QUINOLINE DERIVATIVES"
Abstract	A process for producing a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative represented by formula (I) or a salt thereof: wherein R1, R2, R3, OR4, F, N are herein described.

Full Text	PROCESS FOR PRODUCING 2,3,6-TRIALKYL-8-FLUORO-4-QUINOLINE DERIVATIVES [BACKGROUND OF THE INVENTION] Field of the Invention The present invention relates to a process for producing 2,3,6-trialkyl-8-fluoro-4-quinoline derivatives or pharmaceutically acceptable salts thereof which are useful as agricultural chemicals. Background Art 2,3,6-Trialkyl-8-fluoro-4-quinoline derivatives have a control activity against agricultural and horiticultural diseases as described in WO 01/92231. This publication discloses a production process of the compounds according to the following reaction scheme. (Scheme Removed) In the above process, t-butylaniline as a starting compound is firstly protected at its amino group with a suitable protective group, and then reacts with SELECTFLUOR (1-(chloromethyl)-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetra-fluoroborate)) as a fluorinating reagent to introduce a fluorine atom into a position adjacent to the amino group. The protective group is removed to give 4-t-butyl-2-fluoroaniline as an intermediate. The intermediate is then enaminated with ethyl 2-methylacetoacetate to give an enamine compound which is then heated for cyclization to give a quinolinol compound. Finally, a hydroxyl group in the quinolinol compound is acetylated to give the target compound. In this process, an enamination-cyclization process is known as Conrad-Limpach synthesis. This production process, however, disadvantageously requires 6 steps which complicate the production process. Further, the yield of the product in the Conrad-Limpach synthesis is so low that the overall yield is low and about 4%. Further, in this process, a fluorinating reagent, which is expensive, typified by SELECTFLUOR or the like should be used. Since, this fluorinating reagent is highly irritant and corrosive, the use of the fluorinating reagent in a production process on a commercial scale is not favorable in cost as well as in efficiency. There are only a few general-purpose industrial production processes which can selectively introduce a fluorine atom into a target position of the aromatic ring. Examples thereof include dediazofluorination with sodium borofluoride and a Balz-Schiemann reaction which involves diazotization of an aromatic amino group. These processes, however, suffer from many industrial problems because the target compound is produced through an aromatic tetrafluoroborate which is unstable and highly toxic. The fluorination of the 2-position of a 4-alkylaniline disclosed in WO 01/92231 requires the use of a fluorinating reagent, which is generally highly irritant and corrosive, typified by Selectfluor. When this fluorinating reagent is used in a large amount, the surface of a metallic or glass reactor is corroded. This requires the use of a special reactor. Thus, the fluorinating reagent would be difficult to handle on a commercial scale. Accordingly, the development of a production process, which can provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative without the use of any fluorinating reagent and with high efficiency, has been desired. [SUMMARY OF THE INVENTION] The present inventors have now established a production process which can provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative basically in two steps using 2-fluoroaniline in which fluorine is already introduced thereinto, which is inexpensive, as a starting compound safely and in a high yield. Accordingly, an object of the present invention is to provide a production process which can safely provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative in a high yield. According to one aspect of the present invention, there is provided a process for producing a 2,3,6- trialkyl-8-fluoro-4-quinoline derivative represented by formula (I) or a salt thereof: (Formula Removed) wherein R1 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl; R2 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl; R3 represents optionally substituted C1-10 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl; and R4 represents a hydrogen atom or a protective group of hydroxyl, said process comprising the steps of: (i) alkylating a compound represented by formula (ID : (Formula Removed) with R1-X (where R1 is as defined above and X represents hydroxyl or a halogen atom) or R1' (where R1' is an olefin having the same carbon atoms as R1) in the presence of zinc chloride under pressure, to give a 4-alkyl-2-fluoroaniline derivative represented by formula (III): (Formula Removed) wherein R1 is as defined above; and (ii) reacting the compound represented by formula (III) with an α-alkyl-ß-ketoester represented by formula (IV) : (Formula Removed) wherein R2 and R3 are as defined above; and R5 represents C1-4 alkyl, to give an enamine intermediate represented by formula (V) : (Formula Removed) wherein R1, R2, R3, and R5 are as defined above, cyclizing the enamine intermediate to give the compound represented by formula (I) , wherein R4 represents a hydrogen atom, and optionally protecting hydroxyl at the 4-position with a protective group. [DETAILED DESCRIPTION OF THE INVENTION] Definition In the present specification, alkyl as a group or a part of a group may be straight chain or branched chain. The term "halogen atom" as used herein means a fluorine, chlorine, bromine, or iodine atom. Compounds represented by formula (I) Compounds to be produced by the production process according to the present invention are 2,3,6-trialkyl-8-fluoro-4-quinoline derivatives represented by formula (I) . In formula (I) , R1 and R2 each independently represent C1-10 alkyl, preferably C1-6 alkyl, or C3-6 cycloalkyl. This alkyl group is optionally substituted by one or more substituents, which includes halogen atoms, hydroxyl, and C1-4 alkoxy. Further, in formula (I) , R3 represents C1-10 alkyl, preferably C1-6 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl. The C1-10 alkyl group is optionally substituted, and examples of preferred substituents include substituents as described above for R1 and R2. The compounds represented by formula (I) may form salts. Examples of the salts include: alkali metal salts, alkaline earth metal salts, hydrochloric acid salts, sulfuric acid salts, citric acid salts, oxalic acid salts, p-toluenesulfonic acid salts, and methanesulfonic acid salts. Production of compounds represented by formula (I) Step (i) Step (i) in the present invention is an alkylation reaction, which can be carried out according to the description of Japanese Patent Laid-Open No. 944/1983. Specifically, a fluoroaniline hydrochloride and an alkylating agent are subjected to a thermal reaction under pressure in the presence of an acid catalyst preferably in a pressure vessel to cause a Friedel- Crafts reaction. The alkylating agent is a compound represented by formula R1-X, wherein R1 is as defined in formula (I) and X represents hydroxyl or a halogen atom, or an olefin having the same carbon atoms as R1. In the case of R1-X (X = OH) , the utilization of a secondary alcohol or tertiary alcohol is preferred. The amount of the alkylating agent used may be properly determined. Preferably, however, the amount of the alkylating agent used is about 1 to 10 equivalents, more preferably about 1 to 5 equivalents, based on the compound represented by formula (II). A preferred catalyst in the Friedel-Crafts reaction is a combination of a protonic acid typified by hydrochloric acid, sulfuric acid or the like with a Lewis acid typified by zinc chloride. The use of zinc chloride is more preferred. While the amount of the catalyst used is not limited, the amount of the catalyst used is preferably in the range of 0.25 to 0.5 equivalent. The reaction temperature is preferably 150°C or above from the viewpoint of allowing the reaction to proceed efficiently. The reaction temperature is more preferably in the range of 150 to 200°C. In the process according to the present invention, pressure is applied to increase the rate of the alkylation reaction and to enhance regioselectivity of alkylation to the 4-position of the aromatic ring. The pressure is not less than 3 atm from the practical point of view, more preferably in the range of 4 to 10 atm. Step (i) can be generally carried out in the absence of a solvent or alternatively can be carried out in an inert solvent such as carbon disulfide or nitrobenzyl. The reaction vessel is preferably a pressure-resistant glass vessel or stainless steel vessel. Since the surface of the stainless steel is corroded in an acidic atmosphere, the use of a stainless steel vessel, in which a glass vessel has been hermetically sealed, or a tantalum-clad stainless steel vessel is preferred. The step (i) gives a compound represented by formula (III). The compound represented by formula (III) may be purified by taking advantage of a difference in lipophilicity between the product and the starting compound. Specifically, the product may be extracted with a suitable organic solvent such as hexane or ethyl acetate to give the compound represented by formula (III) while allowing only the starting compound having higher water solubility than the product to selectively stay in the aqueous layer. The compound represented by formula (III) can also be isolated and purified by distillation. In the present invention, step (ii), subsequent to step (i), involves enamination and then cyclization. The enamination and the cyclization may also be carried out in a one-pot manner afer step (i) . Alternatively, after enamination, post-treatment is carried out to take out the enamine compound (V) from the reaction system and is then subjected to cyclization to complete step (ii). It appears that the compound represented by formula (V) is a tautomer and can exist as a compound represented by formula (V) : (Formula Removed) wherein R1, R2, R3, and R5 are as defined above. Step (ii) In step (ii), enamination is first carried out by reacting the compound represented by formula (III) with a compound represented by formula (IV) . R2 and R3 of the compound represented by formula (IV) correspond to those in the compound represented by formula (I) . Therefore, the structure of the compound represented by formula (IV) may be properly determined by taking into consideration the structure of the target compound, i.e., the compound represented by formula (I). R5 represents C1-4 alkyl, preferably methyl or ethyl. Specific examples of preferred compounds represented by formula (IV) include methyl 2-methylacetoacetate, ethyl 2-methylacetoacetate, ethyl 2-benzyl acetoacetate, ethyl 2-ethylacetoacetate, ethyl 2-isopropylacetoacetate, and ethyl 2-allylacetoacetate. The amount of the α-alkyl-ß-ketoester represented by formula (IV) used may be properly determined by taking into consideration, for example, reaction conditions. Preferably, however, the amount of the α-alkyl-ß-ketoester represented by formula (IV) used is about 0.8 to 2.0 equivalents, more preferably about 1.0 to 1.5 equivalents, most preferably about 1.2 to 1.3 equivalents. The reaction is preferably carried out in the presence of an acid or base catalyst. The use of the acid catalyst is more preferred. Acid catalysts include protonic acids, such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and Lewis acids such as boron trifluoride diethyl ether complex. Basic catalysts include piperidine. When piperidine is used, the use of an ethanol solvent is preferred. In this case, the reaction time is generally longer than that in the case where the acid catalyst is used. The enamination may also be carried out in the absence of a solvent. In general, however, the enamination is carried out in an inert solvent, such as toluene, xylene, or ethanol, which, together with water, forms an azeotropic mixture. The enamination is preferably carried out with heating at 100 to 140°C while efficiently removing water produced by azeotropy to allow the reaction to proceed. In order to efficiently remove water being produced with the progress of the reaction, preferably, the reaction vessel should be devised. For example, a Dean-Stark trap device or a suitable dehydrating agent such as molecular sieves may be incorporated in the reactor to efficiently remove water. The reaction in toluene as the solvent is carried out under reflux with stirring for 2 to 5 hr. The completeness of the reaction can be monitored by the 4-alkyl-2-fluoroaniline derivative, for example, by high performance liquid chromatography. Since the reaction is an equilibrium reaction, the starting compound is not completely consumed. Preferably, the reaction is stopped when the reduction of the 4-alkyl-2-fluoroaniline derivative is substantially stopped. This is because, even when the reaction is further continued, an unfavorable reaction such as redecomposition of the produced enamine compound represented by formula (V) sometimes occurs leading to a lowered yield. Since the enamine compound thus obtained is unstable and is rapidly decomposed in silica gel, the isolation of the enamine compound by chromatography on silica gel is difficult. Isolation by distillation is preferred. In general, the enamine compound can be used in the subsequent cyclization reaction without isolation. In the present invention, when the 4-alkyl-2-fluoroaniline as the starting compound remains unreacted, in the cyclization reaction, there is a fear that the ketone site at the 4-position of the quinolinol compound represented by formula (VI) , which is a tautomer of the form represented by formula (I) (R4 = H) as the product, is reacted with the amino group of the 4-alkyl-2- fluoroaniline to form a by-product which significantly lowers the yield. To avoid this unfavorable reaction, in a preferred embodiment of the present invention, after the enamination reaction, a base, such as piperidine or triethylamine is added to the solution to make the solution steadily basic, and an acetylating agent such as acetic anhydride or acetyl chloride is then added to acetylate the amino group of 4-alkyl-2-fluoroaniline remaining unreacted. This suppresses the nucleophilicity of the amino group to suppress the formation of by-products. The protective group of the amino group is not limited to the acetyl group, and commonly used protective groups, for example, amide type protective groups such as pivaloyl and carbamate type protective groups such as benzyloxycarbonyl and t-butoxycarbonyl may be used. In step (ii), the subsequent cyclization reaction of the compound represented by formula (V) is carried out by heating. The reaction is allowed to proceed in a suitable solvent with heating preferably at the reflux temperature of the solvent. Examples of preferred solvents include diphenyl ether, xylene, polyphosphoric acid, durene, biphenyl, dimethylformamide, and dimethylsulfoxide. In a preferred embodiment of the present invention, when the enamine reaction and the subsequent cyclization reaction are carried out in a one-pot manner, diphenyl ether is added to the enamine reaction solution and the mixture is heated to the boiling point of diphenyl ether, 250°C, with removing toluene by evaporation. This reaction is a multicentered reaction of dienophile, which is an α,ß-unsaturated carbonyl moiety of enamine, with a benzene nucleus which thermally takes place within the molecule. This is a reaction generally called "Conrad-Limpach quinolinol synthesis." The reaction can be carried out in a xylene solvent at a temperature of 140°C to the reflux temperature of the solvent. Alternatively, it is carried out according to a method described in WO 00/47577. Specifically, by heating in polyphosphoric acid as a solvent to 160°C, enamination and cyclization reaction occur in one breath to give the quinolinol compound represented by formula (I) wherein R4 = H. The compound represented by formula (I), wherein R4 = H, is a tautomer and may also exist in the form represented by formula (VI): (Formula Removed) wherein R1, R2, and R3 are as defined above. The cyclization reaction can be carried out by mixing the enamine reaction mixture with a solvent and then heating the reaction system. Alternatiely, it is carried out by adding the enamine reaction mixture (from which toluene is already removed by evaporation), dropwise to a boiling solvent. The reaction proceeds rapidly and is completed when the temperature of the reaction solution reaches 245 to 250°C. The reaction solution is cooled to room temperature and is generally slowly stirred for about 12 hr for crystallization to give the compound represented by formula (I), wherein R4 = H, as a substantially single compound. In the present invention, if necessary, the hydroxyl group at the 4-position of the compound represented by formula (I), wherein R4 = H, is protected by a conventional method. The protective group of the hydroxyl group is not particularly limited. Specific examples of preferred protective groups include C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyloxy C1-6 alkylcarbonyl, C1-6 alkyl carbonyloxy C1-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, and C3-6 cycloalkyloxycarbonyl. The protective group may be introduced by a method commonly used for the protective group. For example, when acetyl is used as a protective group, a 2,3,6-trialkyl-8-fluoro-4-acetoxyquinoline derivative as the target compound can be substantially quantitatively prepared by adding a solution of the compound represented by formula (I) , wherein R4 = H, dissolved in pyridine and a sufficient quantity of acetic anhydride or acetyl chloride and allowing a reaction to proceed at 80°C for one hr. After the completion of the reaction, the compound represented by formula (I) can be provided as a pure crystal by evaporating the solvent and effecting recrystallization from n-hexane. When a carbonate protected compound is contemplated, the hydroxyl group at the 4-position of the compound represented by formula (I) , wherein R4 = H, is subjected to a proton abstraction reaction with a suitable base such as sodium hydride followed by reaction with a carbonate esterifying reagent typified by ethyl chloroformate. On the other hand, when an alkyl ether protected compound is contemplated, the compound represented by formula (I) , wherein R4 = H, is reacted with a base such as potassium carbonate and an alkylating agent typified by methyl iodide. [EXAMPLES] The following Examples further illustrate the present invention. Example 1: 4-t-Butyl-2-fluoroaniline A stirrer and 5.50 mL of 36% hydrochloric acid were placed in a glass reaction vessel, and zinc chloride (5.24 g, 0.0383 mol) was dissolved therein. 2-Fluoroaniline (10.0 mL, 0.104 mol) and t-butanol (9.90 mL, 0.104 mol) were added in that order while stirring the solution. This glass vessel was housed in a stainless steel pressure vessel, which was then hermetical sealed so as to prevent the leakage of the internal pressure. Thereafter, the contents of the vessel were heated to 190°C to allow a reaction to proceed with stirring. The initial pressure was about 5 atm. The reaction was continued for 72 hr. After satisfactory lowering in temperature was confirmed, the pressure vessel was opened. Ethyl acetate (200 mL) was added to the reaction mixture, followed by stirring to homogenize the whole mixture. After water (200 mL) was added thereto, the mixture was neutralized with sodium hydroxide to adjust the pH value to 9. A large amount of precipitated brown solid was filtered off. The organic layer was separated from the filtrate and was again washed with water. The organic layer was concentrated to give 16.9 g of a dark brown oily substance. This substance was quantitatively determined by an absolute calibration curve method using a standard sample as a reference. As a result, the yield was found to be 79.2%. EI-MS: m/z 170 (M+H)+ ; 1H NMR (CDC13) : δ 1.26 (9H, s, t-Bu) , 3.56 (br, NH2) , 6.74 (1H, t-like, J = 9.3 Hz, H6) , 6.95 (1H, ddd, J = 7.5, 2.1, 0.7 Hz, H5) , 7.94 (1H, dd, J = 13.4, 1.9 Hz, H3) . Example 2: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol In toluene (120 mL) , 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) was dissolved, and then ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) and p-toluenesulfonic acid monohydrate (50 mg) were added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device for 3 hr. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL), piperidine (2.0 mL), and acetic anhydride (1.0 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (4.82 g, yield 64.5%). FAB-MS: m/z 248 (M+H) + ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.34 (1H, dd, J = 12.9, 2.2 Hz, H3-aromatic) , 8.10 (1H, d, J = 1.5 Hz, H5-aromatic), 8.92 (1H, bs, NH). Example 3: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (EMA dropping method) In toluene (80 mL), 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol), was dissolved, and then p-toluenesulfonic acid monohydrate (50 mg) was added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device. A solution of ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) in toluene (20 mL) was added dropwise to the heated solution over a period of 2 hr. After the completion of the dropwise addition, the mixture was heated under reflux for additional 2 hr. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL), piperidine (2.0 mL) , and acetic anhydride (1.0 mL) were added in that order, and the mixture was then stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (5.17 g, yield 69.0%). Example 4: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol Polyphosphoric acid (10.8 g) was heated to 160°C. A mixture of 4-t-butyl-2-fluoroaniline (1.89 g, 11.3 mmol) with ethyl 2-methylacetoacetate (1.96 g, 13.5 mmol) was added dropwise thereto, and the mixture was stirred at that temperature for 3 hr. The reaction solution was allowed to cool, water (50 mL) was then added thereto. The mixture was extracted twice with ethyl acetate (50 rnL). The organic layers were combined and were washed with water. The solvent in the combined organic layer was removed by evaporation under the reduced pressure to give an oil as the residue. The oil was recrystallized from ethyl acetate-n-hexane to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol as white crystals (0.97 g, yield 34.7%). FAB-MS: m/z 248 (M+H)+ ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu) , 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.33 (1H, dd, J = 12.9, 2.2 Hz, H3-aromatic) , 8.10 (1H, d, J = 1.5 Hz, H5-aromatic), 8.93 (1H, bs, NH). Example 5: 6-t-Butyl-8-fluoro-2,3-dimethyl-4- quinolinol In toluene (120 mL) , 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) was dissolved, and then ethyl 2- methylacetoacetate (5.75 mL, 40.6 mmol) and p- toluenesulfonic acid monohydrate (50 mg) were added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device for 3 hr. The reaction solution was allowed to cool and was then poured into a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate (50 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solid was filtered off. The filtrate was then concentrated to give 5.99 g of a brown oil. The oil was dissolved in xylene (155 mL) to prepare a solution which was then heated at 160°C with stirring for one hr. After the reaction solution was allowed to cool, the solvent was then removed by evaporation. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 1 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (845 mg, yield 11.3%). FAB-MS: m/z 248 (M+H) + ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.33 (1H, dd, J = 12.9, 2.1 Hz, H3-aromatic) , 8.11 (1H, d, J = 1.5 Hz, Hs-aromatic), 8.92 (1H, bs, NH). Example 6: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.93 g, 15.9 mmol) prepared in Example 5 was dissolved in pyridine (13 mL, 159 mmol) . Acetic anhydride (15 mL, 159 mmol) was added thereto, and the mixture was heated at 80°C with stirring for one hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure to give 4.90 g of an oil as the residue. The oil was dissolved in n-hexane (4.5 mL) to prepare a solution. After crystal seeds were added to the solution, the mixture was gently stirred at room temperature for 12 hr to give a large amount of white crystals. The crystals were collected by filtration, were rapidly washed with cold n-hexane (4.5 mL) , and were dried at room temperature for 12 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline as white crystals (2.53 g, yield 90.1%). FAB-MS: m/z 290 (M+H) + ; 1H NMR (CDC13) : δ 1.38 (9H, s, t-Bu), 2.26 (3H, s, acetyl), 2.52 (3H, s, CH3) , 2.75 (3H, s, CH3) , 7.37 (1H, d, J = 1.9 Hz, H5-aromatic) , 7.43 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic) . Example 7: 4-t-Amyl-2-fluoroaniline A stirrer and 5.50 mL of 36% hydrochloric acid were added to a glass reaction vessel, and zinc chloride (5.24 g, 0.0383 mol) was dissolved therein. 2- Fluoroaniline (10.0 mL, 0.104 mol) and t-amyl alcohol (11.4 mL, 0.104 mol) were added in that order while stirring the solution. This glass vessel was housed in a stainless steel pressure vessel, which was hermetical sealed so as to prevent the leakage of the internal pressure. Thereafter, the vessel were heated to 190°C to allow a reaction to proceed with stirring. The initial pressure was about 5 atm. The reaction was continued for 72 hr. After satisfactory lowering in temperature was confirmed, the pressure vessel was opened. Ethyl acetate (200 mL) was added to the reaction mixture, followed by stirring to homogenize the whole mixture. After water (200 mL) was added thereto, the mixture was neutralized with sodium hydroxide to adjust the pH value to 9. A large amount of precipitated brown solid was filtered off. The organic layer was separated from the filtrate and was again washed with water. The organic layer was concentrated to give 17.5 g of a dark brown oily substance. This oily substance was purified by column chromatography on silica gel (n-hexane-ethyl acetate = 10 : 1) to give 4-t-amyl-2-fluoroaniline (9.22 g, yield 49.0%). The structure was confirmed by sampling a part of the product and acetylating the amino group to give an acetyl compound. 4-t-Amyl-2-fluoro-N-acetylaniline EI-MS: m/z 224 (M+H) + ; 1H NMR (CDC13) : δ 0.67 (3H, t, J = 7.3 Hz, amyl-CH2CH3) , 1.25 (6H, s, amyl-CH3) , 1.60 (2H, q, J = 7.5 Hz, amyl-CH2CH3) , 2.21 (3H, s, acetyl- CH3) , 7.03 (1H, dd, J = 17.1, 1.9 Hz, H3), 7.07 (1H, dd, J = 8.3, 2.0 Hz, H5) , 7.29 (1H, brs, NH), 8.16 (1H, dd, J = 8.5, 8.5 Hz, H6) . Example 8: 6-t-Amyl-8-fluoro-2,3-dimethyl-4- quinolinol In toluene (15 mL) , 4-t-amyl-2-fluoroaniline (2.00 g, 11.1 mmol) was dissolved and then ethyl 2-methylacetoacetate (1.56 mL, 11.1 mmol) and a boron trifluoride diethyl ether complex (50 mL) were added. The mixture was heated under reflux for 6 hr in a reactor having a flask fully equipped on its top with a reflux tube packed with molecular sieves. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL) , piperidine (0.7 mL) , and acetic anhydride (0.3 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated brown crystal was collected by filtration and was washed with n-hexane. The brown crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-amyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.18 g, yield 41.0%). FAB-MS: m/z 263 (M+H) + ; 1H NMR (CDC13) : δ 0.64 (3H, t, J = 7.6 Hz, amyl-CH2CH3) , 1.31 (6H, s, amyl-CH3) , 1.65 (2H, q, J = 7.3 Hz, amyl-CH2CH3) , 2.14 (3H, s, 2-CH3) , 2.48 (3H, s, 3-CH3) , 2.52 (3H, s, CH3) , 7.29 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic) , 8.05 (1H, d, J = 1.2 Hz, H5-aromatic), 8.51 (1H, bs, NH). Example 9: 6-t-Amyl-8-f luoro-2 ,3-dimethyl-4- acetoxyquinoline 6-t-Amyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.10 g, 4.21 mmol) prepared in Example 8 was dissolved in pyridine (3.4 mL, 42.1 mmol). Acetic anhydride (6.0 mL, 63.6 mmol) was added thereto, and the mixture was heated at 80°C with stirring for 2 hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure. Ethyl acetate (100 mL) was added to the residue, followed by washing with saturated brine, a 10% aqueous citric acid solution, and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The oil as the residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate =8:1) to give 6-t-amyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline (1.22 g, yield 95.9%). FAB-MS: m/z 304 (M+H) + ; 1H NMR (CDC13): δ 0.68 (3H, t, J = 7.3 Hz, amyl-CHzCHa) , 1.34 (6H, s, amyl-CH3) , 1.69 (2H, q, J = 7.6 Hz, amyl-CH2CH3) , 2.26 (3H, s, acetyl-CH3) , 2.52 (3H, s, 2-CH3) , 2.75 (3H, s, 3-CH3) , 7.32 (1H, d, J = 1.7 Hz, H5-aromatic) , 7.37 (1H, dd, J = 12.9, 2.0 Hz, H7-aromatic) . Example 10: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.00 g, 4.05 mmol) prepared in Example 5 was dissolved in dry tetrahydrofuran (20 mL) . To the solution was added 60% sodium hydride (160 mg) in an argon atmosphere under ice cooling. The temperature of the mixture was returned to room temperature before the mixture was stirred for one hr until the evolution of gas stopped. The mixture was again cooled in an ice bath and was then added dropwise to a solution of methyl chloroformate (376 mL, 4.86 mmol) in dry tetrahydrofuran (5 mL) , and stirring was continued at room temperature for additional 3 hr. The reaction solution was poured into ice water, followed by extraction with ethyl acetate (50 mL) . The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 3 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline (784 mg, yield 63.5%). FAB-MS: m/z 306 (M+H) + ; 1H NMR (CDC13): δ 1.38 (9H, s, t-Bu) , 2.32 (3H, s, 2-CH3) , 2.76 (3H, s, 3-CH3) , 4.00 (3H, s, OCH3) , 7.42 (1H, d, J = 1.9 Hz, H5-aromatic) , 7.45 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic). Example 11: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.00 g, 4.05 mmol) prepared in Example 5 was dissolved in dry tetrahydrofuran (20 mL) . To the solution was added 60% sodium hydride (320 mg) in an argon atmosphere under ice cooling. The temperature of the mixture was returned to room temperature before the mixture was stirred for one hr until the evolution of gas stopped. The mixture was again cooled in an ice bath and was then added dropwise to a solution of ethoxymethyl chloride (761 mL, 8.10 mmol) in dry tetrahydrofuran (5 mL) , and stirring was continued at room temperature for additional 6 hr. The reaction solution was poured into ice water, followed by extraction with ethyl acetate (50 mL) . The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 3 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline (145 mg, yield 11.7%). FAB-MS: m/z 306 (M+H) + ; 1H NMR (CDCl3) : δ 1.21 (3H, t, J = 7.1 Hz), 1.36 (9H, s, t-Bu), 2.17 (3H, s, 2-CH3) , 2.53 (3H, s, 3-CH3) , 3.51 (2H, q, J = 7.1 Hz), 5.53 (2H, s) , 7.37 (1H, dd, J = 17.3, 2.4 Hz, H7-aromatic) , 8.21 (1H, d, J = 2.4 Hz, H5-aromatic) . Example 12: 4-Cyclohexyl-2-fluoroaniline A stirrer and 5.50 mL of 36% hydrochloric acid were added to a glass reaction vessel, and zinc chloride (5.24 g, 0.0383 mol) was dissolved therein. 2-Fluoroaniline (10.0 mL, 0.104 mol) and cyclohexanol (10.4 mL, 0.104 mol) were added in that order while stirring the solution. This glass vessel was housed in a stainless steel pressure vessel, which was then hermetical sealed so as to prevent the leakage of the internal pressure. Thereafter, the vessel were heated to 190°C to allow a reaction to proceed with stirring. The initial pressure was about 5 atm. The reaction was continued for 72 hr. After satisfactory lowering in temperature was confirmed, the pressure vessel was opened. Ethyl acetate (200 mL) was added to the reaction mixture, followed by stirring to homogenize the whole mixture. After water (200 mL) was added thereto, the mixture was neutralized with sodium hydroxide to adjust the pH value to 9. A large amount of precipitated brown solid was filtered off. The organic layer was separated from the filtrate and was again washed with water. The organic layer was concentrated to give 15.1 g of a dark brown oily substance. This oily substance was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 1 : 5) to give 4-cyclohexyl-2-fluoroaniline (6.63 g, yield 33.0%). EI-MS: m/z 194 (M+H) + ; 1H NMR (CDC13): δ 1.34 (6H, m) , 1.82 (4H, m) , 2.39 (1H, m) , 3.55 2H, (bs, NH2) , 6.73 (1H, dd, J = 17.1, 8.1 Hz), 6.78 (1H, dd, J = 8.0, 1.9 Hz), 6.84 (1H, dd, J = 12.4, 1.7 Hz). Example 13: 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol In toluene (100 mL), 4-cyclohexyl-2-fluoroaniline (5.00 g, 25.9 mmol) was dissolved, and then ethyl 2- methylacetoacetate (4.77 mL, 33.7 mmol) and p- toluenesulfonic acid monohydrate (50 mg) were added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device for 3 hr. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL) , piperidine (2.0 mL) , and acetic anhydride (1.0 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.56 g, yield 50.4%). FAB-MS: m/z 274 (M+H) + ; 1H NMR (d6-DMSO) : δ 1.40 (6H, m) , 1.60 (4H, m) , 2.41 (3H, s) , 7.41 (1H, d, J = 12.9), 7.68 (1H, s), 11.25 (1H, s). Example 14: 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.00 g, 11.0 mmol) prepared in Example 5 was dissolved in pyridine (8.70 mL, 110 mmol). After acetic anhydride (11.2 mL, 110 mmol) was added thereto, the mixture was heated at 80°C with stirring for 2 hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure. Ethyl acetate (100 mL) was added to the residue, followed by washing with saturated brine, a 10% aqueous citric acid solution, and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The oil as the residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate = 8 : 1) to give 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline (3.17 g, yield 91.2%). FAB-MS: m/z 317 (M+H) + ; 1H NMR (CDC13): δ 1.27 (2H, m) , 1.45 (4H, m) , 1.90 (4H, m) , 2.26 (3H, s, acetyl-CH3) , 2.25 (3H, s) , 2.52 (3H, s) , 2.75 (3H, s), 2.64 (1H, m) , 7.25 (2H, m). We claim 1. A process for producing a 2,3,6-trialkyl-8-fiuoro-4-quinoline derivative represented by formula (I) or a salt thereof: (Formula Removed) wherein R1 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl; R2 represents optionally substituted C1-10 alkyl or C3-6 cydoalkyl; R3 represents optionally substituted C1-10 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl; and R4 represents a hydrogen atom or a protective group of hydroxyl, said process comprising the steps of: (i) alkylating a compound represented by formula (II): (Formula Removed) with R1-X (where R1 is as defined above and X represents hydroxyl or a halogen atom) or R1 (where R1 is an olefin having the same carbon atoms as R1) in the presence of zinc chloride at a temperature of 150 to 200°C under pressure of 4 to 10 atm, to give a 4-alkyl-2-fluoroaniline derivative represented by formula (III) (Formula Removed) wherein R1 is as defined above; and (ii) reacting the compound represented by formula (III) with an α-alkyl-ß-ketoester represented by formula (IV) : (Formula Removed) wherein R2 and R3 are as defined above; and R5 represents C1-4 alkyl, to give an enamine intermediate represented by formula (V) : (Formula Removed) wherein R1, R2, R3, and R5 are as defined above, cyclizing the enamine intermediate to give the compound represented by formula (I) , wherein R4 represents a hydrogen atom, and optionally protecting hydroxyl at the 4-position with a protective group. 2. The process as claimed in claim 1, wherein the compound represented by formula (IV) is ethyl 2- methylacetoacetate. 3. The process as claimed in claim 1, wherein, in the compound represented by formula (I), R1 represents t-butyl, R2 and R3 represent methyl, and R4 represents a hydrogen atom. 4. The process as claimed in claim 1, wherein, in the compound represented by formula (I), R1 represents t-butyl, R2 and R3 represent methyl, and R4 represents acetyl. 5. The process as claimed in claim 1, wherein the compound represented by formula (II) is a hydrochloric acid addition salt. 6. The process as claimed in claim 1, wherein the protective group of hydroxyl represented by R4 is C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyloxy C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, or C3-6 cycloalkyloxycarbonyl. 7. The process as claimed in claim 1, wherein step (i) and step (ii) are carried out in a one-pot manner.

Full Text

PROCESS FOR PRODUCING 2,3,6-TRIALKYL-8-FLUORO-4-QUINOLINE DERIVATIVES
[BACKGROUND OF THE INVENTION] Field of the Invention
The present invention relates to a process for producing 2,3,6-trialkyl-8-fluoro-4-quinoline derivatives or pharmaceutically acceptable salts thereof which are useful as agricultural chemicals. Background Art
2,3,6-Trialkyl-8-fluoro-4-quinoline derivatives have a control activity against agricultural and horiticultural diseases as described in WO 01/92231. This publication discloses a production process of the compounds according to the following reaction scheme.
(Scheme Removed)
In the above process, t-butylaniline as a starting
compound is firstly protected at its amino group with a
suitable protective group, and then reacts with
SELECTFLUOR (1-(chloromethyl)-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetra-fluoroborate)) as a fluorinating reagent to introduce a fluorine atom into a position adjacent to the amino group. The protective group is removed to give 4-t-butyl-2-fluoroaniline as an intermediate. The intermediate is then enaminated with ethyl 2-methylacetoacetate to give an enamine compound which is then heated for cyclization to give a quinolinol compound. Finally, a hydroxyl group in the quinolinol compound is acetylated to give the target compound. In this process, an enamination-cyclization process is known as Conrad-Limpach synthesis. This production process, however, disadvantageously requires 6 steps which complicate the production process. Further, the yield of the product in the Conrad-Limpach synthesis is so low that the overall yield is low and about 4%. Further, in this process, a fluorinating reagent, which is expensive, typified by SELECTFLUOR or the like should be used. Since, this fluorinating reagent is highly irritant and corrosive, the use of the fluorinating reagent in a production process on a commercial scale is not favorable in cost as well as in efficiency.
There are only a few general-purpose industrial production processes which can selectively introduce a fluorine atom into a target position of the aromatic ring. Examples thereof include dediazofluorination with sodium borofluoride and a Balz-Schiemann reaction which involves diazotization of an aromatic amino group. These processes, however, suffer from many industrial problems because the target compound is produced through an aromatic tetrafluoroborate which is unstable and highly toxic. The fluorination of the 2-position of a 4-alkylaniline disclosed in WO 01/92231 requires the use of a fluorinating reagent, which is generally highly irritant and corrosive, typified by Selectfluor. When this fluorinating reagent is used in a large amount, the surface of a metallic or glass reactor is corroded. This requires the use of a special reactor. Thus, the fluorinating reagent would be difficult to handle on a commercial scale.
Accordingly, the development of a production process, which can provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative without the use of any fluorinating reagent and with high efficiency, has been desired.
[SUMMARY OF THE INVENTION]
The present inventors have now established a production process which can provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative basically in two steps using 2-fluoroaniline in which fluorine is already introduced thereinto, which is inexpensive, as a starting compound safely and in a high yield.
Accordingly, an object of the present invention is to provide a production process which can safely provide a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative in a high yield.
According to one aspect of the present invention, there is provided a process for producing a 2,3,6-
trialkyl-8-fluoro-4-quinoline derivative represented by formula (I) or a salt thereof:
(Formula Removed)
wherein
R1 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl;
R2 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl;
R3 represents optionally substituted C1-10 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl; and
R4 represents a hydrogen atom or a protective group of hydroxyl,
said process comprising the steps of:
(i) alkylating a compound represented by formula (ID :
(Formula Removed)
with R1-X (where R1 is as defined above and X represents hydroxyl or a halogen atom) or R1' (where R1' is an olefin having the same carbon atoms as R1) in the presence of zinc chloride under pressure, to give a 4-alkyl-2-fluoroaniline derivative represented by formula (III):
(Formula Removed)
wherein R1 is as defined above; and
(ii) reacting the compound represented by formula
(III) with an α-alkyl-ß-ketoester represented by formula
(IV) :
(Formula Removed)
wherein R2 and R3 are as defined above; and R5 represents
C1-4 alkyl,
to give an enamine intermediate represented by formula
(V) :
(Formula Removed)
wherein R1, R2, R3, and R5 are as defined above, cyclizing the enamine intermediate to give the compound represented by formula (I) , wherein R4 represents a hydrogen atom, and optionally protecting hydroxyl at the 4-position with a protective group.
[DETAILED DESCRIPTION OF THE INVENTION] Definition
In the present specification, alkyl as a group or a part of a group may be straight chain or branched chain. The term "halogen atom" as used herein means a fluorine, chlorine, bromine, or iodine atom. Compounds represented by formula (I)
Compounds to be produced by the production process according to the present invention are 2,3,6-trialkyl-8-fluoro-4-quinoline derivatives represented by formula (I) . In formula (I) , R1 and R2 each independently represent C1-10 alkyl, preferably C1-6 alkyl, or C3-6 cycloalkyl. This alkyl group is optionally substituted by one or more substituents, which includes halogen atoms, hydroxyl, and C1-4 alkoxy.
Further, in formula (I) , R3 represents C1-10 alkyl, preferably C1-6 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl. The C1-10 alkyl group is optionally substituted, and examples of preferred substituents include substituents as described above for R1 and R2.
The compounds represented by formula (I) may form salts. Examples of the salts include: alkali metal salts, alkaline earth metal salts, hydrochloric acid salts, sulfuric acid salts, citric acid salts, oxalic acid salts, p-toluenesulfonic acid salts, and methanesulfonic acid salts.
Production of compounds represented by formula (I) Step (i)
Step (i) in the present invention is an alkylation reaction, which can be carried out according to the description of Japanese Patent Laid-Open No. 944/1983. Specifically, a fluoroaniline hydrochloride and an alkylating agent are subjected to a thermal reaction under pressure in the presence of an acid catalyst preferably in a pressure vessel to cause a Friedel-
Crafts reaction.
The alkylating agent is a compound represented by formula R1-X, wherein R1 is as defined in formula (I) and X represents hydroxyl or a halogen atom, or an olefin having the same carbon atoms as R1. In the case of R1-X (X = OH) , the utilization of a secondary alcohol or tertiary alcohol is preferred. The amount of the alkylating agent used may be properly determined. Preferably, however, the amount of the alkylating agent used is about 1 to 10 equivalents, more preferably about 1 to 5 equivalents, based on the compound represented by formula (II).
A preferred catalyst in the Friedel-Crafts reaction is a combination of a protonic acid typified by hydrochloric acid, sulfuric acid or the like with a Lewis acid typified by zinc chloride. The use of zinc chloride is more preferred. While the amount of the catalyst used is not limited, the amount of the catalyst used is preferably in the range of 0.25 to 0.5 equivalent.
The reaction temperature is preferably 150°C or above from the viewpoint of allowing the reaction to proceed efficiently. The reaction temperature is more preferably in the range of 150 to 200°C.
In the process according to the present invention, pressure is applied to increase the rate of the alkylation reaction and to enhance regioselectivity of alkylation to the 4-position of the aromatic ring. The pressure is not less than 3 atm from the practical point of view, more preferably in the range of 4 to 10 atm.
Step (i) can be generally carried out in the absence of a solvent or alternatively can be carried out in an inert solvent such as carbon disulfide or nitrobenzyl. The reaction vessel is preferably a pressure-resistant glass vessel or stainless steel vessel. Since the surface of the stainless steel is
corroded in an acidic atmosphere, the use of a stainless steel vessel, in which a glass vessel has been hermetically sealed, or a tantalum-clad stainless steel vessel is preferred.
The step (i) gives a compound represented by formula (III). The compound represented by formula (III) may be purified by taking advantage of a difference in lipophilicity between the product and the starting compound. Specifically, the product may be extracted with a suitable organic solvent such as hexane or ethyl acetate to give the compound represented by formula (III) while allowing only the starting compound having higher water solubility than the product to selectively stay in the aqueous layer. The compound represented by formula (III) can also be isolated and purified by distillation.
In the present invention, step (ii), subsequent to step (i), involves enamination and then cyclization. The enamination and the cyclization may also be carried out in a one-pot manner afer step (i) . Alternatively, after enamination, post-treatment is carried out to take out the enamine compound (V) from the reaction system and is then subjected to cyclization to complete step (ii).
It appears that the compound represented by formula (V) is a tautomer and can exist as a compound represented by formula (V) :
(Formula Removed)
wherein R1, R2, R3, and R5 are as defined above. Step (ii)

In step (ii), enamination is first carried out by reacting the compound represented by formula (III) with a compound represented by formula (IV) . R2 and R3 of the compound represented by formula (IV) correspond to those in the compound represented by formula (I) . Therefore, the structure of the compound represented by formula (IV) may be properly determined by taking into consideration the structure of the target compound, i.e., the compound represented by formula (I). R5 represents C1-4 alkyl, preferably methyl or ethyl. Specific examples of preferred compounds represented by formula (IV) include methyl 2-methylacetoacetate, ethyl 2-methylacetoacetate, ethyl 2-benzyl acetoacetate, ethyl 2-ethylacetoacetate, ethyl 2-isopropylacetoacetate, and ethyl 2-allylacetoacetate. The amount of the α-alkyl-ß-ketoester represented by formula (IV) used may be properly determined by taking into consideration, for example, reaction conditions. Preferably, however, the amount of the α-alkyl-ß-ketoester represented by formula (IV) used is about 0.8 to 2.0 equivalents, more preferably about 1.0 to 1.5 equivalents, most preferably about 1.2 to 1.3 equivalents.
The reaction is preferably carried out in the presence of an acid or base catalyst. The use of the acid catalyst is more preferred. Acid catalysts include protonic acids, such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and Lewis acids such as boron trifluoride diethyl ether complex. Basic catalysts include piperidine. When piperidine is used, the use of an ethanol solvent is preferred. In this case, the reaction time is generally longer than that in the case where the acid catalyst is used.
The enamination may also be carried out in the absence of a solvent. In general, however, the enamination is carried out in an inert solvent, such as toluene, xylene, or ethanol, which, together with water,
forms an azeotropic mixture. The enamination is preferably carried out with heating at 100 to 140°C while efficiently removing water produced by azeotropy to allow the reaction to proceed. In order to efficiently remove water being produced with the progress of the reaction, preferably, the reaction vessel should be devised. For example, a Dean-Stark trap device or a suitable dehydrating agent such as molecular sieves may be incorporated in the reactor to efficiently remove water.
The reaction in toluene as the solvent is carried out under reflux with stirring for 2 to 5 hr. The completeness of the reaction can be monitored by the 4-alkyl-2-fluoroaniline derivative, for example, by high performance liquid chromatography. Since the reaction is an equilibrium reaction, the starting compound is not completely consumed. Preferably, the reaction is stopped when the reduction of the 4-alkyl-2-fluoroaniline derivative is substantially stopped. This is because, even when the reaction is further continued, an unfavorable reaction such as redecomposition of the produced enamine compound represented by formula (V) sometimes occurs leading to a lowered yield.
Since the enamine compound thus obtained is unstable and is rapidly decomposed in silica gel, the isolation of the enamine compound by chromatography on silica gel is difficult. Isolation by distillation is preferred. In general, the enamine compound can be used in the subsequent cyclization reaction without isolation.
In the present invention, when the 4-alkyl-2-fluoroaniline as the starting compound remains unreacted, in the cyclization reaction, there is a fear that the ketone site at the 4-position of the quinolinol compound represented by formula (VI) , which is a tautomer of the form represented by formula (I) (R4 = H) as the product, is reacted with the amino group of the 4-alkyl-2-
fluoroaniline to form a by-product which significantly lowers the yield. To avoid this unfavorable reaction, in a preferred embodiment of the present invention, after the enamination reaction, a base, such as piperidine or triethylamine is added to the solution to make the solution steadily basic, and an acetylating agent such as acetic anhydride or acetyl chloride is then added to acetylate the amino group of 4-alkyl-2-fluoroaniline remaining unreacted. This suppresses the nucleophilicity of the amino group to suppress the formation of by-products. The protective group of the amino group is not limited to the acetyl group, and commonly used protective groups, for example, amide type protective groups such as pivaloyl and carbamate type protective groups such as benzyloxycarbonyl and t-butoxycarbonyl may be used.
In step (ii), the subsequent cyclization reaction of the compound represented by formula (V) is carried out by heating. The reaction is allowed to proceed in a suitable solvent with heating preferably at the reflux temperature of the solvent. Examples of preferred solvents include diphenyl ether, xylene, polyphosphoric acid, durene, biphenyl, dimethylformamide, and dimethylsulfoxide.
In a preferred embodiment of the present invention, when the enamine reaction and the subsequent cyclization reaction are carried out in a one-pot manner, diphenyl ether is added to the enamine reaction solution and the mixture is heated to the boiling point of diphenyl ether, 250°C, with removing toluene by evaporation. This reaction is a multicentered reaction of dienophile, which is an α,ß-unsaturated carbonyl moiety of enamine, with a benzene nucleus which thermally takes place within the molecule. This is a reaction generally called "Conrad-Limpach quinolinol synthesis." The reaction can be carried out in a xylene solvent at a temperature of
140°C to the reflux temperature of the solvent. Alternatively, it is carried out according to a method described in WO 00/47577. Specifically, by heating in polyphosphoric acid as a solvent to 160°C, enamination and cyclization reaction occur in one breath to give the quinolinol compound represented by formula (I) wherein R4 = H.
The compound represented by formula (I), wherein R4 = H, is a tautomer and may also exist in the form represented by formula (VI):
(Formula Removed)
wherein R1, R2, and R3 are as defined above.
The cyclization reaction can be carried out by mixing the enamine reaction mixture with a solvent and then heating the reaction system. Alternatiely, it is carried out by adding the enamine reaction mixture (from which toluene is already removed by evaporation), dropwise to a boiling solvent. The reaction proceeds rapidly and is completed when the temperature of the reaction solution reaches 245 to 250°C. The reaction solution is cooled to room temperature and is generally slowly stirred for about 12 hr for crystallization to give the compound represented by formula (I), wherein R4 = H, as a substantially single compound.
In the present invention, if necessary, the hydroxyl group at the 4-position of the compound represented by formula (I), wherein R4 = H, is protected by a conventional method. The protective group of the hydroxyl group is not particularly limited. Specific
examples of preferred protective groups include C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyloxy C1-6 alkylcarbonyl, C1-6 alkyl carbonyloxy C1-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, and C3-6 cycloalkyloxycarbonyl. The protective group may be introduced by a method commonly used for the protective group. For example, when acetyl is used as a protective group, a 2,3,6-trialkyl-8-fluoro-4-acetoxyquinoline derivative as the target compound can be substantially quantitatively prepared by adding a solution of the compound represented by formula (I) , wherein R4 = H, dissolved in pyridine and a sufficient quantity of acetic anhydride or acetyl chloride and allowing a reaction to proceed at 80°C for one hr.
After the completion of the reaction, the compound represented by formula (I) can be provided as a pure crystal by evaporating the solvent and effecting recrystallization from n-hexane. When a carbonate protected compound is contemplated, the hydroxyl group at the 4-position of the compound represented by formula (I) , wherein R4 = H, is subjected to a proton abstraction reaction with a suitable base such as sodium hydride followed by reaction with a carbonate esterifying reagent typified by ethyl chloroformate. On the other hand, when an alkyl ether protected compound is contemplated, the compound represented by formula (I) , wherein R4 = H, is reacted with a base such as potassium carbonate and an alkylating agent typified by methyl iodide.
[EXAMPLES]
The following Examples further illustrate the present invention.
Example 1: 4-t-Butyl-2-fluoroaniline
A stirrer and 5.50 mL of 36% hydrochloric acid were placed in a glass reaction vessel, and zinc chloride
(5.24 g, 0.0383 mol) was dissolved therein. 2-Fluoroaniline (10.0 mL, 0.104 mol) and t-butanol (9.90 mL, 0.104 mol) were added in that order while stirring the solution. This glass vessel was housed in a stainless steel pressure vessel, which was then hermetical sealed so as to prevent the leakage of the internal pressure. Thereafter, the contents of the vessel were heated to 190°C to allow a reaction to proceed with stirring. The initial pressure was about 5 atm. The reaction was continued for 72 hr. After satisfactory lowering in temperature was confirmed, the pressure vessel was opened. Ethyl acetate (200 mL) was added to the reaction mixture, followed by stirring to homogenize the whole mixture. After water (200 mL) was added thereto, the mixture was neutralized with sodium hydroxide to adjust the pH value to 9. A large amount of precipitated brown solid was filtered off. The organic layer was separated from the filtrate and was again washed with water. The organic layer was concentrated to give 16.9 g of a dark brown oily substance. This substance was quantitatively determined by an absolute calibration curve method using a standard sample as a reference. As a result, the yield was found to be 79.2%. EI-MS: m/z 170 (M+H)+ ; 1H NMR (CDC13) : δ 1.26 (9H, s, t-Bu) , 3.56 (br, NH2) , 6.74 (1H, t-like, J = 9.3 Hz, H6) , 6.95 (1H, ddd, J = 7.5, 2.1, 0.7 Hz, H5) , 7.94 (1H, dd, J = 13.4, 1.9 Hz, H3) .
Example 2: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol
In toluene (120 mL) , 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) was dissolved, and then ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) and p-toluenesulfonic acid monohydrate (50 mg) were added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device for 3 hr. The reaction solution was cooled to room temperature. Diphenyl ether
(50 mL), piperidine (2.0 mL), and acetic anhydride (1.0 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (4.82 g, yield 64.5%).
FAB-MS: m/z 248 (M+H) + ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.34 (1H, dd, J = 12.9, 2.2 Hz, H3-aromatic) , 8.10 (1H, d, J = 1.5 Hz, H5-aromatic), 8.92 (1H, bs, NH).
Example 3: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (EMA dropping method)
In toluene (80 mL), 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol), was dissolved, and then p-toluenesulfonic acid monohydrate (50 mg) was added. The mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device. A solution of ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) in toluene (20 mL) was added dropwise to the heated solution over a period of 2 hr. After the completion of the dropwise addition, the mixture was heated under reflux for additional 2 hr. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL), piperidine (2.0 mL) , and acetic anhydride (1.0 mL) were added in that order, and the mixture was then stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at
that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (5.17 g, yield 69.0%).
Example 4: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol
Polyphosphoric acid (10.8 g) was heated to 160°C. A mixture of 4-t-butyl-2-fluoroaniline (1.89 g, 11.3 mmol) with ethyl 2-methylacetoacetate (1.96 g, 13.5 mmol) was added dropwise thereto, and the mixture was stirred at that temperature for 3 hr. The reaction solution was allowed to cool, water (50 mL) was then added thereto. The mixture was extracted twice with ethyl acetate (50 rnL). The organic layers were combined and were washed with water. The solvent in the combined organic layer was removed by evaporation under the reduced pressure to give an oil as the residue. The oil was recrystallized from ethyl acetate-n-hexane to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol as white crystals (0.97 g, yield 34.7%).
FAB-MS: m/z 248 (M+H)+ ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu) , 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.33 (1H, dd, J = 12.9, 2.2 Hz, H3-aromatic) , 8.10 (1H, d, J = 1.5 Hz, H5-aromatic), 8.93 (1H, bs, NH).
Example 5: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-
quinolinol
In toluene (120 mL) , 4-t-butyl-2-fluoroaniline
(5.06 g, 30.3 mmol) was dissolved, and then ethyl 2-
methylacetoacetate (5.75 mL, 40.6 mmol) and p-
toluenesulfonic acid monohydrate (50 mg) were added. The
mixture was heated under reflux in a reactor fully
equipped with a Dean-Stark device for 3 hr. The reaction solution was allowed to cool and was then poured into a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate (50 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solid was filtered off. The filtrate was then concentrated to give 5.99 g of a brown oil. The oil was dissolved in xylene (155 mL) to prepare a solution which was then heated at 160°C with stirring for one hr. After the reaction solution was allowed to cool, the solvent was then removed by evaporation. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 1 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (845 mg, yield 11.3%).
FAB-MS: m/z 248 (M+H) + ; 1H NMR (CDC13) : δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH3) , 2.52 (3H, s, CH3) , 7.33 (1H, dd, J = 12.9, 2.1 Hz, H3-aromatic) , 8.11 (1H, d, J = 1.5 Hz, Hs-aromatic), 8.92 (1H, bs, NH).
Example 6: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline
6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.93 g, 15.9 mmol) prepared in Example 5 was dissolved in pyridine (13 mL, 159 mmol) . Acetic anhydride (15 mL, 159 mmol) was added thereto, and the mixture was heated at 80°C with stirring for one hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure to give 4.90 g of an oil as the residue. The oil was dissolved in n-hexane (4.5 mL) to prepare a solution. After crystal seeds were added to the solution, the mixture was gently stirred at room temperature for 12 hr to give a large amount of white crystals. The crystals were collected by filtration, were rapidly washed with cold n-hexane (4.5 mL) , and were dried at room temperature for 12 hr to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline as white crystals (2.53 g, yield 90.1%).
FAB-MS: m/z 290 (M+H) + ; 1H NMR (CDC13) : δ 1.38 (9H, s, t-Bu), 2.26 (3H, s, acetyl), 2.52 (3H, s, CH3) , 2.75 (3H, s, CH3) , 7.37 (1H, d, J = 1.9 Hz, H5-aromatic) , 7.43 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic) .
Example 7: 4-t-Amyl-2-fluoroaniline
A stirrer and 5.50 mL of 36% hydrochloric acid were
added to a glass reaction vessel, and zinc chloride
(5.24 g, 0.0383 mol) was dissolved therein. 2-
Fluoroaniline (10.0 mL, 0.104 mol) and t-amyl alcohol
(11.4 mL, 0.104 mol) were added in that order while
stirring the solution. This glass vessel was housed in a
stainless steel pressure vessel, which was hermetical
sealed so as to prevent the leakage of the internal
pressure. Thereafter, the vessel were heated to 190°C to
allow a reaction to proceed with stirring. The initial
pressure was about 5 atm. The reaction was continued for
72 hr. After satisfactory lowering in temperature was
confirmed, the pressure vessel was opened. Ethyl acetate
(200 mL) was added to the reaction mixture, followed by
stirring to homogenize the whole mixture. After water
(200 mL) was added thereto, the mixture was neutralized
with sodium hydroxide to adjust the pH value to 9. A
large amount of precipitated brown solid was filtered
off. The organic layer was separated from the filtrate
and was again washed with water. The organic layer was
concentrated to give 17.5 g of a dark brown oily
substance. This oily substance was purified by column
chromatography on silica gel (n-hexane-ethyl acetate =
10 : 1) to give 4-t-amyl-2-fluoroaniline (9.22 g, yield
49.0%). The structure was confirmed by sampling a part
of the product and acetylating the amino group to give
an acetyl compound.
4-t-Amyl-2-fluoro-N-acetylaniline
EI-MS: m/z 224 (M+H) + ; 1H NMR (CDC13) : δ 0.67 (3H, t, J = 7.3 Hz, amyl-CH2CH3) , 1.25 (6H, s, amyl-CH3) , 1.60 (2H, q, J = 7.5 Hz, amyl-CH2CH3) , 2.21 (3H, s, acetyl-
CH3) , 7.03 (1H, dd, J = 17.1, 1.9 Hz, H3), 7.07 (1H, dd, J = 8.3, 2.0 Hz, H5) , 7.29 (1H, brs, NH), 8.16 (1H, dd, J = 8.5, 8.5 Hz, H6) .
Example 8: 6-t-Amyl-8-fluoro-2,3-dimethyl-4-
quinolinol
In toluene (15 mL) , 4-t-amyl-2-fluoroaniline (2.00 g, 11.1 mmol) was dissolved and then ethyl 2-methylacetoacetate (1.56 mL, 11.1 mmol) and a boron trifluoride diethyl ether complex (50 mL) were added. The mixture was heated under reflux for 6 hr in a reactor having a flask fully equipped on its top with a reflux tube packed with molecular sieves. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL) , piperidine (0.7 mL) , and acetic anhydride (0.3 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated brown crystal was collected by filtration and was washed with n-hexane. The brown crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-t-amyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.18 g, yield 41.0%).
FAB-MS: m/z 263 (M+H) + ; 1H NMR (CDC13) : δ 0.64 (3H, t, J = 7.6 Hz, amyl-CH2CH3) , 1.31 (6H, s, amyl-CH3) , 1.65 (2H, q, J = 7.3 Hz, amyl-CH2CH3) , 2.14 (3H, s, 2-CH3) , 2.48 (3H, s, 3-CH3) , 2.52 (3H, s, CH3) , 7.29 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic) , 8.05 (1H, d, J = 1.2 Hz, H5-aromatic), 8.51 (1H, bs, NH).
Example 9: 6-t-Amyl-8-f luoro-2 ,3-dimethyl-4-
acetoxyquinoline
6-t-Amyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.10 g,
4.21 mmol) prepared in Example 8 was dissolved in pyridine (3.4 mL, 42.1 mmol). Acetic anhydride (6.0 mL, 63.6 mmol) was added thereto, and the mixture was heated at 80°C with stirring for 2 hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure. Ethyl acetate (100 mL) was added to the residue, followed by washing with saturated brine, a 10% aqueous citric acid solution, and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The oil as the residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate =8:1) to give 6-t-amyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline (1.22 g, yield 95.9%).
FAB-MS: m/z 304 (M+H) + ; 1H NMR (CDC13): δ 0.68 (3H, t, J = 7.3 Hz, amyl-CHzCHa) , 1.34 (6H, s, amyl-CH3) , 1.69 (2H, q, J = 7.6 Hz, amyl-CH2CH3) , 2.26 (3H, s, acetyl-CH3) , 2.52 (3H, s, 2-CH3) , 2.75 (3H, s, 3-CH3) , 7.32 (1H, d, J = 1.7 Hz, H5-aromatic) , 7.37 (1H, dd, J = 12.9, 2.0 Hz, H7-aromatic) .
Example 10: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline
6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.00 g, 4.05 mmol) prepared in Example 5 was dissolved in dry tetrahydrofuran (20 mL) . To the solution was added 60% sodium hydride (160 mg) in an argon atmosphere under ice cooling. The temperature of the mixture was returned to room temperature before the mixture was stirred for one hr until the evolution of gas stopped. The mixture was again cooled in an ice bath and was then added dropwise to a solution of methyl chloroformate (376 mL, 4.86 mmol) in dry tetrahydrofuran (5 mL) , and stirring was continued at room temperature for additional 3 hr. The reaction solution was poured into ice water, followed by extraction with ethyl acetate (50 mL) . The organic layer
was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 3 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline (784 mg, yield 63.5%).
FAB-MS: m/z 306 (M+H) + ; 1H NMR (CDC13): δ 1.38 (9H, s, t-Bu) , 2.32 (3H, s, 2-CH3) , 2.76 (3H, s, 3-CH3) , 4.00 (3H, s, OCH3) , 7.42 (1H, d, J = 1.9 Hz, H5-aromatic) , 7.45 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic).
Example 11: 6-t-Butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline
6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.00 g, 4.05 mmol) prepared in Example 5 was dissolved in dry tetrahydrofuran (20 mL) . To the solution was added 60% sodium hydride (320 mg) in an argon atmosphere under ice cooling. The temperature of the mixture was returned to room temperature before the mixture was stirred for one hr until the evolution of gas stopped. The mixture was again cooled in an ice bath and was then added dropwise to a solution of ethoxymethyl chloride (761 mL, 8.10 mmol) in dry tetrahydrofuran (5 mL) , and stirring was continued at room temperature for additional 6 hr. The reaction solution was poured into ice water, followed by extraction with ethyl acetate (50 mL) . The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 3 : 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline (145 mg, yield 11.7%).
FAB-MS: m/z 306 (M+H) + ; 1H NMR (CDCl3) : δ 1.21 (3H,
t, J = 7.1 Hz), 1.36 (9H, s, t-Bu), 2.17 (3H, s, 2-CH3) ,
2.53 (3H, s, 3-CH3) , 3.51 (2H, q, J = 7.1 Hz), 5.53 (2H,
s) , 7.37 (1H, dd, J = 17.3, 2.4 Hz, H7-aromatic) , 8.21
(1H, d, J = 2.4 Hz, H5-aromatic) .
Example 12: 4-Cyclohexyl-2-fluoroaniline
A stirrer and 5.50 mL of 36% hydrochloric acid were added to a glass reaction vessel, and zinc chloride (5.24 g, 0.0383 mol) was dissolved therein. 2-Fluoroaniline (10.0 mL, 0.104 mol) and cyclohexanol (10.4 mL, 0.104 mol) were added in that order while stirring the solution. This glass vessel was housed in a stainless steel pressure vessel, which was then hermetical sealed so as to prevent the leakage of the internal pressure. Thereafter, the vessel were heated to 190°C to allow a reaction to proceed with stirring. The initial pressure was about 5 atm. The reaction was continued for 72 hr. After satisfactory lowering in temperature was confirmed, the pressure vessel was opened. Ethyl acetate (200 mL) was added to the reaction mixture, followed by stirring to homogenize the whole mixture. After water (200 mL) was added thereto, the mixture was neutralized with sodium hydroxide to adjust the pH value to 9. A large amount of precipitated brown solid was filtered off. The organic layer was separated from the filtrate and was again washed with water. The organic layer was concentrated to give 15.1 g of a dark brown oily substance. This oily substance was purified by column chromatography on silica gel (ethyl acetate-n-hexane = 1 : 5) to give 4-cyclohexyl-2-fluoroaniline (6.63 g, yield 33.0%).
EI-MS: m/z 194 (M+H) + ; 1H NMR (CDC13): δ 1.34 (6H, m) , 1.82 (4H, m) , 2.39 (1H, m) , 3.55 2H, (bs, NH2) , 6.73 (1H, dd, J = 17.1, 8.1 Hz), 6.78 (1H, dd, J = 8.0, 1.9 Hz), 6.84 (1H, dd, J = 12.4, 1.7 Hz).
Example 13: 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol
In toluene (100 mL), 4-cyclohexyl-2-fluoroaniline
(5.00 g, 25.9 mmol) was dissolved, and then ethyl 2-
methylacetoacetate (4.77 mL, 33.7 mmol) and p-
toluenesulfonic acid monohydrate (50 mg) were added. The
mixture was heated under reflux in a reactor fully equipped with a Dean-Stark device for 3 hr. The reaction solution was cooled to room temperature. Diphenyl ether (50 mL) , piperidine (2.0 mL) , and acetic anhydride (1.0 mL) were added in that order, and the mixture was stirred for 30 min. The stirred mixture was again heated, and the toluene as the solvent was removed by evaporation. Further, the reaction temperature was raised to 250°C and was kept at that temperature for 10 min to complete cyclization. The reaction solution was allowed to cool to room temperature and was then left to stand overnight for crystallization. The precipitated white crystal was collected by filtration and was washed with n-hexane. The white crystal thus obtained was dried at room temperature under the reduced pressure for 3 hr to give 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.56 g, yield 50.4%).
FAB-MS: m/z 274 (M+H) + ; 1H NMR (d6-DMSO) : δ 1.40 (6H, m) , 1.60 (4H, m) , 2.41 (3H, s) , 7.41 (1H, d, J = 12.9), 7.68 (1H, s), 11.25 (1H, s).
Example 14: 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline
6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.00 g, 11.0 mmol) prepared in Example 5 was dissolved in pyridine (8.70 mL, 110 mmol). After acetic anhydride (11.2 mL, 110 mmol) was added thereto, the mixture was heated at 80°C with stirring for 2 hr. The pyridine as the solvent and the remaining acetic anhydride were removed by evaporation under the reduced pressure. Ethyl acetate (100 mL) was added to the residue, followed by washing with saturated brine, a 10% aqueous citric acid solution, and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was then concentrated under the reduced pressure. The oil as the residue was purified by column chromatography on silica
gel (n-hexane-ethyl acetate = 8 : 1) to give 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline (3.17 g, yield 91.2%).
FAB-MS: m/z 317 (M+H) + ; 1H NMR (CDC13): δ 1.27 (2H, m) , 1.45 (4H, m) , 1.90 (4H, m) , 2.26 (3H, s, acetyl-CH3) , 2.25 (3H, s) , 2.52 (3H, s) , 2.75 (3H, s), 2.64 (1H, m) , 7.25 (2H, m).

We claim
1. A process for producing a 2,3,6-trialkyl-8-fiuoro-4-quinoline derivative represented by formula (I) or a salt thereof:
(Formula Removed)
wherein
R1 represents optionally substituted C1-10 alkyl or C3-6 cycloalkyl;
R2 represents optionally substituted C1-10 alkyl or C3-6 cydoalkyl;
R3 represents optionally substituted C1-10 alkyl, C2-6 alkenyl, phenyl C1-6 alkyl, or C3-6 cycloalkyl; and
R4 represents a hydrogen atom or a protective group of hydroxyl,
said process comprising the steps of:
(i) alkylating a compound represented by formula (II):
(Formula Removed)
with R1-X (where R1 is as defined above and X represents hydroxyl or a halogen atom) or R1 (where R1 is an olefin having the same carbon atoms as R1) in the presence of zinc chloride at a temperature of 150 to 200°C under pressure of 4 to 10 atm, to give a 4-alkyl-2-fluoroaniline derivative represented by formula (III)
(Formula Removed)
wherein R1 is as defined above; and
(ii) reacting the compound represented by formula
(III) with an α-alkyl-ß-ketoester represented by formula
(IV) :
(Formula Removed)
wherein R2 and R3 are as defined above; and R5 represents
C1-4 alkyl,
to give an enamine intermediate represented by formula
(V) :
(Formula Removed)
wherein R1, R2, R3, and R5 are as defined above,
cyclizing the enamine intermediate to give the compound
represented by formula (I) , wherein R4 represents a
hydrogen atom, and optionally protecting hydroxyl at the 4-position with a protective group.
2. The process as claimed in claim 1, wherein the compound represented by formula (IV) is ethyl 2- methylacetoacetate.
3. The process as claimed in claim 1, wherein, in the compound represented by formula (I), R1 represents t-butyl, R2 and R3 represent methyl, and R4 represents a hydrogen atom.
4. The process as claimed in claim 1, wherein, in the compound represented by formula (I), R1 represents t-butyl, R2 and R3 represent methyl, and R4 represents acetyl.
5. The process as claimed in claim 1, wherein the compound represented by formula (II) is a hydrochloric acid addition salt.
6. The process as claimed in claim 1, wherein the protective group of hydroxyl represented by R4 is C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyloxy C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, or C3-6 cycloalkyloxycarbonyl.
7. The process as claimed in claim 1, wherein step (i) and step (ii) are carried out in a one-pot manner.

Documents:

2733-delnp-2004-Abstract-(10-08-2011).pdf

2733-delnp-2004-abstract.pdf

2733-delnp-2004-Claims-(10-08-2011).pdf

2733-delnp-2004-claims.pdf

2733-delnp-2004-Correspondence Others-(10-08-2011).pdf

2733-delnp-2004-correspondence-others.pdf

2733-delnp-2004-description (complete).pdf

2733-delnp-2004-form-1.pdf

2733-delnp-2004-form-18.pdf

2733-delnp-2004-form-2.pdf

2733-delnp-2004-Form-3-(10-08-2011).pdf

2733-delnp-2004-form-3.pdf

2733-delnp-2004-form-5.pdf

2733-delnp-2004-GPA-(10-08-2011).pdf

2733-delnp-2004-gpa.pdf

2733-delnp-2004-pct-210.pdf

2733-delnp-2004-pct-304.pdf

2733-delnp-2004-pct-332.pdf

2733-delnp-2004-pct-338.pdf

2733-delnp-2004-pct-409.pdf

2733-delnp-2004-Petition-137-(10-08-2011).pdf

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Patent Number

252195

Indian Patent Application Number

2733/DELNP/2004

PG Journal Number

18/2012

Publication Date

04-May-2012

Grant Date

01-May-2012

Date of Filing

16-Sep-2004

Name of Patentee

MEIJI SEIKA KAISHA, LTD

Applicant Address

4-16, KYOBASHI 2-CHOME, CHUO-KU, TOKYO-TO, JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	TOSHIO NISHIZUKA	C/O MEIJI SEIKA KAISHA, LTD.,4-16, KYOBASHI 2-CHOME, CHUO-KU, TOKYO-TO, JAPAN
2	KAZUMI YAMAMOTO	C/O PHARMACEUTICAL RESEARCH CENTER, MEIJI SEIKA KAISHA, LTD.,760, MOROOKA-CHO, KOUHOKU-KU, YOKOHAMA-SHI, KANAGAWA-KEN, JAPAN
3	HIROSHI KURIHARA	C/O PHARMACEUTICAL RESEARCH CENTER, MEIJI SEIKA KAISHA, LTD., 760, MOROOKA-CHO, KOUKHOKU-KU, YOKOHAMA-SHI, KANAGAWA-KEN, JAPAN

PCT International Classification Number

C07D 215/22

PCT International Application Number

PCT/JP2003/008848

PCT International Filing date

2003-07-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2002-202213	2002-07-11	Japan