Indian Patents. 189267:A PROCESS FOR THE PREPARING 2-(3-CARBOXYMETHYL-4-HALOGENOPHENYL) PROPIONIC ACID

Title of Invention	A PROCESS FOR THE PREPARING 2-(3-CARBOXYMETHYL-4-HALOGENOPHENYL) PROPIONIC ACID
Abstract	Abstract A process for the preparation of 2-(3-carboxymethyl- 4-halogenophenyl) propionic acid of the formula given below: 2-(4-amino-3-carboxymethyl-phenyl) propionic acid is diazotized under acid condition at-10° C to 20° C and sub- sequently reacted with a known halogenat- ing agent at -10° C to 100° C. The reaction product is recovered in a known manner.

Full Text	The present invention provides a process for preparing 2-(3-carboxymethyl-4-halogenophenyl) propionic acid Zaltoprofen is known as a pharmaceutically active compound which shows excellent anti-inflammatory effect as well as excellent analgesic effect. Japanese Patent Provisional Publication No. 55-53282 describes a process for preparing Zaltoprofen which com¬prises hydrolyzing ethyl 5-(a-cyan ethyl)-2-phenylthio-phenylacetate to give 5-(a-cyan ethyl)-2-phenylthio-phenylacetic acid, subjecting the resulting compound to cyclization and amidation of cyano group, and hydrolyzing the amide group of the resulting compound. Japanese Patent Provisional Publication No. 57-106678 describes an reproved process-for preparing Zaltoprofen which cutpurses hydrolyzing ethyl 5-(a-cyano¬ethyl)-2-phenyl thiophenylacetate to give 2-(3-carboxy-methyl-4-phenylthiophenyl)prop ionic acid and stylizing the resulting compound in the presence of a condensation agent. Japanese Patent Provisional Publications No. 62-292760 and No. 63-10756 describe a process for preparing Zaltoprofen which starts from: a haloketal compound. Japanese Patent Provisional Publication No. 63-2970 describes a process for preparing Zaltoprofen in which methyl 5-propionyl-2-phenylthiophenylacetate is reacted with an orthoformic acid ester and metallic zinc or zinc halide to produce methyl 2-(3-methoxycarbonylmethyl-4-phenylthiophenyl)propionate, and this product is reemployed for the preparation of Zaltoprofen. As described above, a variety of processes for pre¬paring Zaltoprofen are known. However, more improved processes are desired from the viewpoints of availability of the starting materials and easy handling of the mate¬rials participating in the reactions for the preparation, as well as economical viewpoints such as yields. The present invention has an object to provide new processes for preparing Zaltoprofen. Specifically, the invention has an object to provide new processes for preparing Zaltoprofen which are advan¬tageously employable in industry from the viewpoints of availability of the starting materials and easy handling of the materials participating in the reactions for the preparation, as well as economical viewpoints such as yields. SUMMARY OF THE INVENTION The present invention resides in a process for pre¬paring 2- (10,11-dihydro-lO-oxodibenzo [b, f ]thiepin-2-yl) -propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazo-tization and subsequent reaction with thiophenol to pro¬duce 2-(3-carboxymethyl-4-phenylthiophenyl) propionic acid or its salt, and subjecting the product to cyclization reaction — (Preparation-I). The invention also resides in a process for prepar¬ing 2- (10,11-dihydro-l0-oxodibenzo [b, f] thiepin-2-yl)pro¬pionic acid which comprises subjecting 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt to diazotization and subsequent reaction with a halogenations agent to produce 2-(3-carbDxymethyl-4-halogenophenyl)propionic acid or its salt, causing a reaction of the product with thiophenyl to produce 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt, and subjecting the product to cyclization reaction — (Preparation-II). The invention further resides in a process for pre¬paring 2- (10,11-dihydro-lO-oxodibenzo [b,f] thiepin-2-yl) -propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazo¬tization and subsequent reaction with thiosalicylic acid to produce 2-[3-carboxymethyl-4-(2-carboxyphenylthio)-phenyl]propionic acid or its salt, etherifying the prod¬uct to give a 2-[3-(lower)al]coxycarbonylmethyl-4-(2-(low¬er) alkoxycarbcnylphenylthio) phenyl] propionic acid (low¬er) alkyl ester, stylizing the resulting ester to produce a 2-(10,11-dihydro-ll-(lower)alkoxycarbonyl-10-oxodi-]Denzo[b,f]thiepin-2-yl) propionic acid (lower) alkyl ester, and subjecting the resulting ester to hydrolysis and de¬carboxylation — (Preparation-Ill). the invention furthermore resides in a process for preparing 2- (10,11-dihydro-l0-oxodibenzo [b, f] thiepin-2-yl)propionic acid which comprises subjecting 2-(4-ainino-3-carboxymethylphenyl) propionic acid or its salt to diazotization and subsequent reaction with a lialogenating agent to produce 2-(3-carboxymethyl-4-halogenophenyl)-propionic acid or its salt, causing a reaction of the product with thiosalicylic acid to produce 2-[3-carboxy-methyl - 4 - (2 - carboxyphenylthio) phenyl ] propionic acid or its salt, etherifying the product to give a 2- [3- (low¬er) alkoxycarbonylmethyl-4- (2-(lower)alkoxycarbcnylphenyl¬thio) phenyl] propionic acid (lower) alkyl ester, stylizing the resulting ester to produce a 2-(10,11-dihydro-ll-(lower) alkoxycarbonyl-10-oxodibenzo [b, f ] thiepin-2-yl) pro¬pionic acid (lower)alkyl ester, and subjecting the re¬sulting ester to hydrolysis and decarboxylation — (Pre¬paration-IV) . The 2 - (4 - amino - 3 - carboxymet±ylphenyl) propionic acid or its salt is a new compound, and it can be produced by a variety of processes described below. 1) A process which comprises reducing 2-(3-car-boxyraethyl-4-nitrophenyl)propionic acid or its salt. 2) A process which comprises subjecting a methy malonic acid derivative of the following formula (A) : in which R^ represents cyano, carboxyl, carbamoyl, alkyl-carbonyl having 2 to 7 carbon atoms, alkoxycarbonyl hav¬ing 2 to 7 carbon atoms, aryloxycarbonyl having 7 to 13 carbon atoms, or aralkyloxycarbonyl having 8 to 19 carbon atoms; and each of R1, R2 and R3 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or a alkyl having 7 to 18 carbon atoms to hydrolysis and decarboxylation, to produce 2-(3-car-boxymethyl-4-nitrophenyl)propionic acid or its salt, and reducing the product. 3) A process which comprises causing a reaction of an acetic acid ester derivative with a 2-(3-halogeno-4-nitrophenyl)-2-methylmalonic acid daily ester[=2-(3-halogeno-4-nitrophenyl)-2-methylpropanedioic acid dialkyl ester], to give a methy malonic acid derivative of the above-mentioned formula (A) / subjecting the methy malonic acid derivative to hydrolysis and decarboxylation, to produce 2-(3-carboxymethyl-4-nitrophenyl)propionic acid or its salt; and reducing the product. 4) A process which comprises causing successive reactions of a 2,4-dihalogenonitrobenzene with a methyl- malonic acid diester and with an acetic acid ester deriv¬ative, to give a methylnialonic acid derivative of the aforementioned formula (A) / subjecting the methy malonic acid derivative to hydrolysis and decarboxylation, to produce 2-(3-carboxymethyl-4-nitrophenyl)propionic acid or its salt; and reducing the product. 5) A process which comprises reducing a methy malonic acid derivative of the aforementioned formula (A), to give another methy malonic acid derivative having the following formula (B): in which each of R^, R^, R^ and R* has the meaning as defined above for the formula (A) / and subjecting the "methy malonic acid derivative of the formula (B) to hy¬drolysis and decarboxylation. The invention furthermore resides in a process for preparing 2- (10, ll-dihydro-lO-oxcdibenzo [b, f] thiepin-2-yl) propionic acid which comprises causing a reaction of 2-(3-carboxycnethyl-4-halogenophenyl)propionic acid or its salt with thiophenyl, to produce 2-(3-carbo3cymethyl-4-phenylthiophenyl)propionic acid or its salt, and cycles-ing the product — (Preparation-V). The invention furthermore resides in a process for preparing 2- (10, ll-dihydro-10-oxodibenzo [b, f ] thiepin-2-yl) propionic acid which comprises causing a reaction of 2 - (3 - carboxymethyl - 4 -halogen phenyl) propionic acid or its salt with thiosalicylic acid, to produce 2-[3-carboxy-Tlethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or Lets salt, etherifying the product to give a 2-[3-(low-;r) alkoxycarbonylmethyl-4- (2- (lower) alkoxycarbonylphenyl-:hio)phenyl]propionic acid (lower) alkyl ester, cyclizing the resulting ester, and subjecting the cyclone ester to hydrolysis and decarboxylation — (Preparation-VI) . Furthermore, the invention resides in a compound having the following formula (C) : in which X represents NO2, NH2, halogen, or a group of the following formula; in which R7 represents hydrogen, alkyl having 1 to 6 car¬bon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms, and each of R5 and R6 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms. The compound of the formula (C) is of value as an intermediate compound for preparing the 2-(10,11-dihydro-10 -oxodibenzo [b, f ] thiepin-2 -yl)propionic acid. Representative examples of the compounds of the formula (C) include the following: a) 2-(3-Carboxymethyl-4-nitrophenyl)propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt. b) 2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt. c) 2 - [ 3 - Carboxymethyl - 4 - (2 - carboxypheny lthio) -phenyl] propionic acid, its alkyl ester in which the alkyl has 1 to 6 carbon atoms, or its salt. d) 2 - (3 -Carboxymet±.yl-4 -halogen phenyl) propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt. e) An alkyl ester of 2- [3-alkoxycarbonylmethyl-4-(2-alkoxycarbonylphenylthio) phenyl] propionic acid in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms. Furthermore, the invention resides in a compound having the following formula (D) : in which Y represents NO2 or NH2, R1 represents cyano, carboxyl, carbamoyl, alkyl carbonyl having 2 to 7 carbon atoms, alkoxycarbonyl having 2 to 7 carbon atoms, aryl-ox carbonyl having 7 to 13 carbon atoms, or aralkyloxy carbonyl having 8 to 19 carbon atoms; and each of R2, R3 and R4 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms. The compound of the formula (D) also is of value as an intermediate cot pound for preparing the 2-(10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl)propionic acid. Representative examples of the compounds of the formula (D) include the following: a) Dialkyl ester of 2-[3-bis(alkoxycarbonyl)-methyl-4-nitrophenyl] -2-methylmalonic acid in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms. b) Dialkyl ester of 2-[3-[(alkoxycarbonyl)cyano-methyl] -4-nitrophenyl] -2-methylmalonic acid in which the alkyl lias 1 to 6 carbon atoms and the alkoxy lias 1 to 6 carbon atoms. c) Dialkyl ester of 2-[3-[acetyl(alkoxycarix)nyl)-methyl] -4-nitrophenyl] -2-methylmalonic acid in which the allcyl has 1 to 6 carbon atoms and the alkyoxy has 1 to 6 carbon atoms. d) Dialkyl ester of 2-[4-amino-3-bis(alkoxycar-bonyl)methyl phenyl]-2-methylmalonate in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms. Furthermore, the invention resides in a compound having the following formula (E) : in which each of R5 and R6 independently represents hydro¬gen, alkyl having 1 to 6 carbon atoms, aryl having 6 to "12 carbon atoms, or aralkyl having 7 to 18 carbon atoms. The compound of the formula (E) also is of value as an intermediate compound for preparing the 2-(10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl)propionic acid. Representative examples of the compounds of the formula (E) include an alkyl ester of 2-(11-alkoxycar-bonyl-10, ll-dihydro-lO-oxodibenzo [b, f] thiepin-2-yl)pro¬pionic acid in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms. PREFERRED EMBQDINENTS OF THE INVENTION The processes of the invention for preparing Zaltoprofen, that is, 2-(I0,ll-dihydro-l0-oxodibenzo-[b/f] thiepin-2-yl)propionic acid, are further described below in more detail. (1) Preparation-I Preparation-1 of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiophenyl to give 2-(3-carboxy-methyl-4-phenylthiophenyl)propionic acid. or its salt, and the resulting product is then subjected to cyclization reaction. Preparation-1 is illustrated in the following reaction scheme I: [Reaction Scheme I] 1) Preparation of 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt 2-(4-Amino-3-carboxymethylphenyl)propionic acid or its salt (e.g., disodium salt, dipotassium salt, di-lithium salt) is diazotized by the use of a diazotizing agent, for instance, under acidic conditions (made acidic with hydrochloric acid), and the resulting compound (i.e., diazo compound) is reacted with thiophenyl in a solvent. The diazotization reaction can be performed by-bringing the starting compound into contact with a diazo¬tizing agent (e.g., sodium nitrite, nitrosyl hydrogensul-fate, nitrosyl chloride) at -10 to 20'C under acidic conditions (made acidic with hydrochloric acid, sulfuric acid, or acetic acid) . The resulting compound (i.e., diazo compound) is then brought into contact with thio-phenol at 0 to 100°C under basic conditions (e.g., in an aqueous sodium hydroxide or potassium hydroxide solution) to give the 2 - (3 - carboxyraethyl - 4 -phenyl thiophenyl) pro -panic acid or its salt. 2) Preparation of Zaltoprofen The above-mentioned 2-(3-carboxymethyl-4-phenyl-thiophenyl)propionic acid or its salt is a known com¬pound. The preparation of Zaltoprofen by cyclizing this compound in the presence of a condensation agent is de¬scribed in Japanese Patent Publication Hl-29793. The condensation agent can be sulfuric acid, polyphosphoric acid, or polyphosphoric acid ester, and the reaction is generally performed at a temperature of 0 to 150°C. (2) Preparation-II and Preparation-V Preparation-11 of the invention for preparing Zaltoprofen is characterized in that 2- (4-amino-3-car-boxymethylphenyl) propionic acid or its salt is diazotized and then reacted with a halogenations agent to give 2-(3-carboxymethyl - 4-halogenophenyl) propionic acid or its . salt, and the resulting compound is reacted with thio-phenol to give 2-(3-carboxymethyl-4-phenylthiophenyl) pro¬pionic acid or its salt, which is finally subjected to cyclization reaction. Preparation-II is illustrated in the following reaction scheme II (in the scheme, "Hal-" means a halogen group): [Reaction Scheme II] In Reaction Scheme II, the route in which 2-(3-car-boxymethyl-4-halogenophenyl) propionic acid or its salt is reacted with thiophenyl (not illustrated) to give 2-(3-carboxymethyl-4-phenylthiophenyl) propionic acid or its salt, and this product is cyclized to give Zaltoprofen (final product) corresponds to Preparation-V. 1) Preparation of 2-(3-carboxymethyl-4-halogeno¬ phenyl) propionic acid or its salt 2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid or its salt (e.g., disodium salt) is diazotized in the same maimer as in Preparation-1, and the resulting compound (i.e., diazole compound) is treated with a halogenations agent (e.g., potassium iodide, copper(I) chloride, copper (I) bromide, copper (I) iodide, or hydrotropic acid gener¬ally in the presence of powdery copper) at -10 to 100°C, to give the 2-(3-carboxyinethyl-4-halogenophenyl)propionic acid or its salt. 2) Preparation of 2-(3-carboxymethyl-4-phenylthio- phenyl) propionic acid or its salt The above-mentioned 2-(3-carboxynethyl-4-halogeno-phenyl)propionic acid or its salt is reacted with thio-phenol in a polar solvent (e.g.. .^dimethylsulfoxide (EMSO), dimeth-ylformamide (DMF), or water) at 25 to 120°C, under basic conditions (e.g., made basic with potassium hydroxide or potassium carbonate) in the presence of a catalyst (e.g., potassium iodide, powdery copper, copper salt), to give the 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt. 3) Preparation of Zaltoprofen The process described in the aforementioned Prepaira-tion-I can be utilized. (3) Preparation-III Preparation-III of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiosalicylic acid to give 2-[3-carboxymethyl-4- (2-carboxyphenylthio)phenyl]propionic acid or its salt; the resulting compound is esterifies to give .2- [3- (lower) alkoxycarbonylmethyl-4- (2- (lower) alkoxy-carbonylphenylthio) phenyl] propionic acid (lower) alkyl ester; the resulting ester is subjected to cyclization reaction, to give 2-(10,11-dihydro-ll-(lower)alkoxycar-bonyl-10-oxodibenzo[b,f] thiepin-2-yl)propionic acid (low¬er) alkyl ester; and the resulting ester is finally sub¬jected to hydrolysis and decarboxylation. Preparation-Ill is illustrated in the following reaction scheme III: [Reaction Scheme III] 1) Preparation of 2-[3-carboxymethyl-4-(2-carboxv- pnenyithio) phenyl] propionic acid or its salt 2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid or its salt is diazotized in the same manner as in Prepara¬tion-!, and the resulting compound (i.e., diazo compound) is reacted with thiosalicylic acid at 0 to l00C, prefer¬ably under basic conditions, to give the 2-[3-carboxy-methyl-4-(2-carboxyphenylthio) phenyl] propionic acid or its salt. 2) Preparation of 2-[3-(lower)alkoxycarbonylmethyl -4- (2- (lower) alkoxycarbcnylphenylthio)phenyl] propionic acid (lower) alkyl ester The esteri-fication reaction can be performed by utilizing a lower alcohol (alcohol having 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol) , utilizing other etherifying agent (e.g., methyl orthoformate, or ethyl orthoformate), or utilizing both of the lower alcohol and other etherifying agent. In the esterification reaction, an inorganic acid such as sulfu¬ric acid or hydrochloric acid, an organic' acid such as an aromatic sulfuric acid, or a Lewis acid such as boron trifluoride ether ate is preferably employed in a cata¬lytic amount or more so that the reaction can be acceler¬ated. 3) Preparation of 2-(10,11-dihydro-ll-(lower)- alkoxycarbonyl-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid (lower) alkyl ester by cyclization of 2-[3-(lower)- alkoxycarbonylmethyl-4 - (2 - (lower) alkoxycarbonylphenyl- thio)phenyl]propionic acid lower alkyl ester The cyclization reaction is known as Deskman reac¬tion, and the compound to be cyclized is brought into contact with a base in a solvent. Examples of the bases include alkali metals (e.g., sodium metal), alcoholisms of alkali metals (e.g., potassium tert-but oxide, and sodium ethoxide), alkali metal hydrides (e.g., sodium hydride), and sodium methyl Ulf inylmethide. The solvent can be benzene, toluene, xylene, ethyl ether, or dimethyl- In Reaction Scheme IV, the route starting from the 2-(3-carboxymethyl-4-halogenophenyl)propionic acid or its salt to give Zaltoprofen (final product) corresponds to Preparation-VI. 1) Preparation of 2-(3-carboxymethyl-4-halogeno- phenyl) propionic acid or its salt The preparation can be performed in the manner as described in Preparation 2) Preparation of 2-[3-carboxymethyl-4-(2-carboxy- phenythio)phenyl3propionic acid or its salt The above-mentioned 2-(3-carboxymethyl-4-halogeno-phenyl)propionic acid or its salt is reacted in a polar solvent (e.g.,DMSO, ESMF, or water) under basic condi¬tions (for instance, in the presence of potassium hydrox- ide or potassium carbonate) at 25 to 120'C in the presence of a catalyst (e.g., potassium iodide, powdery copper, or copper salt). 3) Preparation of 2-[3-(lower)alkoxycarbonyl- methyl-4- (2- (lower)alkoxycarbonylphenylthio)phenyl]pro¬ pionic acid (lower) alkyl ester The preparation can be performed in the manner as described in Preparation 35 , 4) Preparation of 2-(10,11-dihydro-ll-(lower)- alkoxycarbonyl-lO-oxodibenzo [b, f] thiepin-2-yl) propionic acid (lower)alkyl ester by cyclization of 2-[3-(lower)- alkoxycarbonylmethyl-4- (2- (lower) alkoxycarbonylphenyl¬ thio) phenyl] propionic acid lower allcyl ester The preparation can he performed in the manner as described in Preparation 5) Preparation of Zaltoprofen by hydrolysis and decarboxylation of 2-(10,11-dihydro-ll-(lower)alkoxy- cartxsnyl -10 - oxodibenzo [b, f ] thiepin- 2 -yl) propionic acid (lower) alkyl ester The process described in the aforementioned Prepara¬tion-Ill can be utilized. The starting confound etrployed for the aforemen¬tioned various processes for the preparation of Zalto¬profen, that is, 2-(4-amino-3-carboxymethylphenyl)pro¬pionic acid or its salt is, as stated hereinbefore, a new compound. This new compound can be produced from a known compound in the manners described below. (1) Production of 2-(4-amino-3-carboxymethylphenyl)pro-pionic acid or its salt — Production-(1) 2-(3-Halogeno-4-nitrophenyl)-2-methylmalonic acid diester is reacted with an acetic acid ester derivative [which is represented by the formula of R1-CH2COOR2 (each of R1 and R2 has the meaning defined hereinbefore) and can be exemplified by malonic acid dialkyl ester, acetoacetic acid ester, and cyanoacetic acid ester] to give the meth¬ylmalonic acid derivative having the aforementioned for- mula (A); the methylmalonic acid derivative is subjected to hydrolysis and decarboxylation to give 2- (3-carboxy-methyl-4-nitrophenyl)propionic acid or its salt; and finally the resulting compound is reduced to give the desired compound. Production- (1) is illustrated in the following Reaction Scheme V. [Reaction Scheme V] ,COOR* C00R3 ,C00R4 C00R3 COOH OOH COOH OOH 1) Production of the methylmalonic acid derivative having the formula (A) The desired conpound can be produced by reacting 2-(3-halogeno-4-nitrophenyl)-2-methylmalonic acid diester (in which "halogeno" means fluoro, chloro, or bromo) with an acetic acid ester derivative [e.g., malonic acid dialkyl ester having alkyl of 1-6 carbon atoms, such as dimethyl malonate; acetoacetic acid ester such as methyl acetoacetate or ethyl acetoacetate; or cyanoacetic acid ester such as methyl cyanoacetate or ethyl cyanoacetate) . The reaction is preferably carried out in an anhy¬drous organic solvent such as anhydrous dimethylformamide in the presence of a basic compound such as potassium tert-butoxide or sodium hydride, in an inert gas atmo¬sphere such as a nitrogen gas atmosphere. The reaction tenperature generally is in the range of from 50°C (pref¬erably from 70 to the boiling tenperature of the reac- tion solvent. A representative conpound of the 2-(3-halogeno-4-nitrophenyl) -2-methylmalonic acid diallcyl ester eirployed in the above production process is diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate, which is known and described in Japanese Patent Publication No.47-45746. 2) Production of 2-(3-car3^oxymethyl-4-nitro- phenyl)propionic acid or its salt This conpound can be oroduced by subjecting the , , , . /derivatives ^ J r methylmalonic acid/of the formula (A) [which is obtained in the 1) above] to reactions for hydrolysis and decar¬boxylation. The hydrolysis and decarboxylation can be carried out, for instance, in an aqueous acetic acid solution, in the presence of concentrated sulfuric acid as catalyst. The reactions can be performed simultaneously or successively by heating the reaction solution under reflux. 3) Production of 2-(4-amino-3-carboxymethyl- phenyl) propionic acid or its salt This conpound can be produced by reducing the 2-(3-carboxymethyl-4-nitrophenyl) propionic acid or its salt [which is obtained in the 2) above] under basic condi¬tions (in an aqueous alkaline solution containing, for instance, sodium hydroxide, potassium hydroxide, lithium hydroxide, or sodium carbonate). The salt of 2-(4-amine¬s'carboxyne thy Iphenyl) propionic acid can be a disodium salt, a dipotassium salt, or a dilitliium salt. The re¬duction can be performed utilizing hydrogen gas in the presence of palladium/carbon. (2) Production of 2-(4-araino-3-carboxymethylphenyl)pro¬pionic acid or its salt — Production-(2) 2,4-Diiialogenonitrobenzene (known conpoimd) is re¬acted successively with methylmalonic acid diester (e.g., dialkyl methylmalonate) and the aforementioned acetic acid ester derivative, to give the methylmalonic acid derivative of the formula (A) / the methylmalonic acid derivative is then subjected to hydrolysis and decarbox¬ylation, to give 2-(3-carboxymethyl-4-nitrophenyl)pro¬pionic acid or its salt; and finally the product is re¬duced to give the desired conpound. Production-(2) is illustrated in the following Reaction Scheme VI. [Reaction Scheme VI] 1) Production of the methylmalonic acid derivative having the formula (A) 2,4-Dihalogenonitrobenzene (in which "halogeno" means, for instance, chloro or bromo) is reacted succes¬sively with a methylmalonic acid diester (e.g., dialkyl methylmalonate such as diethyl methylmalonate) and the above-mentioned acetic acid ester derivative. The reac¬tion can be carried out by utilizing the procedures de¬scribed in the aforementioned Production-(1)-1) . 2) Production of 2-(3-carboxymethyl-4-nitro- phenyl)propionic acid or its ester The production can be performed in the manner as described in the above-mentioned Production- (1) . 3) Production of 2-(4-amino-3-carboxymethyl- phenyl)propionic acid or its salt The production can be performed in the manner as described in the above-mentioned Production- (1) . (3) Production of 2-{4-amino-3-carboxymethylphenyl)pro¬pionic acid or its salt — Production-(3) The methylmalonic acid derivative of the formula (A) is first reduced to convert into a methylmalonic acid derivative of the fornnula (B), and the resulting deriva¬tive is then subjected to hydrolysis and decarboxylation. Production-(3) is illustrated in the following Reaction Scheme VII. [Reaction Scheme VTI] 1) Production of the methylmalonic acid derivative of the formula (B) by reduction of the methylmalonic acid derivative of the formula (A) The reduction can be performed by bringing the meth¬ylmalonic acid derivative of the formula (A) into contact with hydrogen gas at -10 to 100^'C in the presence of palladium/carbon. 2) Hydrolysis and decarboxylation of the methyl¬ malonic acid derivative of the formula (B) The hydrolysis and decarboxylation can be carried out in the same manner as the hydrolysis and decarboxyl¬ation of the methylmalonic acid derivative of the formula (A) which is described in the Production-(1) . Accordingly the present invention provides a process for preparing 2-(3-carboxymethyi-4-halogenophenyl) propionic acid having the following formula or its salt: in which Hal is a halogen atom, the said process comprises subjecting 2-(4-amino-3-carbo)cymethyl-phenyl)propionic acid having the following formula or its salt: to diazotization at -10°C to 20'C under acidic conditions and subsequent reaction with a halogenating agent, such as hereindescribed, at -10°C to lOO^C and thereafter recovering the 2-(3-carboxymethyl-4-halogenophenyl) propionic acid in a known manner. The present invention is further described by the following examples. Example 1 Preparation (I) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid (1) Preparation of diethyl 2-[3-bis(methoxycarbonyl)- methyl-4-nitrophenyl] -2-methylmalonate Dimethyl malonate (4.04 g, 30.6 mmol.), potassium t-butoxide (3.43 g, 30.6 mmol.) and anhydrous N,N-dimethyl-formamide (15 mL) were mixed and stirred at 90°C for 10 minutes in a nitrogen atmosphere. The mixture was then cooled to room tertperature and added to a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (5.04 g, 15.3 mmol., prepared in the manner as described in Japanese Patent Publication No. 47-45,746) in anhydrous N,N-dimethylformamide (15 mL) . The resulting mixture was stiiired at 90°C for 3 hours, and then poured into IN hydrochloric acid (30 mL) . The mixture was subjected to extraction using two portions of diethyl ether. The ether extracts were combined, washed successively with water and an aqueous satu23.ted sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ex¬tract was placed imder reduced pressure to give 7.97 g of a yellow oil. The oil was adsorbed on silica gel (16 g) and subjected to moderate pressure silica gel column chromatography. The adsorbed oil was eluted using a mix¬ture of ethyl acetate/hexane (1/1, v/v) to give 4.33 g (yield: 66.7%) of the desired confound as a yellow oil. ^H-NMR (CDCl3)6: 1.27 (6H, t, J=7Hz), 1.88 (3H, s), 3.80 (6H, s), 4.24 (2H, q, J=7Hz), 4.25 (2H, q, J=7Hz), 5.35 (IH, s), 7.55 (IH, dd, J=2Hz, 8Hz), 7.57 (IH, d, J=2Hz), 8.05 (IH, d, J=8Hz). (2) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro- Dionic acid The diethyl 2-[3-bis(^1ethoxycarbonyl)methyl-4-nitrophenyl] -2-met±.yltralorLate (obtained in (1) above, 4.13 g, 9.71 mmol.) was dissolved in acetic acid (40 mL) . To the solution were added water (16 mL) and concentrated sulfuric acid (4 mL), and the resulting mixture was heat¬ed for 15 hours under reflux. The acetic acid was dis¬tilled off under reduced pressure. The residue was con¬centrated under reduced pressure after addition of tolu¬ene. The precipitated crystals were collected by filtra¬tion and washed with water to give 2.06 g of the desired conpound as a pale brown crystalline product. The fil¬trate and washing were combined and subjected to extrac¬tion using ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 0.32 g of the desired conpound as a yellow crystalline product. The total amount was 2.38 g "(yield: 96.8 %) . m.p.: 169-171'=C (after recrystallization from ethyl acetate and hexane) ^H-NMR (CD30D)6: . 1.51 (3H, d, J=yHz), 3.86 (IH, q, J=7Hz), 4.04 (2H, s), 7.42 (IH, d, J=7Hz), 7.49 (IH, dd, J=2Hz, 8Hz), 8.09 (IH, d, J=8Hz). IR ^xmK (KBr) cm"^: 2980, 1700, 1610, 1585, 1515, 1450, 1430, 1340, 1300, 1250, 1230, 930. Example 2 Preparation (II) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid In anhydrous N, N-dimethylformamide (20 mL) were dissolved 2,4-dichloronitrobenzene (3.84 g, 20 mmol.) and diethyl methylmalonate (5.23 g, 30 mnral.) . To this was added potassium t-butoxide (3.37 g, 30 mmol.) with stir- ring under chilling with ice. The resulting mixture was fiirther stirred for 5 minutes under chilling with ice, and then for 18 hours at room teiiperature. Independently, dimethyl malonate (5.28 g, 40 mmol-), potassium t-butoxide (4.48 g , 40 mmol.), and anhydrous N, N-dimethylformamide (20 mL) were mixed, and then stirred at 90°C for 10 minutes. The reaction mixture was cooled to room tenperature, and stirred at 90°C for 4 hours after addition of the aforementioned reaction mix¬ture. The resulting reaction mixture was poured into a mixture of 2N hydrochloric acid (40 raL) and ice, and ex¬tracted with two portions of diethyl ether. The diethyl ether portions were combined, washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solu¬tion was placed under reduced pressure to distill off the solvent, to leave 7.70 g of a dark brown oil. Thus obtained crude diethyl 2-[3-bis(methoxycarbon-yl)methyl-4-nitrophenyl]-2-methylmalonate was dissolved in acetic acid (80 mL), and heated under reflux for 14 hours, after addition of water (32 mL) and concentrated sulfuric acid (8 mL) . The acetic acid was then distilled off under reduced pressiure to leave a residue. The resi¬due was diluted with water, and extracted with ethyl acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo¬ride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 3.50 g of a dark brown crystalline product. The crystalline product was washed with chloroform to give 2.27 g (yield: 44.8%) of the desired conpound as a brown crystalline product. Exanplg 3 Preparation (III) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid (1) Preparation of diethyl 2-[3-[acetyKraethoxycarbon- yDmethyl]-4-nitrophenyl]-2-tnethylmalonate To a solution of diethyl 2-{3-chloro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.03 mmol.) in dimethyl sulfox¬ide (aviso, 3mL) were added potassium carbonate (1.25 g, 9.09 mmol.) and methyl acetoacetate (0.99 mL, 9.0 imol,). The resulting mixture was stirred at 70°C for 6 hours. The reaction mixture was cooled to room terrperature, neutralized with diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The dried portion was' concentrated to leave a residue. The residue was puri¬fied by silica gel column chromatography (Wako Gel C-300, available from Wako JyunyaJcu Industry Co., Ltd., tolu¬ene/ethyl acetate=100/4, v/v), to give 0.64 g (yield: 52%) of the desired cotrpoumd as a yellow oil. CI-MASS(m/e): 410(M+1), 378, 336 (2) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro¬ pionic acid In methanol (1 mL) was dissolved diethyl 2-[3-[ace¬tyl (methoxycarbonyl) methyl] -4-nitrophenyl]-2-methyl¬malonate (obtained in (1) above, 50.9 mg, 0.124 mmol.). The resulting solution was stirred for 15 hours at room teitperature after addition of 2M aqueous sodium hydroxide solution (1.5 mL, 3 mmol.) . The reaction mixture was then stirred at 600 for 3 hours after addition of 6M hydrochloric acid (1 mL, 3 mmol.) . The mixtiire was cooled and extracted with ethyl acetate. Tlie ethyl ace¬tate portion was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried organic portion was concentrated and pxirif ied by silica gel column chromatography (Wako Gel C-200, available from Wako Jyunyaku Industry Co., Ltd., hexane/ ethyl acetate/acetic acid=:7/3/l, v/v/v), to give 20.3 rag (yield: 65%) of the desired conpound. Example 4 Preparation (IV) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid (1) Preparation of diethyl 2-[3-[cyano(ethoxycarbonyl)- methyl] -4-nitrophenyl] -2-methylmalonate Diethyl 2-{3-chloro-4-nitrophenyl)-2-raethylraalonate (119 mg, 0.36 mraol.), ethyl cyanoacetate (81 rag, 0.72 mmol.), powdery potassium carbonate (119 rag, 0.86 ramol.), and dimethyl sulfoxide (1 mL) were mixed and stirred at SO^C for 2 hours. The reaction mixture was cooled to room terrperature, and washed with diethyl ether after addition of water. The aqueous portion was made acidic by addi¬tion of 6N hydrochloric acid, and extracted with diethyl ether. The ether poirtion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to give 133 rrg (yield: 92%) of the desired conpound as a yellow oil. ^H-NMR (CDCl3)6: 1.28 (3H, t, J=7Hz), 1.28 (3H, t, J=7Hz), 1.33 (3H, t, J=7Hz), 1.92 (3H, s), 4.2-4.4 (6H, m) , 5.69 (IH, s), 7.66 (IH, dd, J=2Hz, 9Hz), 7.82 (IH, d, J=2Hz) , 8.20 (IH, d, J=:9Hz) . (2) Preparation of 2-[3-cyano(ethoxycarbonyl)raethyl-4- nitrophenyl] -2-propionic acid In dimethyl sulfoxide (1.5 mL) was dissolved diethyl 2- [3- [cyano(ethoxycarbonyl)methyl] -4-nitrophenyl] -2-methylmalonate (obtained in the same manner as tiiat of the aix3ve (1), 163 mg, 0.4 mmol.). The solution was stirred for 40 hours at room tenperature after addition of 4N aqueous sodiiom hydroxide solution (1.5 raL) . The reaction mixtiire was made acidic by addition of 2N hydro¬chloric acid, and extracted with toluene. The toluene portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was distilled off imder reduced pressure to give 112 rag (yield: 92%) of the desired com¬pound as a yellow oil. ^H-NMR (CDCl3)6: 1.33 (3H, t, J=7Hz), 1.60 (3H, d, J=7Hz), 3.91 (IH, q, J=7Hz), 4.31 (2H, q, J=7Hz), 5.65, 5.66 (IH, sx2), 7.60 (IH, dd, J=lHz, 8Hz) , 7.69 (IH, d; J=lHz), 8.21 (IH, d, J=aHz). (3) Preparation of 2-(3-cyanomethyl-4-nitrqphenyl)-2-propionic acid In acetic acid (0.4 raL) was dissolved 2-[3-cyano-(ethoxycarbonyl)methyl-4-nitrophenyl] -2-propionic acid (obtained in (2) above, 110 rag, 0.36 mmol.). The solu¬tion was heated for 4 hours under reflux, after addition of water (0.36 mL) and concentrated sulfuric acid (0.04 mL) . The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous satu- . rated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave a dark red oil. The oil was adsorbed on silica gel and subjected to silica gel column chromatography. The elution was performed using a mix¬ture of acetic acid and chloroform (1/100, v/v), to give 61 rag (yield: 72%) of the desired conpound as a white crystalline product. m.p.: 55-59°C ^H-NMR (CDCl3)8: 1.60 (3H, d, J=7Hz), 3.90 (IH, q, J=7Hz), 4.21 (2H, s), 7.52 (IH, dd, J=2Hz, 9Hz), 7.65 (IH, d, J=2Hz), 8.18 (IH, d, J=:9Hz) . 3000, 2260, 1720, 1615, 1590, 1530, 1420, 1340. (4) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro¬pionic acid In acetic acid (0.3 mL) was dissolved 2-(3-cyano-niethyl-4-nitrophenyl)-2-propionic acid (obtained in (3) above., 14 mg, 0.06 mmol.) . The solution was heated for 24 hours under reflux, after addition of water (0.27 raL) and concentrated sulfuric acid (0.03 mL) . The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo¬ride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off imder reduced pressure to leave a residue. The residue was dissolved in toluene and concentrated under reduced pressure to give 13 mg (yield: 85%) of the desired conpound as a brown cirystal-line product. m.p.: 169-171='C (after recrystallization from ethyl acetate and hexane) Example 5 Preparation (V) of 2 - (3 - carboxymethyl - 4 -nitrophenyl) -propionic acid In aiihydrous dimethyl sulfoxide (10 mL) was sus¬pended 60% sodiijm hydride (1.04 g, 26 mmol.) . To the suspension was dropwise added diethyl methylmalonate (5.0 mL, ^0 mmol.) for 2 minutes, while the suspension was stirred under cooling with water. The mixture was stirred at 60-100°C for 30 minutes. To the resulting homogeneous solution was dropwise added a solution of 2,4-dichloronitrobenzene (3.84 g, 20 mmol.) in anhydrous dimethyl sulfoxide (4 mL) for 5 minutes, while the solu¬tion was stirred under cooling with water. The resulting mixture was then stirred at for 2 hours. The reac¬tion mixture was stirred at 70'C for 2 hours, after addi- tion of ethyl cyanoacetate (5.3 mL, 50 mmol.) and powdery potassium carbonate (13.8 g, 100 mmol.). To the result-, ing reaction mixture was added 3N hydrochloric acid, while the mixture was stirred under cooling with water. The mixture was extracted with toluene. The toluene portion was washed successively with an aqueous 20% po-tassii:im carbonate solution (14 mL), water, 2N hydrochlo¬ric acid (5 mL), water and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave an orange oil (12.0 g). The obtained orange oil was placed urder reduced pressure to distill the solvent off, to give 8.5 g of a crude diethyl 2-[3-[cyano(ethoxycarbonyl) methyl] -4-nitrophenyl] -2-methyl-malonate as an orange oil. The crude product was dis¬solved in acetic acid (30 mL), and heated for 60 hours under reflux after addition of water (24 mL) and concen¬trated sulfuric acid (6 mL). The upper colorless oil layer was separated and removed. The acetic acid was distilled off under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pres¬sure. This concentration procedure was repeated once, and to the residue were added water (20 mL) and chloro¬form (10 mL) . Insolubles were filtered off, and to the filtrate was added a small amount of separately obtained crystals of 2-(3-carboxymethyl-4-nitrophenyl)propionic acid. The precipitated crystals were collected by fil¬tration and washed successively with three portions of water, chloroform, and hexane. The washed crystalline product was air-dried, and then dried imder reduced pres¬sure, to give 2.20 g (yield: 43%) of the desired compound as a pale brown powder. Preparation (VI) of 2-(3-carboxymethyl-4-nitrophenyl)- propionic acid In acetic acid (1 mL) was dissolved diethyl 2-[3-[cyano(ethoxycarbonyl) methyl] -4-nitrophenyl] -2-methyl-malonate (obtained/in Exanple 5, 406 mg, 1 rnmol.). The solution was heated for 36 hours under reflux, after addition of water (0,9 niL) and concentrated sulfuric acid (0.1 mL) . The reaction mixture was diluted with water, and then extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium cliloride solution, and dried over anhy¬drous sodixom sulfate. The solvent was distilled off under reduced pressure, to give 189 mg (yield: 75%) of the desired conpound as a brown crystalline product. Example 7 Preparation (I) of 2-(4-amino-3-carboxymethylphenyl)-propionic acid disodiimi salt In 0.5N aqueous sodium hydroxide solution (0.8 mL) was dissolved 2-(3-car3DOxyraethyl-4-nitrophenyl) propionic acid (obtained in Exartple 1, 50 rrg, 0.2 mmol.). The solution was stirred for 18 hours at room tettperatiire in a hydrogen gas atmosphere, after addition of 10% palladi-lom/carbon (10 ng) . Insolubles were removed by filtra¬tion, and the filtrate was concentrated under reduced pressure to give 55 mg (yield: quantitative amount) of the desired cotipound as a colorless oil. ^H-NMR (DjOfi: 1.37 (3H, d, J=7Hz), 3.45 (2H, s), 3.54 (IH, q, J=7Hz), 6.83 (IH, d, J=8Hz), 7.0-7.1 (2H, m). Example 8 Preparation (II) of 2-(4-amino-3-carboxymethylphenyl)-propionic acid disodium salt In IN aqueous sodiimi hydroxide solution (6 mL) was dissolved 2 - (3 -carboxymethyl-4 -nitrophenyl) propionic acid (obtained in Example 1, 760 mg, 3 nrool.) . The solution was stirred for 18 hours at room terrperature in a hydro- gen gas atmosphere, after addition of 10% palladium/car¬bon (15 mg) . Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give a brown crystalline product. Ihe obtained crystal¬line product was washed successively with ethanol and hexane to give 734 mg (yield: 91.7%) of the desired com¬pound as a white crystalline product, m.p.: 160-163°C ^H-NMR (D20)6: 1.37 (3H, d, J=7Hz), 3.45 (2H, s), 3.54 (IH, q, J=7Hz), 6.83 (IH, d, J=8Hz), 7.0-7.1 (2H, m) . IR v^ (KBr) cm-^- 3400, 1560, 1400. Example 9 Preparation of diethyl 2-[4-amino-3-bis(methoxycarbonyl)-methylphenyl] -2-methylmalonate In ethanol (1 mL) was dissolved diethyl 2- [3-bis-(methoxycarbonyl) methyl-4-nitrophenyl] propionate (ob¬tained in Example 1-(1), 30 mg, 0.07 mmol.). The solu¬tion was stirred for 3.5 hours at room teitperature in a hydrogen gas atmosphere, after addition of 10% palladi¬um/carbon (2.5 mg) . Insolubles were removed by filtra¬tion, and the filtrate was concentrated under reduced pressure to give 28 mg (yield: quantitative amoimt) of the desired compound as a white crystalline product, m.p.: 91-92°C (after recrystallization from ethyl acetate and hexane) ^H-NMR (CDCl3)6: 1.24 (6H, t, J=7Hz), 1.82 (3H, s), 3.75 (6H, s), 4.21 (4H, q, J=7Hz), 4.63 (IH, s), 6.68 (IH, d, J=8Hz), 7.1-7.2 (2H, m) . Preparation (I) of 2-(3-carboxymethyl-4-phenylthiophen-yl)propionic acid In 2N hydrochloric acid (0.5 mL) was dissolved 2-{4-aInino-3-carboxymethylphenyl)prqpionic acid disodium salt (prepared in Exanple 1, 53 mg, 0.2 mmol.) . Sodium ni¬trite (14 mg, 0.2 mmol.) was added to the resulting solu¬tion under stirring and chilling with ice. The mixture was stirred for 30 minutes londer chilling with ice. The mixture was then neutralized with a chilled aqueous satu¬rated sodium acetate solution. To the neutralized mix¬ture was added a solution of thiophenol (0.02 mL, 0.2 mmol.) in 6N aqueous sodium hydroxide solution (0.1 mL), and the mixture was stirred for 2 hours at room teirpera.-ture. The reaction mixture was then made acidic by addi¬tion of 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was extracted with an aqueous saturated sodium hydrogen carixDnate solution. The aqueous portion was then made acidic by addition of 6N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 28 mg (yield: 45%) of the desired conpound. Example 11 Preparation (II) of 2-(3-carboxymethyl-4-phenylthiophen-yl)propionic acid In 0.5N aqueous sodium hydroxide solution (8 mL) was dissolved 2-(3-carboxymethyl-4-nitrqphenyl)propionic acid (prepared in Exarrple 2, 504 mg, 1.99 mmol.) . The solu¬tion was stirred for 19 hours at room temperature in a hydrogen gas atmosphere after addition of 10% palladi-\im/carbon (50 mg) . Insolubles was filtered off and washed with water (8 mL). The filtrate and washing were combined and stirred under chilling with ice. The stirred liquid was made acidic by addition of concentrat¬ed hydrochloric acid (1 mL). To this was added sodium nitrite (138 mg, 2 mmol.) . The resulting mixture was then stirred at 4-5°C for 30 minutes. The mixture was -neutralized with a chilled aqueous saturated sodium ace¬tate solution, and stirred for 1 hour at room tenpeirature and at SS'C for 1 hour after addition of a solution of thiophenol (0.25 mL, 2.4 mmol.) in 4N aqueous sodium hydroxide solution (2 mL) . The reaction mixture was made acidic by addition of concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate portion was washed with water and extracted with an aqueous satu¬rated sodium hydrogen carbonate solution. The aqueous portion was made acidic by addition of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate por¬tion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhy¬drous sodium sulfate. The solvent was distilled off ijnder reduced pressure, to leave 471 mg of a red oil. The oil was. subjected to moderate pressure silica gel column chromatography and eluted with methanol/chloroform (1/40, v/v) mixture, to give 265 mg (yield: 42.1%) of the desired conpound as a white crystalline product, m.p. 143-145°C. Sxanple 12 Preparation (I) of 2-(3-carboxymethyl-4-iodophenyl)pro-pionic acid An aqueous solution (16.05 g) of 2-(4-amino-3-car-boxymethylphenyl)propionic acid disodium salt (802 mg, 3.00 mmol.) and sodium hydroxide (107 mg, 2.68 mmol.) was cooled to 4°C, and stirred at 3-5°C for 4 minutes after addition of 6M(12N) sulfuric acid (1.5 mL) and sodium nitrite (0.23 g, 3.3 mmol.). The resulting reaction mix¬ture was stirred at 4°C for 20 minutes and then at 250 for 16 hours, after addition of potassium iodide (1.49 g, 9.0 mmol.). These reactions were performed in an argon gas atmosphere. The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sxilfate. The dried ethyl acetate portion was ana¬lyzed by HPLC (high performance liquid chromatography) to confirm that 196 mg (0.59 mmol., yield: 20%) of 2-(3-car-boxytnethyl-4-iodophenyl)propionic acid was contained. The ethyl acetate portion was concent2:a.ted and subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain the desired compound as a crystalline product. ^H-NMR (CD30D)6: 1.44 (3H, d, J=7Hz), 3.68 (IH, q, J=7Hz), 3.78 . (2H, s), 6.97 (IH, dd, J=2Hz, 8Hz), 7.30 (IH, d, J=2Hz), 7.79 (IH, d, J=8Hz). EI-MASS(m/e): 334 (M) , 289, 207 Exanple 13 Preparation (II) of 2-(3-carboxymethyl-4-iodophenyl)pro¬pionic acid The procedures of Exaitple 12 were repeated except for eirploying copper (I) iodide (99 wt.%, 1.73 g, 9.0 mmol.) in place of potassium iodide, to give an ethyl acetate portion containing 151 mg (0.45 mmol., yield: 15%) of the desired conpound. Thereafter, the ethyl ace¬tate portion was processed in the manner as described in Exanple 12 to give the desired compound as a purified product. gy^piplg 14 Preparation of 2-[4-bromo-3-(carboxymethyDphenyDpro-pionic acid An aqueous solution (23.65 g) of 2-(4-amino-3-car-boxymethylphenyl) propionic acid disodium salt (1.07 g, 4.00 monol.) and sodiiim hydroxide (142 mg, 3.55 mmol.) was cooled to 3^, and stirred at 3-5®C for 5 minutes after addition of hydrobromic acid (47%, 4.0 mL, 34 mmol.) and sodium nitrite (0.29 g, 4.1 mmol.) . The resulting reac-. tion mixture was dropwise added to a mixture of copper (I) bromide (99 wt.%, 0.87 g, 6.0 mmol.) and hydrobromic acid (47%, 2.5 mL, 22 mmol.), for a period of 7 minutes under chilling with ice. The resulting mixture was stirred at S^C for 1 hour and then at 25°C for 1 hour. These reac¬tions were performed in an argon gas atmosphere. The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sulfate. The dried ethyl acetate portion was ana¬lyzed by HPLC (high performance liquid chromatography) to confirm that 1.02 g (3.56 mmol., yield: 89%) of 2-[4-bromo-3-(carboxymethyl)phenyl] propionic acid was con¬tained. The ethyl acetate portion was concentrated and subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain the desired coitpound as a purified crystalline product. ^H-NMR (CD30D)5: 1.45 (3H, d, J=7Hz), 3.70 (IH, q, J=7Hz), 3.78 (2H, s), 7.15 (IH, dd, J=2Hz, 8Hz), 7.31 (IH, d, J=2Hz), 7.53 (IH, d, J=8Hz). EI-MASS(m/e): 288 (M+2), 286, 207 E?c^mplg 15 Preparation of 2-(3-carboxymethyl-4-chlorophenyl)pro¬pionic acid AQ aqueous solution (23.65 g) of 2-(4-amino-3-car-boxymethylphenyl) propionic acid disodium salt (1.07 g, 4.00 mmol.) and sodium hydroxide (142 mg, 3.55 mmol.) was cooled to 3C, and stirred at 3-5°C for 5 minutes after addition of hydrochloric acid (36%, 3.9 mL, 47 raraol.) and sodium nitrite (0.29 g, 4.1 mmol.) . The resulting mix¬ture was stirred at 3°C for 20 minutes and then at 25°C . for 1 hour, after addition of copper (I) chloride (95 wt.%, 1.25 g, 12 mraol.). These reactions were performed in an argon gas atmosphere. The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sulfate. The dried ethyl acetate portion was con¬centrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 0.71 g (2.9 mmol., yield: 73%)/the desired conpound as a crystalline product. ^H-NMR (CD3OD) 6: 1.45 (3H, d, J=7Hz), 3.71 (IH, q, J=7Hz), 3.75 (2H, s), 7.1-7.4 (3H, m) . EI-MASS(m/e): 242 (M) , 197, 163 Bx^nplg 1$ Preparation (III) of 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid 0.3 M Aqueous potassium hydroxide solution (10 mL, oxygen was removed by addition of 20 mg of sodium hydro-sulfite in advance) was mixed with 2-(3-carboxymethyl-4-iodophenyl)propionic acid (prepared in the manner as described in Exanple 12, 203 n^, 0.607 mmol.) and thio-phenol (95 wt.%, 94 mg, 0.81 mmol.) . The resulting mix¬ture was heated for 19 hours under reflux (tenperature: approx. lOO^C) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was extracted with an aqueous saturated sodium hydrogen carbonate solution. The aque¬ous portion was washed with ethyl acetate, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesiiom sulfate, and concentrated to leave a residue. The resi¬due was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 133 mg (0.420 mmol., yield: 69%)/the desired conpound. Exanple 17 Preparation (IV) of 2- (3-carboxymethyl-4-phenylthio-phenyl)propionic acid 2 - (3 - Carboxyraethyl - 4 - iodophenyl) propionic acid (pre -pared in the manner as described in Exanple 12, 202 mg, 0.605 mmol.), potassium carbonate (380 mg, 2.8 mmol.), N, N-dimethylformamide {LMP, 10 mL), and thiophenol (95 wt.%, 92 mg, 0.79 mmol.) were mixed. The resiilting mix¬ture was heated for 19 hours under reflux (teitperature: approx. ■115°C) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 94 wg (0.30 mmol., yield: 49%) desired conpound. Exanple 18 Preparation of 2-(10,ll-dihydro-10-oxodibenzo[b,f]-thiepin-2 -yl) propionic acid [i.e., Zaltoprofen] 2- (3 -Carboxymethyl-4-phenylthiophenyl) propionic acid (prepared in the manner as described in Exanple 10, 174 mg, 0.55 mmol.) was mixed with polyphosphoric acid (3.5 g) . The mixture was stirred at 60-70'C for 3 hours. The reaction mixture was then extracted with ethyl acetate after addition of chilled water. The ethyl acetate por¬tion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhy-irous sodium sulfate. The solvent was distilled off under reduced pressure to leave a brown crystalline resi¬due. The residue was recrystallized from benzene-hexane, to give 123 mg (yield: 75%) of the desired coiipound as a pale yellow crystalline product, m.p. 130.5-131.5°C ^H-NMR (CDCl3)8: 1.49 (3H, d, J=7Hz), 3.73 (IH, q, J=7Hz), 4.36 (2H, s), 7.16 (IH, dd, J=2Hz, 8Hz), 7.3-7.5 (3H, m), 7.5-7.6 (2H, m), 8.19 (IH, dd, J=lHz, 8Hz) Exanple 19 Preparation (I) of 2-[3-carboxymethyl-4-(2-carboxyphenyl-thio) phenyl] propionic acid In IN aqueous sodium hydroxide solution (12 mL) was dissolved 2-(3-carboxymethyl-4-nitrophenyl)propionic acid (prepared in Exanple 2, 1.52 g, 6.0 ramol.) . The result¬ing solution was stirred for 41 hours at room tenperature in a hydrogen gas atmosphere, after addition of 10% pal¬ladium/carbon (0.03 g). Insolubles were filtered off and washed with water. The filtrate and washing were com¬bined. This was stirred under chilling with ice and made acidic by addition of concentrated hydrochloric acid (2.5 mL) . The acidic solution was stirred at 5°C for 30 min¬utes after addition of sodium nitrite (0.42 g, 6.1 mmol.). To the resulting aqueous diazonium salt solution was dropwise added a solution of thiosalicylic acid (1.39 g, 9.0 mmol.) in 4N aqueous sodium hydroxide solution (12 mL) at 5-15°C for a period of 2 minutes. After the drop-wise addition was conplete, the mixture was stirred at room terrperature for 1 hour and at 95°C for 1 hour. The reaction mixture was made acidic by addition of concen¬trated hydrochloric acid and extracted with three por¬tions of ethyl acetate. The ethyl acetate portions were^ combined, washed successively with water and an aqueous saturated sodium chloride solution, and finally dried over anhydrous sodium sulfate. The solvent was distilled off imder reduced pressure to leave 2.98 g of a brown solid residue. The residue was suspended in ethyl ace¬tate, and insolubles were filtered off. The filtrate was concentirated under reduced pressure after addition of silica gel (4.2 g) . The concentrate was subjected to moderate pressure silica gel column chromatography and eluted with acetic acid/chloroform (1/10, v/v), to give 0.30 g of the desired compound as a yellow crystalline product. m.p.: 229-232°C ^H-NMR (CD30D)6; 1.51 (3H, d, J=7Hz), 3.76 (2H, s), 3.79 (IH, q, J=7Hz), 6.67 (IH, dd, J=1H2, 8Hz), 7.14 (IH, ddd, J=lHz, 7Hz, BHz), 7.24, (IH, ddd, J=2Hz, 7Hz, 8Hz), 7.34 (IH, dd, J=2Hz, 8Hz) , 7.44 (IH, d, J=2Hz), 7.52 (IH, d, J=8Hz), 7.99 (IH, dd, J=2Hz, 8Hz) . IR ^wax (KBr) cm'^: 2980, 1700, 1465, 1410, 1310, 1255, 1230, 750. Example 20 Preparation (II) of 2-[3-carboxymethyl-4-(2-carboxy-phenylthio)phenyl]propionic acid In 2N hydrochloric acid (1.5 mL) was dissolved 2-(4-amino-3-carboxymethylphenyl) propionic acid disodium salt (prepared in the manner as described in Example J, 134 mg, 0.5 mmol.) . To the resulting solution was added sodi¬um nitrite (35 mg, 0.5 ramol.) under stirring and chilling with ice. The mixture was stirred at 5°C for 30 minutes. To the resulting aqueous diazonium salt solution was dropwise added a solution of thiosalicylic acid (154 mg, 1.0 mmol.) in 4N aqueous sodium hydroxide solution (2 mL). After the dropwise addition was conplete, the mix¬ture was stirred at room tenperature for 1 hour and at 95'C for 1 hour. The reaction mixture was made acidic by addition of 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo- . ride solution, and finally dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 230 mg of a brown solid residue. The residue was suspended in ethyl acetate, and insolubles were filtered off. The filtrate was concentrated under reduced pressure after addition of silica gel (0.4 g). The concentrate was subjected to moderate pressure silica gel column chromatography and eluted with acetic acid/ chloroform (1/10, v/v), to give 24 rag of the desired com¬pound as a white crystalline product- Example 21 Preparation of methyl 2-[3-methDxycarbonylmethyl-4-(2-methoxycarbonylphenylthio) phenyl] propionate 2- [3-Carboxymethyl-4- (2-carboxyphenylthio)phenyl] -propipniq acid (72 mg, 0.2 mmol.), metlianol (0.8 mL), trlmethyl orthoformate mL), and concentrated sulfuric acid (0.05 mL) were mixed, and the mixture was heated for 6 hours under reflux. The reaction mixture was diluted with water and washed with diethyl ether. The diethyl ether portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 78 rag of the desired compound as a colorless oil. Preparation of tnet±,yl 2-.(10,ll-dihydro-ll-niethoxycarbonyl -10 -oxodibenzo [b, f ] thiepin- 2 -yl) propionate Methyl 2- [3-methoxycarbonylmethyl-4- (2-methoxycar-bonylphenylthio) phenyl] propionate (prepared in Exarrple 21, 78 mg, 0.19 rnraol.), toluene (1 niL) and potassium t- butoxide (43 mg, 0.38 mmol.) were mixed, and the mixtiore was stirred for 16 hours at room tenperature. The reac¬ tion mixture was then extracted with ethyl acetate after addition of 2N hydrochloric acid. The ethyl acetate portion was washed with an aqueous saturated sodium chlo¬ ride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off, to leave 78 mg of a pale yellow oil. The oil was subjected to moderate pres¬ sure silica gel column chromatography and eluted with ethyl acetate/hexane (1/4, v/v), to give 21 mg of the desired cottpound as a colorless oil (a mixture of 1:1 diastereomers) . The following NMR data are those of the Example 23 Preparation of 2- (10,11-dihydro-11-oxodibenzo [b, f] -thiepin-2-yl) propionic acid Methyl 2- (10, ll-dihydro-11-methoxycarbonyl-lO-oxodir benzo[b,f] thiepin-2-yl)propionate (prepared in Exanple 22, 18 mg, 0.040 mmol.), acetic acid (0.3 mL) and 6N hydrochloric acid (0.3 mL) were mixed, and the mixture was heated for 2 hours under reflux. To the reaction mixture was added water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous satu- rated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The residue was dissolved in toluene and concentrated under reduced pressure to give 14 mg of the desired com¬pound as a white crystalline product.' m.p.: 130,5 - 131.5°C 1H-NMR (CDCl3)6: 1.49 (3H, d, J=7Hz), 3.73 (1H, q, J=7Hz), 4.36 (2H, s), 7.16 (1H, dd, J=2Hz, 8Hz), 7.3-7.5 (3H, m) , 7.5-7.6 (2H, m) , 8.19 (1H, dd, J=lHz, 8Hz). ' Example 24 Preparation (III) 2-[3-carboxymethyl-4-(2-carboxyphenyl-thio) phenyl] propionic acid 0.2 M Aqueous potassium hydroxide solution (5 mL, oxygen was removed by addition of 15 mg of sodium hydro-sulfite in advance) was mixed with 2-(3-carboxymethyl-4- . iodophenyl)propionic acid (prepared in Exanple 12, 40.7 mg, 0.122 mmol.) and thiosalicylic acid (37.3 mg, 0.242 mmol.) . The resulting mixture was heated for 20 hours under reflux (temperature: approx. 100°C) after addition of 10 wg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry. Co., Ltd., hexane/ethyl acetate/acetic acid=s7/3/l, v/v/v) to obtain 40.6 mg (0.084 mmol., yield: 69%) of the de¬sired conpound. This application is divided out of Indian Patent Application No.1862/MAS/97 which relates to a new process for the preparation of substituted propionic acid. The nain clain of said specification reads as follows: A process for preparing 2-(10,ll-dihydro-10-oxodibenzo[b,f3thiepin-2-Yl) propionic acid comprising reacting 2-(3-carboxymethyl-4-halogenophenyl)propionic acid or its salt with thiophenol in a polar solvent, under basic conditions, in the presence of a known catalyst, to produce 2-(3-oarboxymethyl-4-phenylthiophenyl)propionic acid or its salt cyclizing the product in the presence of a known condensation agent under known conditions and recovering 2-(10,ll-dihydro-10-oxodibenzo[b,f]thiepin-2,Yl)propionic acid by a known manner. WE CLAIM: 1. A process for preparing 2-(3-carboxymethyl-4-halogenophenyi) propionic acid having the following formula or its salt: in which Hal is a halogen atom, the said process comprises subjecting 2-(4-amino-3-carboxymethyl-phenyl)propionic acid having the following formula or its salt: to diazotization at –l0 C to 20°C under acidic conditions alkyl subsequent reaction with a halogenations agent, such as herein described, at -10*C to 100°C and thereafter recovering the 2-(3-carboxymethyl-4-ha]ogenophenyl) propionic acid in a known manner.

Full Text

The present invention provides a process for preparing 2-(3-carboxymethyl-4-halogenophenyl) propionic acid
Zaltoprofen is known as a pharmaceutically active compound which shows excellent anti-inflammatory effect as well as excellent analgesic effect.
Japanese Patent Provisional Publication No. 55-53282 describes a process for preparing Zaltoprofen which com¬prises hydrolyzing ethyl 5-(a-cyan ethyl)-2-phenylthio-phenylacetate to give 5-(a-cyan ethyl)-2-phenylthio-phenylacetic acid, subjecting the resulting compound to cyclization and amidation of cyano group, and hydrolyzing the amide group of the resulting compound.
Japanese Patent Provisional Publication No. 57-106678 describes an reproved process-for preparing Zaltoprofen which cutpurses hydrolyzing ethyl 5-(a-cyano¬ethyl)-2-phenyl thiophenylacetate to give 2-(3-carboxy-methyl-4-phenylthiophenyl)prop ionic acid and stylizing the resulting compound in the presence of a condensation agent.
Japanese Patent Provisional Publications No. 62-292760 and No. 63-10756 describe a process for preparing Zaltoprofen which starts from: a haloketal compound.
Japanese Patent Provisional Publication No. 63-2970 describes a process for preparing Zaltoprofen in which

methyl 5-propionyl-2-phenylthiophenylacetate is reacted with an orthoformic acid ester and metallic zinc or zinc halide to produce methyl 2-(3-methoxycarbonylmethyl-4-phenylthiophenyl)propionate, and this product is reemployed for the preparation of Zaltoprofen.
As described above, a variety of processes for pre¬paring Zaltoprofen are known. However, more improved processes are desired from the viewpoints of availability of the starting materials and easy handling of the mate¬rials participating in the reactions for the preparation, as well as economical viewpoints such as yields.
The present invention has an object to provide new processes for preparing Zaltoprofen.
Specifically, the invention has an object to provide new processes for preparing Zaltoprofen which are advan¬tageously employable in industry from the viewpoints of availability of the starting materials and easy handling of the materials participating in the reactions for the preparation, as well as economical viewpoints such as yields.
SUMMARY OF THE INVENTION
The present invention resides in a process for pre¬paring 2- (10,11-dihydro-lO-oxodibenzo [b, f ]thiepin-2-yl) -propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazo-tization and subsequent reaction with thiophenol to pro¬duce 2-(3-carboxymethyl-4-phenylthiophenyl) propionic acid or its salt, and subjecting the product to cyclization reaction — (Preparation-I).
The invention also resides in a process for prepar¬ing 2- (10,11-dihydro-l0-oxodibenzo [b, f] thiepin-2-yl)pro¬pionic acid which comprises subjecting 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt to diazotization and subsequent reaction with a halogenations agent

to produce 2-(3-carbDxymethyl-4-halogenophenyl)propionic acid or its salt, causing a reaction of the product with thiophenyl to produce 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt, and subjecting the product to cyclization reaction — (Preparation-II).
The invention further resides in a process for pre¬paring 2- (10,11-dihydro-lO-oxodibenzo [b,f] thiepin-2-yl) -propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazo¬tization and subsequent reaction with thiosalicylic acid to produce 2-[3-carboxymethyl-4-(2-carboxyphenylthio)-phenyl]propionic acid or its salt, etherifying the prod¬uct to give a 2-[3-(lower)al]coxycarbonylmethyl-4-(2-(low¬er) alkoxycarbcnylphenylthio) phenyl] propionic acid (low¬er) alkyl ester, stylizing the resulting ester to produce a 2-(10,11-dihydro-ll-(lower)alkoxycarbonyl-10-oxodi-]Denzo[b,f]thiepin-2-yl) propionic acid (lower) alkyl ester, and subjecting the resulting ester to hydrolysis and de¬carboxylation — (Preparation-Ill).
the invention furthermore resides in a process for preparing 2- (10,11-dihydro-l0-oxodibenzo [b, f] thiepin-2-yl)propionic acid which comprises subjecting 2-(4-ainino-3-carboxymethylphenyl) propionic acid or its salt to diazotization and subsequent reaction with a lialogenating agent to produce 2-(3-carboxymethyl-4-halogenophenyl)-propionic acid or its salt, causing a reaction of the product with thiosalicylic acid to produce 2-[3-carboxy-methyl - 4 - (2 - carboxyphenylthio) phenyl ] propionic acid or its salt, etherifying the product to give a 2- [3- (low¬er) alkoxycarbonylmethyl-4- (2-(lower)alkoxycarbcnylphenyl¬thio) phenyl] propionic acid (lower) alkyl ester, stylizing the resulting ester to produce a 2-(10,11-dihydro-ll-(lower) alkoxycarbonyl-10-oxodibenzo [b, f ] thiepin-2-yl) pro¬pionic acid (lower)alkyl ester, and subjecting the re¬sulting ester to hydrolysis and decarboxylation — (Pre¬paration-IV) .

The 2 - (4 - amino - 3 - carboxymet±ylphenyl) propionic acid or its salt is a new compound, and it can be produced by a variety of processes described below.
1) A process which comprises reducing 2-(3-car-boxyraethyl-4-nitrophenyl)propionic acid or its salt.
2) A process which comprises subjecting a methy malonic acid derivative of the following formula (A) :

in which R^ represents cyano, carboxyl, carbamoyl, alkyl-carbonyl having 2 to 7 carbon atoms, alkoxycarbonyl hav¬ing 2 to 7 carbon atoms, aryloxycarbonyl having 7 to 13 carbon atoms, or aralkyloxycarbonyl having 8 to 19 carbon atoms; and each of R1, R2 and R3 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or a alkyl having 7 to 18 carbon atoms
to hydrolysis and decarboxylation, to produce 2-(3-car-boxymethyl-4-nitrophenyl)propionic acid or its salt, and reducing the product.
3) A process which comprises causing a reaction of an acetic acid ester derivative with a 2-(3-halogeno-4-nitrophenyl)-2-methylmalonic acid daily ester[=2-(3-halogeno-4-nitrophenyl)-2-methylpropanedioic acid dialkyl ester], to give a methy malonic acid derivative of the above-mentioned formula (A) / subjecting the methy malonic acid derivative to hydrolysis and decarboxylation, to produce 2-(3-carboxymethyl-4-nitrophenyl)propionic acid or its salt; and reducing the product.
4) A process which comprises causing successive reactions of a 2,4-dihalogenonitrobenzene with a methyl-

malonic acid diester and with an acetic acid ester deriv¬ative, to give a methylnialonic acid derivative of the aforementioned formula (A) / subjecting the methy malonic acid derivative to hydrolysis and decarboxylation, to produce 2-(3-carboxymethyl-4-nitrophenyl)propionic acid or its salt; and reducing the product.
5) A process which comprises reducing a methy malonic acid derivative of the aforementioned formula (A), to give another methy malonic acid derivative having the following formula (B):

in which each of R^, R^, R^ and R* has the meaning as defined above for the formula (A) / and subjecting the "methy malonic acid derivative of the formula (B) to hy¬drolysis and decarboxylation.
The invention furthermore resides in a process for preparing 2- (10, ll-dihydro-lO-oxcdibenzo [b, f] thiepin-2-yl) propionic acid which comprises causing a reaction of 2-(3-carboxycnethyl-4-halogenophenyl)propionic acid or its salt with thiophenyl, to produce 2-(3-carbo3cymethyl-4-phenylthiophenyl)propionic acid or its salt, and cycles-ing the product — (Preparation-V).
The invention furthermore resides in a process for preparing 2- (10, ll-dihydro-10-oxodibenzo [b, f ] thiepin-2-yl) propionic acid which comprises causing a reaction of 2 - (3 - carboxymethyl - 4 -halogen phenyl) propionic acid or its salt with thiosalicylic acid, to produce 2-[3-carboxy-Tlethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or Lets salt, etherifying the product to give a 2-[3-(low-;r) alkoxycarbonylmethyl-4- (2- (lower) alkoxycarbonylphenyl-:hio)phenyl]propionic acid (lower) alkyl ester, cyclizing

the resulting ester, and subjecting the cyclone ester to hydrolysis and decarboxylation — (Preparation-VI) .
Furthermore, the invention resides in a compound having the following formula (C) :

in which X represents NO2, NH2, halogen, or a group of the following formula;
in which R7 represents hydrogen, alkyl having 1 to 6 car¬bon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms,
and each of R5 and R6 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms.
The compound of the formula (C) is of value as an intermediate compound for preparing the 2-(10,11-dihydro-10 -oxodibenzo [b, f ] thiepin-2 -yl)propionic acid.
Representative examples of the compounds of the formula (C) include the following:
a) 2-(3-Carboxymethyl-4-nitrophenyl)propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt.
b) 2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt.
c) 2 - [ 3 - Carboxymethyl - 4 - (2 - carboxypheny lthio) -phenyl] propionic acid, its alkyl ester in which the alkyl has 1 to 6 carbon atoms, or its salt.

d) 2 - (3 -Carboxymet±.yl-4 -halogen phenyl) propionic acid, its alkyl ester in which the alkyl has 1 to 6 car¬bon atoms, or its salt.
e) An alkyl ester of 2- [3-alkoxycarbonylmethyl-4-(2-alkoxycarbonylphenylthio) phenyl] propionic acid in
which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms.
Furthermore, the invention resides in a compound having the following formula (D) :

in which Y represents NO2 or NH2, R1 represents cyano, carboxyl, carbamoyl, alkyl carbonyl having 2 to 7 carbon atoms, alkoxycarbonyl having 2 to 7 carbon atoms, aryl-ox carbonyl having 7 to 13 carbon atoms, or aralkyloxy carbonyl having 8 to 19 carbon atoms; and each of R2, R3 and R4 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 18 carbon atoms.
The compound of the formula (D) also is of value as an intermediate cot pound for preparing the 2-(10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl)propionic acid.
Representative examples of the compounds of the formula (D) include the following:
a) Dialkyl ester of 2-[3-bis(alkoxycarbonyl)-methyl-4-nitrophenyl] -2-methylmalonic acid in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms.
b) Dialkyl ester of 2-[3-[(alkoxycarbonyl)cyano-methyl] -4-nitrophenyl] -2-methylmalonic acid in which the alkyl lias 1 to 6 carbon atoms and the alkoxy lias 1 to 6 carbon atoms.

c) Dialkyl ester of 2-[3-[acetyl(alkoxycarix)nyl)-methyl] -4-nitrophenyl] -2-methylmalonic acid in which the allcyl has 1 to 6 carbon atoms and the alkyoxy has 1 to 6 carbon atoms.
d) Dialkyl ester of 2-[4-amino-3-bis(alkoxycar-bonyl)methyl phenyl]-2-methylmalonate in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms.
Furthermore, the invention resides in a compound having the following formula (E) :

in which each of R5 and R6 independently represents hydro¬gen, alkyl having 1 to 6 carbon atoms, aryl having 6 to "12 carbon atoms, or aralkyl having 7 to 18 carbon atoms.
The compound of the formula (E) also is of value as an intermediate compound for preparing the 2-(10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl)propionic acid.
Representative examples of the compounds of the formula (E) include an alkyl ester of 2-(11-alkoxycar-bonyl-10, ll-dihydro-lO-oxodibenzo [b, f] thiepin-2-yl)pro¬pionic acid in which the alkyl has 1 to 6 carbon atoms and the alkoxy has 1 to 6 carbon atoms.
PREFERRED EMBQDINENTS OF THE INVENTION
The processes of the invention for preparing Zaltoprofen, that is, 2-(I0,ll-dihydro-l0-oxodibenzo-[b/f] thiepin-2-yl)propionic acid, are further described below in more detail. (1) Preparation-I
Preparation-1 of the invention for preparing

Zaltoprofen is characterized in that 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiophenyl to give 2-(3-carboxy-methyl-4-phenylthiophenyl)propionic acid. or its salt, and the resulting product is then subjected to cyclization reaction. Preparation-1 is illustrated in the following reaction scheme I: [Reaction Scheme I]

1) Preparation of 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt
2-(4-Amino-3-carboxymethylphenyl)propionic acid or its salt (e.g., disodium salt, dipotassium salt, di-lithium salt) is diazotized by the use of a diazotizing agent, for instance, under acidic conditions (made acidic with hydrochloric acid), and the resulting compound (i.e., diazo compound) is reacted with thiophenyl in a solvent. The diazotization reaction can be performed by-bringing the starting compound into contact with a diazo¬tizing agent (e.g., sodium nitrite, nitrosyl hydrogensul-fate, nitrosyl chloride) at -10 to 20'C under acidic conditions (made acidic with hydrochloric acid, sulfuric acid, or acetic acid) . The resulting compound (i.e.,

diazo compound) is then brought into contact with thio-phenol at 0 to 100°C under basic conditions (e.g., in an aqueous sodium hydroxide or potassium hydroxide solution) to give the 2 - (3 - carboxyraethyl - 4 -phenyl thiophenyl) pro -panic acid or its salt.
2) Preparation of Zaltoprofen The above-mentioned 2-(3-carboxymethyl-4-phenyl-thiophenyl)propionic acid or its salt is a known com¬pound. The preparation of Zaltoprofen by cyclizing this compound in the presence of a condensation agent is de¬scribed in Japanese Patent Publication Hl-29793. The condensation agent can be sulfuric acid, polyphosphoric acid, or polyphosphoric acid ester, and the reaction is generally performed at a temperature of 0 to 150°C. (2) Preparation-II and Preparation-V
Preparation-11 of the invention for preparing Zaltoprofen is characterized in that 2- (4-amino-3-car-boxymethylphenyl) propionic acid or its salt is diazotized and then reacted with a halogenations agent to give 2-(3-carboxymethyl - 4-halogenophenyl) propionic acid or its . salt, and the resulting compound is reacted with thio-phenol to give 2-(3-carboxymethyl-4-phenylthiophenyl) pro¬pionic acid or its salt, which is finally subjected to cyclization reaction. Preparation-II is illustrated in the following reaction scheme II (in the scheme, "Hal-" means a halogen group): [Reaction Scheme II]

In Reaction Scheme II, the route in which 2-(3-car-boxymethyl-4-halogenophenyl) propionic acid or its salt is reacted with thiophenyl (not illustrated) to give 2-(3-carboxymethyl-4-phenylthiophenyl) propionic acid or its salt, and this product is cyclized to give Zaltoprofen (final product) corresponds to Preparation-V.
1) Preparation of 2-(3-carboxymethyl-4-halogeno¬
phenyl) propionic acid or its salt
2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid or its salt (e.g., disodium salt) is diazotized in the same maimer as in Preparation-1, and the resulting compound (i.e., diazole compound) is treated with a halogenations agent (e.g., potassium iodide, copper(I) chloride, copper (I) bromide, copper (I) iodide, or hydrotropic acid gener¬ally in the presence of powdery copper) at -10 to 100°C, to give the 2-(3-carboxyinethyl-4-halogenophenyl)propionic acid or its salt.
2) Preparation of 2-(3-carboxymethyl-4-phenylthio-
phenyl) propionic acid or its salt
The above-mentioned 2-(3-carboxynethyl-4-halogeno-phenyl)propionic acid or its salt is reacted with thio-phenol in a polar solvent (e.g.. .^dimethylsulfoxide (EMSO), dimeth-ylformamide (DMF), or water) at 25 to 120°C, under basic conditions (e.g., made basic with potassium hydroxide or potassium carbonate) in the presence of a catalyst (e.g., potassium iodide, powdery copper, copper salt), to give the 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid or its salt.
3) Preparation of Zaltoprofen
The process described in the aforementioned Prepaira-tion-I can be utilized. (3) Preparation-III

Preparation-III of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-car-boxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiosalicylic acid to give 2-[3-carboxymethyl-4- (2-carboxyphenylthio)phenyl]propionic acid or its salt; the resulting compound is esterifies to give .2- [3- (lower) alkoxycarbonylmethyl-4- (2- (lower) alkoxy-carbonylphenylthio) phenyl] propionic acid (lower) alkyl ester; the resulting ester is subjected to cyclization reaction, to give 2-(10,11-dihydro-ll-(lower)alkoxycar-bonyl-10-oxodibenzo[b,f] thiepin-2-yl)propionic acid (low¬er) alkyl ester; and the resulting ester is finally sub¬jected to hydrolysis and decarboxylation. Preparation-Ill is illustrated in the following reaction scheme III: [Reaction Scheme III]

1) Preparation of 2-[3-carboxymethyl-4-(2-carboxv-

pnenyithio) phenyl] propionic acid or its salt
2 - (4 -Amino - 3 - carboxymethylphenyl) propionic acid or its salt is diazotized in the same manner as in Prepara¬tion-!, and the resulting compound (i.e., diazo compound) is reacted with thiosalicylic acid at 0 to l00C, prefer¬ably under basic conditions, to give the 2-[3-carboxy-methyl-4-(2-carboxyphenylthio) phenyl] propionic acid or its salt.
2) Preparation of 2-[3-(lower)alkoxycarbonylmethyl
-4- (2- (lower) alkoxycarbcnylphenylthio)phenyl] propionic
acid (lower) alkyl ester
The esteri-fication reaction can be performed by utilizing a lower alcohol (alcohol having 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol) , utilizing other etherifying agent (e.g., methyl orthoformate, or ethyl orthoformate), or utilizing both of the lower alcohol and other etherifying agent. In the esterification reaction, an inorganic acid such as sulfu¬ric acid or hydrochloric acid, an organic' acid such as an aromatic sulfuric acid, or a Lewis acid such as boron trifluoride ether ate is preferably employed in a cata¬lytic amount or more so that the reaction can be acceler¬ated.
3) Preparation of 2-(10,11-dihydro-ll-(lower)-
alkoxycarbonyl-10-oxodibenzo [b, f] thiepin-2-yl) propionic
acid (lower) alkyl ester by cyclization of 2-[3-(lower)-
alkoxycarbonylmethyl-4 - (2 - (lower) alkoxycarbonylphenyl-
thio)phenyl]propionic acid lower alkyl ester
The cyclization reaction is known as Deskman reac¬tion, and the compound to be cyclized is brought into contact with a base in a solvent. Examples of the bases include alkali metals (e.g., sodium metal), alcoholisms of alkali metals (e.g., potassium tert-but oxide, and sodium ethoxide), alkali metal hydrides (e.g., sodium hydride), and sodium methyl Ulf inylmethide. The solvent can be benzene, toluene, xylene, ethyl ether, or dimethyl-

In Reaction Scheme IV, the route starting from the 2-(3-carboxymethyl-4-halogenophenyl)propionic acid or its salt to give Zaltoprofen (final product) corresponds to Preparation-VI.
1) Preparation of 2-(3-carboxymethyl-4-halogeno-
phenyl) propionic acid or its salt
The preparation can be performed in the manner as described in Preparation
2) Preparation of 2-[3-carboxymethyl-4-(2-carboxy-
phenythio)phenyl3propionic acid or its salt
The above-mentioned 2-(3-carboxymethyl-4-halogeno-phenyl)propionic acid or its salt is reacted in a polar solvent (e.g.,DMSO, ESMF, or water) under basic condi¬tions (for instance, in the presence of potassium hydrox-

ide or potassium carbonate) at 25 to 120'C in the presence of a catalyst (e.g., potassium iodide, powdery copper, or copper salt).
3) Preparation of 2-[3-(lower)alkoxycarbonyl-
methyl-4- (2- (lower)alkoxycarbonylphenylthio)phenyl]pro¬
pionic acid (lower) alkyl ester
The preparation can be performed in the manner as described in Preparation 35 ,
4) Preparation of 2-(10,11-dihydro-ll-(lower)-
alkoxycarbonyl-lO-oxodibenzo [b, f] thiepin-2-yl) propionic
acid (lower)alkyl ester by cyclization of 2-[3-(lower)-
alkoxycarbonylmethyl-4- (2- (lower) alkoxycarbonylphenyl¬
thio) phenyl] propionic acid lower allcyl ester
The preparation can he performed in the manner as described in Preparation
5) Preparation of Zaltoprofen by hydrolysis and
decarboxylation of 2-(10,11-dihydro-ll-(lower)alkoxy-
cartxsnyl -10 - oxodibenzo [b, f ] thiepin- 2 -yl) propionic acid
(lower) alkyl ester
The process described in the aforementioned Prepara¬tion-Ill can be utilized.
The starting confound etrployed for the aforemen¬tioned various processes for the preparation of Zalto¬profen, that is, 2-(4-amino-3-carboxymethylphenyl)pro¬pionic acid or its salt is, as stated hereinbefore, a new compound. This new compound can be produced from a known compound in the manners described below. (1) Production of 2-(4-amino-3-carboxymethylphenyl)pro-pionic acid or its salt — Production-(1)
2-(3-Halogeno-4-nitrophenyl)-2-methylmalonic acid diester is reacted with an acetic acid ester derivative [which is represented by the formula of R1-CH2COOR2 (each of R1 and R2 has the meaning defined hereinbefore) and can be exemplified by malonic acid dialkyl ester, acetoacetic acid ester, and cyanoacetic acid ester] to give the meth¬ylmalonic acid derivative having the aforementioned for-

mula (A); the methylmalonic acid derivative is subjected to hydrolysis and decarboxylation to give 2- (3-carboxy-methyl-4-nitrophenyl)propionic acid or its salt; and finally the resulting compound is reduced to give the desired compound. Production- (1) is illustrated in the following Reaction Scheme V. [Reaction Scheme V]

,COOR* C00R3
,C00R4 C00R3

COOH

OOH

COOH

OOH

1) Production of the methylmalonic acid derivative having the formula (A)
The desired conpound can be produced by reacting 2-(3-halogeno-4-nitrophenyl)-2-methylmalonic acid diester (in which "halogeno" means fluoro, chloro, or bromo) with an acetic acid ester derivative [e.g., malonic acid dialkyl ester having alkyl of 1-6 carbon atoms, such as dimethyl malonate; acetoacetic acid ester such as methyl acetoacetate or ethyl acetoacetate; or cyanoacetic acid ester such as methyl cyanoacetate or ethyl cyanoacetate) .
The reaction is preferably carried out in an anhy¬drous organic solvent such as anhydrous dimethylformamide in the presence of a basic compound such as potassium tert-butoxide or sodium hydride, in an inert gas atmo¬sphere such as a nitrogen gas atmosphere. The reaction tenperature generally is in the range of from 50°C (pref¬erably from 70 to the boiling tenperature of the reac-

tion solvent. A representative conpound of the 2-(3-halogeno-4-nitrophenyl) -2-methylmalonic acid diallcyl ester eirployed in the above production process is diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate, which is known and described in Japanese Patent Publication No.47-45746.
2) Production of 2-(3-car3^oxymethyl-4-nitro-
phenyl)propionic acid or its salt
This conpound can be oroduced by subjecting the , , , . /derivatives ^ J r
methylmalonic acid/of the formula (A) [which is obtained
in the 1) above] to reactions for hydrolysis and decar¬boxylation. The hydrolysis and decarboxylation can be carried out, for instance, in an aqueous acetic acid solution, in the presence of concentrated sulfuric acid as catalyst. The reactions can be performed simultaneously or successively by heating the reaction solution under reflux.
3) Production of 2-(4-amino-3-carboxymethyl-
phenyl) propionic acid or its salt
This conpound can be produced by reducing the 2-(3-carboxymethyl-4-nitrophenyl) propionic acid or its salt [which is obtained in the 2) above] under basic condi¬tions (in an aqueous alkaline solution containing, for instance, sodium hydroxide, potassium hydroxide, lithium hydroxide, or sodium carbonate). The salt of 2-(4-amine¬s'carboxyne thy Iphenyl) propionic acid can be a disodium salt, a dipotassium salt, or a dilitliium salt. The re¬duction can be performed utilizing hydrogen gas in the presence of palladium/carbon.
(2) Production of 2-(4-araino-3-carboxymethylphenyl)pro¬pionic acid or its salt — Production-(2)
2,4-Diiialogenonitrobenzene (known conpoimd) is re¬acted successively with methylmalonic acid diester (e.g., dialkyl methylmalonate) and the aforementioned acetic acid ester derivative, to give the methylmalonic acid derivative of the formula (A) / the methylmalonic acid

derivative is then subjected to hydrolysis and decarbox¬ylation, to give 2-(3-carboxymethyl-4-nitrophenyl)pro¬pionic acid or its salt; and finally the product is re¬duced to give the desired conpound. Production-(2) is illustrated in the following Reaction Scheme VI. [Reaction Scheme VI]

1) Production of the methylmalonic acid derivative
having the formula (A)
2,4-Dihalogenonitrobenzene (in which "halogeno" means, for instance, chloro or bromo) is reacted succes¬sively with a methylmalonic acid diester (e.g., dialkyl methylmalonate such as diethyl methylmalonate) and the above-mentioned acetic acid ester derivative. The reac¬tion can be carried out by utilizing the procedures de¬scribed in the aforementioned Production-(1)-1) .
2) Production of 2-(3-carboxymethyl-4-nitro-
phenyl)propionic acid or its ester
The production can be performed in the manner as described in the above-mentioned Production- (1) .
3) Production of 2-(4-amino-3-carboxymethyl-

phenyl)propionic acid or its salt
The production can be performed in the manner as described in the above-mentioned Production- (1) . (3) Production of 2-{4-amino-3-carboxymethylphenyl)pro¬pionic acid or its salt — Production-(3)
The methylmalonic acid derivative of the formula (A) is first reduced to convert into a methylmalonic acid derivative of the fornnula (B), and the resulting deriva¬tive is then subjected to hydrolysis and decarboxylation. Production-(3) is illustrated in the following Reaction Scheme VII. [Reaction Scheme VTI]

1) Production of the methylmalonic acid derivative
of the formula (B) by reduction of the methylmalonic acid
derivative of the formula (A)
The reduction can be performed by bringing the meth¬ylmalonic acid derivative of the formula (A) into contact with hydrogen gas at -10 to 100^'C in the presence of palladium/carbon.
2) Hydrolysis and decarboxylation of the methyl¬
malonic acid derivative of the formula (B)
The hydrolysis and decarboxylation can be carried out in the same manner as the hydrolysis and decarboxyl¬ation of the methylmalonic acid derivative of the formula (A) which is described in the Production-(1) .

Accordingly the present invention provides a process for preparing 2-(3-carboxymethyi-4-halogenophenyl) propionic acid having the following formula or its salt:

in which Hal is a halogen atom, the said process comprises subjecting 2-(4-amino-3-carbo)cymethyl-phenyl)propionic acid having the following formula or its salt:

to diazotization at -10°C to 20*'C under acidic conditions and subsequent reaction with a halogenating agent, such as hereindescribed, at -10°C to lOO^C and thereafter recovering the 2-(3-carboxymethyl-4-halogenophenyl) propionic acid in a known manner.

The present invention is further described by the following examples.
Example 1 Preparation (I) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid
(1) Preparation of diethyl 2-[3-bis(methoxycarbonyl)-
methyl-4-nitrophenyl] -2-methylmalonate
Dimethyl malonate (4.04 g, 30.6 mmol.), potassium t-butoxide (3.43 g, 30.6 mmol.) and anhydrous N,N-dimethyl-formamide (15 mL) were mixed and stirred at 90°C for 10 minutes in a nitrogen atmosphere. The mixture was then cooled to room tertperature and added to a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (5.04 g, 15.3 mmol., prepared in the manner as described in Japanese Patent Publication No. 47-45,746) in anhydrous N,N-dimethylformamide (15 mL) . The resulting mixture was stiiired at 90°C for 3 hours, and then poured into IN hydrochloric acid (30 mL) . The mixture was subjected to extraction using two portions of diethyl ether. The ether extracts were combined, washed successively with water and an aqueous satu23.ted sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ex¬tract was placed imder reduced pressure to give 7.97 g of a yellow oil. The oil was adsorbed on silica gel (16 g) and subjected to moderate pressure silica gel column chromatography. The adsorbed oil was eluted using a mix¬ture of ethyl acetate/hexane (1/1, v/v) to give 4.33 g (yield: 66.7%) of the desired confound as a yellow oil. ^H-NMR (CDCl3)6:
1.27 (6H, t, J=7Hz), 1.88 (3H, s), 3.80 (6H, s), 4.24 (2H, q, J=7Hz), 4.25 (2H, q, J=7Hz), 5.35 (IH, s), 7.55 (IH, dd, J=2Hz, 8Hz), 7.57 (IH, d, J=2Hz), 8.05 (IH, d, J=8Hz).
(2) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro-
Dionic acid

The diethyl 2-[3-bis(^1ethoxycarbonyl)methyl-4-nitrophenyl] -2-met±.yltralorLate (obtained in (1) above, 4.13 g, 9.71 mmol.) was dissolved in acetic acid (40 mL) . To the solution were added water (16 mL) and concentrated sulfuric acid (4 mL), and the resulting mixture was heat¬ed for 15 hours under reflux. The acetic acid was dis¬tilled off under reduced pressure. *The residue was con¬centrated under reduced pressure after addition of tolu¬ene. The precipitated crystals were collected by filtra¬tion and washed with water to give 2.06 g of the desired conpound as a pale brown crystalline product. The fil¬trate and washing were combined and subjected to extrac¬tion using ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 0.32 g of the desired conpound as a yellow crystalline product. The total amount was 2.38 g "(yield: 96.8 %) .
m.p.: 169-171'=C (after recrystallization from ethyl
acetate and hexane) ^H-NMR (CD30D)6: .
1.51 (3H, d, J=yHz), 3.86 (IH, q, J=7Hz), 4.04
(2H, s), 7.42 (IH, d, J=7Hz), 7.49 (IH, dd,
J=2Hz, 8Hz), 8.09 (IH, d, J=8Hz). IR ^xmK (KBr) cm"^:
2980, 1700, 1610, 1585, 1515, 1450, 1430, 1340,
1300, 1250, 1230, 930.
Example 2 Preparation (II) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid
In anhydrous N, N-dimethylformamide (20 mL) were dissolved 2,4-dichloronitrobenzene (3.84 g, 20 mmol.) and diethyl methylmalonate (5.23 g, 30 mnral.) . To this was added potassium t-butoxide (3.37 g, 30 mmol.) with stir-

ring under chilling with ice. The resulting mixture was fiirther stirred for 5 minutes under chilling with ice, and then for 18 hours at room teiiperature.
Independently, dimethyl malonate (5.28 g, 40 mmol-), potassium t-butoxide (4.48 g , 40 mmol.), and anhydrous N, N-dimethylformamide (20 mL) were mixed, and then stirred at 90°C for 10 minutes. The reaction mixture was cooled to room tenperature, and stirred at 90°C for 4 hours after addition of the aforementioned reaction mix¬ture. The resulting reaction mixture was poured into a mixture of 2N hydrochloric acid (40 raL) and ice, and ex¬tracted with two portions of diethyl ether. The diethyl ether portions were combined, washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solu¬tion was placed under reduced pressure to distill off the solvent, to leave 7.70 g of a dark brown oil.
Thus obtained crude diethyl 2-[3-bis(methoxycarbon-yl)methyl-4-nitrophenyl]-2-methylmalonate was dissolved in acetic acid (80 mL), and heated under reflux for 14 hours, after addition of water (32 mL) and concentrated sulfuric acid (8 mL) . The acetic acid was then distilled off under reduced pressiure to leave a residue. The resi¬due was diluted with water, and extracted with ethyl acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo¬ride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 3.50 g of a dark brown crystalline product. The crystalline product was washed with chloroform to give 2.27 g (yield: 44.8%) of the desired conpound as a brown crystalline product.
Exanplg 3 Preparation (III) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid

(1) Preparation of diethyl 2-[3-[acetyKraethoxycarbon-
yDmethyl]-4-nitrophenyl]-2-tnethylmalonate
To a solution of diethyl 2-{3-chloro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.03 mmol.) in dimethyl sulfox¬ide (aviso, 3mL) were added potassium carbonate (1.25 g, 9.09 mmol.) and methyl acetoacetate (0.99 mL, 9.0 imol,). The resulting mixture was stirred at 70°C for 6 hours. The reaction mixture was cooled to room terrperature, neutralized with diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The dried portion was' concentrated to leave a residue. The residue was puri¬fied by silica gel column chromatography (Wako Gel C-300, available from Wako JyunyaJcu Industry Co., Ltd., tolu¬ene/ethyl acetate=100/4, v/v), to give 0.64 g (yield: 52%) of the desired cotrpoumd as a yellow oil.

CI-MASS(m/e): 410(M+1), 378, 336
(2) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro¬
pionic acid
In methanol (1 mL) was dissolved diethyl 2-[3-[ace¬tyl (methoxycarbonyl) methyl] -4-nitrophenyl]-2-methyl¬malonate (obtained in (1) above, 50.9 mg, 0.124 mmol.). The resulting solution was stirred for 15 hours at room teitperature after addition of 2M aqueous sodium hydroxide solution (1.5 mL, 3 mmol.) . The reaction mixture was then stirred at 60*0 for 3 hours after addition of 6M hydrochloric acid (1 mL, 3 mmol.) . The mixtiire was cooled and extracted with ethyl acetate. Tlie ethyl ace¬tate portion was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium

sulfate. The dried organic portion was concentrated and pxirif ied by silica gel column chromatography (Wako Gel C-200, available from Wako Jyunyaku Industry Co., Ltd., hexane/ ethyl acetate/acetic acid=:7/3/l, v/v/v), to give 20.3 rag (yield: 65%) of the desired conpound.
Example 4 Preparation (IV) of 2-(3-carboxymethyl-4-nitrophenyl)-propionic acid
(1) Preparation of diethyl 2-[3-[cyano(ethoxycarbonyl)-
methyl] -4-nitrophenyl] -2-methylmalonate
Diethyl 2-{3-chloro-4-nitrophenyl)-2-raethylraalonate (119 mg, 0.36 mraol.), ethyl cyanoacetate (81 rag, 0.72 mmol.), powdery potassium carbonate (119 rag, 0.86 ramol.), and dimethyl sulfoxide (1 mL) were mixed and stirred at SO^C for 2 hours. The reaction mixture was cooled to room terrperature, and washed with diethyl ether after addition of water. The aqueous portion was made acidic by addi¬tion of 6N hydrochloric acid, and extracted with diethyl ether. The ether poirtion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to give 133 rrg (yield: 92%) of the desired conpound as a yellow oil. ^H-NMR (CDCl3)6:
1.28 (3H, t, J=7Hz), 1.28 (3H, t, J=7Hz), 1.33 (3H, t, J=7Hz), 1.92 (3H, s), 4.2-4.4 (6H, m) , 5.69 (IH, s), 7.66 (IH, dd, J=2Hz, 9Hz), 7.82 (IH, d, J=2Hz) , 8.20 (IH, d, J=:9Hz) .
(2) Preparation of 2-[3-cyano(ethoxycarbonyl)raethyl-4-
nitrophenyl] -2-propionic acid
In dimethyl sulfoxide (1.5 mL) was dissolved diethyl 2- [3- [cyano(ethoxycarbonyl)methyl] -4-nitrophenyl] -2-methylmalonate (obtained in the same manner as tiiat of the aix3ve (1), 163 mg, 0.4 mmol.). The solution was stirred for 40 hours at room tenperature after addition

of 4N aqueous sodiiom hydroxide solution (1.5 raL) . The reaction mixtiire was made acidic by addition of 2N hydro¬chloric acid, and extracted with toluene. The toluene portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was distilled off imder reduced pressure to give 112 rag (yield: 92%) of the desired com¬pound as a yellow oil. ^H-NMR (CDCl3)6:
1.33 (3H, t, J=7Hz), 1.60 (3H, d, J=7Hz), 3.91 (IH, q, J=7Hz), 4.31 (2H, q, J=7Hz), 5.65, 5.66 (IH, sx2), 7.60 (IH, dd, J=lHz, 8Hz) , 7.69 (IH, d; J=lHz), 8.21 (IH, d, J=aHz). (3) Preparation of 2-(3-cyanomethyl-4-nitrqphenyl)-2-propionic acid
In acetic acid (0.4 raL) was dissolved 2-[3-cyano-(ethoxycarbonyl)methyl-4-nitrophenyl] -2-propionic acid (obtained in (2) above, 110 rag, 0.36 mmol.). The solu¬tion was heated for 4 hours under reflux, after addition of water (0.36 mL) and concentrated sulfuric acid (0.04 mL) . The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous satu- . rated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave a dark red oil. The oil was adsorbed on silica gel and subjected to silica gel column chromatography. The elution was performed using a mix¬ture of acetic acid and chloroform (1/100, v/v), to give 61 rag (yield: 72%) of the desired conpound as a white crystalline product.
m.p.: 55-59°C ^H-NMR (CDCl3)8:
1.60 (3H, d, J=7Hz), 3.90 (IH, q, J=7Hz), 4.21 (2H, s), 7.52 (IH, dd, J=2Hz, 9Hz), 7.65 (IH, d, J=2Hz), 8.18 (IH, d, J=:9Hz) .

3000, 2260, 1720, 1615, 1590, 1530, 1420, 1340. (4) Preparation of 2-(3-carboxymethyl-4-nitrophenyl)pro¬pionic acid
In acetic acid (0.3 mL) was dissolved 2-(3-cyano-niethyl-4-nitrophenyl)-2-propionic acid (obtained in (3) above., 14 mg, 0.06 mmol.) . The solution was heated for 24 hours under reflux, after addition of water (0.27 raL) and concentrated sulfuric acid (0.03 mL) . The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo¬ride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off imder reduced pressure to leave a residue. The residue was dissolved in toluene and concentrated under reduced pressure to give 13 mg (yield: 85%) of the desired conpound as a brown cirystal-line product.
m.p.: 169-171*='C (after recrystallization from ethyl acetate and hexane)
Example 5 Preparation (V) of 2 - (3 - carboxymethyl - 4 -nitrophenyl) -propionic acid
In aiihydrous dimethyl sulfoxide (10 mL) was sus¬pended 60% sodiijm hydride (1.04 g, 26 mmol.) . To the suspension was dropwise added diethyl methylmalonate (5.0 mL, ^0 mmol.) for 2 minutes, while the suspension was stirred under cooling with water. The mixture was stirred at 60-100°C for 30 minutes. To the resulting homogeneous solution was dropwise added a solution of 2,4-dichloronitrobenzene (3.84 g, 20 mmol.) in anhydrous dimethyl sulfoxide (4 mL) for 5 minutes, while the solu¬tion was stirred under cooling with water. The resulting mixture was then stirred at for 2 hours. The reac¬tion mixture was stirred at 70'C for 2 hours, after addi-

tion of ethyl cyanoacetate (5.3 mL, 50 mmol.) and powdery potassium carbonate (13.8 g, 100 mmol.). To the result-, ing reaction mixture was added 3N hydrochloric acid, while the mixture was stirred under cooling with water. The mixture was extracted with toluene. The toluene portion was washed successively with an aqueous 20% po-tassii:im carbonate solution (14 mL), water, 2N hydrochlo¬ric acid (5 mL), water and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave an orange oil (12.0 g). The obtained orange oil was placed urder reduced pressure to distill the solvent off, to give 8.5 g of a crude diethyl 2-[3-[cyano(ethoxycarbonyl) methyl] -4-nitrophenyl] -2-methyl-malonate as an orange oil. The crude product was dis¬solved in acetic acid (30 mL), and heated for 60 hours under reflux after addition of water (24 mL) and concen¬trated sulfuric acid (6 mL). The upper colorless oil layer was separated and removed. The acetic acid was distilled off under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pres¬sure. This concentration procedure was repeated once, and to the residue were added water (20 mL) and chloro¬form (10 mL) . Insolubles were filtered off, and to the filtrate was added a small amount of separately obtained crystals of 2-(3-carboxymethyl-4-nitrophenyl)propionic acid. The precipitated crystals were collected by fil¬tration and washed successively with three portions of water, chloroform, and hexane. The washed crystalline product was air-dried, and then dried imder reduced pres¬sure, to give 2.20 g (yield: 43%) of the desired compound as a pale brown powder.
Preparation (VI) of 2-(3-carboxymethyl-4-nitrophenyl)-
propionic acid

In acetic acid (1 mL) was dissolved diethyl 2-[3-[cyano(ethoxycarbonyl) methyl] -4-nitrophenyl] -2-methyl-malonate (obtained/in Exanple 5, 406 mg, 1 rnmol.). The solution was heated for 36 hours under reflux, after addition of water (0,9 niL) and concentrated sulfuric acid (0.1 mL) . The reaction mixture was diluted with water, and then extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium cliloride solution, and dried over anhy¬drous sodixom sulfate. The solvent was distilled off under reduced pressure, to give 189 mg (yield: 75%) of the desired conpound as a brown crystalline product.
Example 7 Preparation (I) of 2-(4-amino-3-carboxymethylphenyl)-propionic acid disodiimi salt
In 0.5N aqueous sodium hydroxide solution (0.8 mL) was dissolved 2-(3-car3DOxyraethyl-4-nitrophenyl) propionic acid (obtained in Exartple 1, 50 rrg, 0.2 mmol.). The solution was stirred for 18 hours at room tettperatiire in a hydrogen gas atmosphere, after addition of 10% palladi-lom/carbon (10 ng) . Insolubles were removed by filtra¬tion, and the filtrate was concentrated under reduced pressure to give 55 mg (yield: quantitative amount) of the desired cotipound as a colorless oil.
^H-NMR (DjOfi:
1.37 (3H, d, J=7Hz), 3.45 (2H, s), 3.54 (IH, q, J=7Hz), 6.83 (IH, d, J=8Hz), 7.0-7.1 (2H, m).
Example 8 Preparation (II) of 2-(4-amino-3-carboxymethylphenyl)-propionic acid disodium salt
In IN aqueous sodiimi hydroxide solution (6 mL) was dissolved 2 - (3 -carboxymethyl-4 -nitrophenyl) propionic acid (obtained in Example 1, 760 mg, 3 nrool.) . The solution was stirred for 18 hours at room terrperature in a hydro-

gen gas atmosphere, after addition of 10% palladium/car¬bon (15 mg) . Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give a brown crystalline product. Ihe obtained crystal¬line product was washed successively with ethanol and hexane to give 734 mg (yield: 91.7%) of the desired com¬pound as a white crystalline product, m.p.: 160-163°C ^H-NMR (D20)6:
1.37 (3H, d, J=7Hz), 3.45 (2H, s), 3.54 (IH, q, J=7Hz), 6.83 (IH, d, J=8Hz), 7.0-7.1 (2H, m) . IR v^ (KBr) cm-^-
3400, 1560, 1400.
Example 9 Preparation of diethyl 2-[4-amino-3-bis(methoxycarbonyl)-methylphenyl] -2-methylmalonate
In ethanol (1 mL) was dissolved diethyl 2- [3-bis-(methoxycarbonyl) methyl-4-nitrophenyl] propionate (ob¬tained in Example 1-(1), 30 mg, 0.07 mmol.). The solu¬tion was stirred for 3.5 hours at room teitperature in a hydrogen gas atmosphere, after addition of 10% palladi¬um/carbon (2.5 mg) . Insolubles were removed by filtra¬tion, and the filtrate was concentrated under reduced pressure to give 28 mg (yield: quantitative amoimt) of the desired compound as a white crystalline product, m.p.: 91-92°C (after recrystallization from ethyl
acetate and hexane) ^H-NMR (CDCl3)6:
1.24 (6H, t, J=7Hz), 1.82 (3H, s), 3.75 (6H, s), 4.21 (4H, q, J=7Hz), 4.63 (IH, s), 6.68 (IH, d, J=8Hz), 7.1-7.2 (2H, m) .
Preparation (I) of 2-(3-carboxymethyl-4-phenylthiophen-yl)propionic acid

In 2N hydrochloric acid (0.5 mL) was dissolved 2-{4-aInino-3-carboxymethylphenyl)prqpionic acid disodium salt (prepared in Exanple 1, 53 mg, 0.2 mmol.) . Sodium ni¬trite (14 mg, 0.2 mmol.) was added to the resulting solu¬tion under stirring and chilling with ice. The mixture was stirred for 30 minutes londer chilling with ice. The mixture was then neutralized with a chilled aqueous satu¬rated sodium acetate solution. To the neutralized mix¬ture was added a solution of thiophenol (0.02 mL, 0.2 mmol.) in 6N aqueous sodium hydroxide solution (0.1 mL), and the mixture was stirred for 2 hours at room teirpera.-ture. The reaction mixture was then made acidic by addi¬tion of 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was extracted with an aqueous saturated sodium hydrogen carixDnate solution. The aqueous portion was then made acidic by addition of 6N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 28 mg (yield: 45%) of the desired conpound.
Example 11 Preparation (II) of 2-(3-carboxymethyl-4-phenylthiophen-yl)propionic acid
In 0.5N aqueous sodium hydroxide solution (8 mL) was dissolved 2-(3-carboxymethyl-4-nitrqphenyl)propionic acid (prepared in Exarrple 2, 504 mg, 1.99 mmol.) . The solu¬tion was stirred for 19 hours at room temperature in a hydrogen gas atmosphere after addition of 10% palladi-\im/carbon (50 mg) . Insolubles was filtered off and washed with water (8 mL). The filtrate and washing were combined and stirred under chilling with ice. The stirred liquid was made acidic by addition of concentrat¬ed hydrochloric acid (1 mL). To this was added sodium

nitrite (138 mg, 2 mmol.) . The resulting mixture was then stirred at 4-5°C for 30 minutes. The mixture was -neutralized with a chilled aqueous saturated sodium ace¬tate solution, and stirred for 1 hour at room tenpeirature and at SS'C for 1 hour after addition of a solution of thiophenol (0.25 mL, 2.4 mmol.) in 4N aqueous sodium hydroxide solution (2 mL) . The reaction mixture was made acidic by addition of concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate portion was washed with water and extracted with an aqueous satu¬rated sodium hydrogen carbonate solution. The aqueous portion was made acidic by addition of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate por¬tion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhy¬drous sodium sulfate. The solvent was distilled off ijnder reduced pressure, to leave 471 mg of a red oil. The oil was. subjected to moderate pressure silica gel column chromatography and eluted with methanol/chloroform (1/40, v/v) mixture, to give 265 mg (yield: 42.1%) of the desired conpound as a white crystalline product, m.p. 143-145°C.
Sxanple 12 Preparation (I) of 2-(3-carboxymethyl-4-iodophenyl)pro-pionic acid
An aqueous solution (16.05 g) of 2-(4-amino-3-car-boxymethylphenyl)propionic acid disodium salt (802 mg, 3.00 mmol.) and sodium hydroxide (107 mg, 2.68 mmol.) was cooled to 4°C, and stirred at 3-5°C for 4 minutes after addition of 6M(12N) sulfuric acid (1.5 mL) and sodium nitrite (0.23 g, 3.3 mmol.). The resulting reaction mix¬ture was stirred at 4°C for 20 minutes and then at 25*0 for 16 hours, after addition of potassium iodide (1.49 g, 9.0 mmol.). These reactions were performed in an argon gas atmosphere.

The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sxilfate. The dried ethyl acetate portion was ana¬lyzed by HPLC (high performance liquid chromatography) to confirm that 196 mg (0.59 mmol., yield: 20%) of 2-(3-car-boxytnethyl-4-iodophenyl)propionic acid was contained. The ethyl acetate portion was concent2:a.ted and subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain the desired compound as a crystalline product.
^H-NMR (CD30D)6:
1.44 (3H, d, J=7Hz), 3.68 (IH, q, J=7Hz), 3.78 . (2H, s), 6.97 (IH, dd, J=2Hz, 8Hz), 7.30 (IH, d, J=2Hz), 7.79 (IH, d, J=8Hz).
EI-MASS(m/e): 334 (M) , 289, 207
Exanple 13 Preparation (II) of 2-(3-carboxymethyl-4-iodophenyl)pro¬pionic acid
The procedures of Exaitple 12 were repeated except for eirploying copper (I) iodide (99 wt.%, 1.73 g, 9.0 mmol.) in place of potassium iodide, to give an ethyl acetate portion containing 151 mg (0.45 mmol., yield: 15%) of the desired conpound. Thereafter, the ethyl ace¬tate portion was processed in the manner as described in Exanple 12 to give the desired compound as a purified product.
gy^piplg 14 Preparation of 2-[4-bromo-3-(carboxymethyDphenyDpro-pionic acid
An aqueous solution (23.65 g) of 2-(4-amino-3-car-boxymethylphenyl) propionic acid disodium salt (1.07 g, 4.00 monol.) and sodiiim hydroxide (142 mg, 3.55 mmol.) was cooled to 3*^, and stirred at 3-5®C for 5 minutes after

addition of hydrobromic acid (47%, 4.0 mL, 34 mmol.) and sodium nitrite (0.29 g, 4.1 mmol.) . The resulting reac-. tion mixture was dropwise added to a mixture of copper (I) bromide (99 wt.%, 0.87 g, 6.0 mmol.) and hydrobromic acid (47%, 2.5 mL, 22 mmol.), for a period of 7 minutes under chilling with ice. The resulting mixture was stirred at S^C for 1 hour and then at 25°C for 1 hour. These reac¬tions were performed in an argon gas atmosphere.
The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sulfate. The dried ethyl acetate portion was ana¬lyzed by HPLC (high performance liquid chromatography) to confirm that 1.02 g (3.56 mmol., yield: 89%) of 2-[4-bromo-3-(carboxymethyl)phenyl] propionic acid was con¬tained. The ethyl acetate portion was concentrated and subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain the desired coitpound as a purified crystalline product.
^H-NMR (CD30D)5:
1.45 (3H, d, J=7Hz), 3.70 (IH, q, J=7Hz), 3.78 (2H, s), 7.15 (IH, dd, J=2Hz, 8Hz), 7.31 (IH, d, J=2Hz), 7.53 (IH, d, J=8Hz).
EI-MASS(m/e): 288 (M+2), 286, 207
E?c^mplg 15 Preparation of 2-(3-carboxymethyl-4-chlorophenyl)pro¬pionic acid
AQ aqueous solution (23.65 g) of 2-(4-amino-3-car-boxymethylphenyl) propionic acid disodium salt (1.07 g, 4.00 mmol.) and sodium hydroxide (142 mg, 3.55 mmol.) was cooled to 3*C, and stirred at 3-5°C for 5 minutes after addition of hydrochloric acid (36%, 3.9 mL, 47 raraol.) and sodium nitrite (0.29 g, 4.1 mmol.) . The resulting mix¬ture was stirred at 3°C for 20 minutes and then at 25°C . for 1 hour, after addition of copper (I) chloride (95

wt.%, 1.25 g, 12 mraol.). These reactions were performed in an argon gas atmosphere.
The reaction mixture was extracted with ethyl ace¬tate, and the ethyl acetate portion was dried over magne¬sium sulfate. The dried ethyl acetate portion was con¬centrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 0.71 g (2.9 mmol., yield: 73%)/the desired conpound as a crystalline product.
^H-NMR (CD3OD) 6:
1.45 (3H, d, J=7Hz), 3.71 (IH, q, J=7Hz), 3.75 (2H, s), 7.1-7.4 (3H, m) .
EI-MASS(m/e): 242 (M) , 197, 163
Bx^nplg 1$ Preparation (III) of 2-(3-carboxymethyl-4-phenylthio-phenyl)propionic acid
0.3 M Aqueous potassium hydroxide solution (10 mL, oxygen was removed by addition of 20 mg of sodium hydro-sulfite in advance) was mixed with 2-(3-carboxymethyl-4-iodophenyl)propionic acid (prepared in the manner as described in Exanple 12, 203 n^, 0.607 mmol.) and thio-phenol (95 wt.%, 94 mg, 0.81 mmol.) . The resulting mix¬ture was heated for 19 hours under reflux (tenperature: approx. lOO^C) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was extracted with an aqueous saturated sodium hydrogen carbonate solution. The aque¬ous portion was washed with ethyl acetate, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesiiom sulfate, and concentrated to leave a residue. The resi¬due was subjected to silica gel column chromatography

(Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 133 mg (0.420 mmol., yield: 69%)/the desired conpound.
Exanple 17 Preparation (IV) of 2- (3-carboxymethyl-4-phenylthio-phenyl)propionic acid
2 - (3 - Carboxyraethyl - 4 - iodophenyl) propionic acid (pre -pared in the manner as described in Exanple 12, 202 mg, 0.605 mmol.), potassium carbonate (380 mg, 2.8 mmol.), N, N-dimethylformamide {LMP, 10 mL), and thiophenol (95 wt.%, 92 mg, 0.79 mmol.) were mixed. The resiilting mix¬ture was heated for 19 hours under reflux (teitperature: approx. ■115°C) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/l, v/v/v) to obtain 94 wg (0.30 mmol., yield: 49%) desired conpound.
Exanple 18 Preparation of 2-(10,ll-dihydro-10-oxodibenzo[b,f]-thiepin-2 -yl) propionic acid [i.e., Zaltoprofen]
2- (3 -Carboxymethyl-4-phenylthiophenyl) propionic acid (prepared in the manner as described in Exanple 10, 174 mg, 0.55 mmol.) was mixed with polyphosphoric acid (3.5 g) . The mixture was stirred at 60-70'C for 3 hours. The reaction mixture was then extracted with ethyl acetate after addition of chilled water. The ethyl acetate por¬tion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhy-irous sodium sulfate. The solvent was distilled off

under reduced pressure to leave a brown crystalline resi¬due. The residue was recrystallized from benzene-hexane, to give 123 mg (yield: 75%) of the desired coiipound as a pale yellow crystalline product, m.p. 130.5-131.5°C ^H-NMR (CDCl3)8:
1.49 (3H, d, J=7Hz), 3.73 (IH, q, J=7Hz), 4.36 (2H, s), 7.16 (IH, dd, J=2Hz, 8Hz), 7.3-7.5 (3H, m), 7.5-7.6 (2H, m), 8.19 (IH, dd, J=lHz, 8Hz)
Exanple 19 Preparation (I) of 2-[3-carboxymethyl-4-(2-carboxyphenyl-thio) phenyl] propionic acid
In IN aqueous sodium hydroxide solution (12 mL) was dissolved 2-(3-carboxymethyl-4-nitrophenyl)propionic acid (prepared in Exanple 2, 1.52 g, 6.0 ramol.) . The result¬ing solution was stirred for 41 hours at room tenperature in a hydrogen gas atmosphere, after addition of 10% pal¬ladium/carbon (0.03 g). Insolubles were filtered off and washed with water. The filtrate and washing were com¬bined. This was stirred under chilling with ice and made acidic by addition of concentrated hydrochloric acid (2.5 mL) . The acidic solution was stirred at 5°C for 30 min¬utes after addition of sodium nitrite (0.42 g, 6.1 mmol.). To the resulting aqueous diazonium salt solution was dropwise added a solution of thiosalicylic acid (1.39 g, 9.0 mmol.) in 4N aqueous sodium hydroxide solution (12 mL) at 5-15°C for a period of 2 minutes. After the drop-wise addition was conplete, the mixture was stirred at room terrperature for 1 hour and at 95°C for 1 hour. The reaction mixture was made acidic by addition of concen¬trated hydrochloric acid and extracted with three por¬tions of ethyl acetate. The ethyl acetate portions were^ combined, washed successively with water and an aqueous saturated sodium chloride solution, and finally dried over anhydrous sodium sulfate. The solvent was distilled

off imder reduced pressure to leave 2.98 g of a brown solid residue. The residue was suspended in ethyl ace¬tate, and insolubles were filtered off. The filtrate was concentirated under reduced pressure after addition of silica gel (4.2 g) . The concentrate was subjected to moderate pressure silica gel column chromatography and eluted with acetic acid/chloroform (1/10, v/v), to give 0.30 g of the desired compound as a yellow crystalline product.
m.p.: 229-232°C ^H-NMR (CD30D)6;
1.51 (3H, d, J=7Hz), 3.76 (2H, s), 3.79 (IH, q, J=7Hz), 6.67 (IH, dd, J=1H2, 8Hz), 7.14 (IH, ddd, J=lHz, 7Hz, BHz), 7.24, (IH, ddd, J=2Hz, 7Hz, 8Hz), 7.34 (IH, dd, J=2Hz, 8Hz) , 7.44 (IH, d, J=2Hz), 7.52 (IH, d, J=8Hz), 7.99 (IH, dd, J=2Hz, 8Hz) . IR ^wax (KBr) cm'^:
2980, 1700, 1465, 1410, 1310, 1255, 1230, 750.
Example 20 Preparation (II) of 2-[3-carboxymethyl-4-(2-carboxy-phenylthio)phenyl]propionic acid
In 2N hydrochloric acid (1.5 mL) was dissolved 2-(4-amino-3-carboxymethylphenyl) propionic acid disodium salt (prepared in the manner as described in Example J, 134 mg, 0.5 mmol.) . To the resulting solution was added sodi¬um nitrite (35 mg, 0.5 ramol.) under stirring and chilling with ice. The mixture was stirred at 5°C for 30 minutes. To the resulting aqueous diazonium salt solution was dropwise added a solution of thiosalicylic acid (154 mg, 1.0 mmol.) in 4N aqueous sodium hydroxide solution (2 mL). After the dropwise addition was conplete, the mix¬ture was stirred at room tenperature for 1 hour and at 95'C for 1 hour. The reaction mixture was made acidic by addition of 2N hydrochloric acid and extracted with ethyl

acetate. The ethyl acetate portion was washed succes¬sively with water and an aqueous saturated sodium chlo- . ride solution, and finally dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 230 mg of a brown solid residue. The residue was suspended in ethyl acetate, and insolubles were filtered off. The filtrate was concentrated under reduced pressure after addition of silica gel (0.4 g). The concentrate was subjected to moderate pressure silica gel column chromatography and eluted with acetic acid/ chloroform (1/10, v/v), to give 24 rag of the desired com¬pound as a white crystalline product-
Example 21 Preparation of methyl 2-[3-methDxycarbonylmethyl-4-(2-methoxycarbonylphenylthio) phenyl] propionate
2- [3-Carboxymethyl-4- (2-carboxyphenylthio)phenyl] -propipniq acid (72 mg, 0.2 mmol.), metlianol (0.8 mL), trlmethyl orthoformate mL), and concentrated sulfuric acid (0.05 mL) were mixed, and the mixture was heated for 6 hours under reflux. The reaction mixture was diluted with water and washed with diethyl ether. The diethyl ether portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 78 rag of the desired compound as a colorless oil.

Preparation of tnet±,yl 2-.(10,ll-dihydro-ll-niethoxycarbonyl -10 -oxodibenzo [b, f ] thiepin- 2 -yl) propionate
Methyl 2- [3-methoxycarbonylmethyl-4- (2-methoxycar-bonylphenylthio) phenyl] propionate (prepared in Exarrple
21, 78 mg, 0.19 rnraol.), toluene (1 niL) and potassium t-
butoxide (43 mg, 0.38 mmol.) were mixed, and the mixtiore
was stirred for 16 hours at room tenperature. The reac¬
tion mixture was then extracted with ethyl acetate after
addition of 2N hydrochloric acid. The ethyl acetate
portion was washed with an aqueous saturated sodium chlo¬
ride solution, and dried over anhydrous sodium sulfate.
The dried ethyl acetate portion was placed under reduced
pressure to distill the solvent off, to leave 78 mg of a
pale yellow oil. The oil was subjected to moderate pres¬
sure silica gel column chromatography and eluted with
ethyl acetate/hexane (1/4, v/v), to give 21 mg of the
desired cottpound as a colorless oil (a mixture of 1:1
diastereomers) . The following NMR data are those of the

Example 23 Preparation of 2- (10,11-dihydro-11-oxodibenzo [b, f] -thiepin-2-yl) propionic acid
Methyl 2- (10, ll-dihydro-11-methoxycarbonyl-lO-oxodir benzo[b,f] thiepin-2-yl)propionate (prepared in Exanple
22, 18 mg, 0.040 mmol.), acetic acid (0.3 mL) and 6N
hydrochloric acid (0.3 mL) were mixed, and the mixture
was heated for 2 hours under reflux. To the reaction
mixture was added water, and the aqueous mixture was
extracted with ethyl acetate. The ethyl acetate portion
was washed successively with water and an aqueous satu-

rated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The residue was dissolved in toluene and concentrated under reduced pressure to give 14 mg of the desired com¬pound as a white crystalline product.'
m.p.: 130,5 - 131.5°C
1H-NMR (CDCl3)6:
1.49 (3H, d, J=7Hz), 3.73 (1H, q, J=7Hz), 4.36
(2H, s), 7.16 (1H, dd, J=2Hz, 8Hz), 7.3-7.5
(3H, m) , 7.5-7.6 (2H, m) , 8.19 (1H, dd, J=lHz,
8Hz). '
Example 24 Preparation (III) 2-[3-carboxymethyl-4-(2-carboxyphenyl-thio) phenyl] propionic acid
0.2 M Aqueous potassium hydroxide solution (5 mL, oxygen was removed by addition of 15 mg of sodium hydro-sulfite in advance) was mixed with 2-(3-carboxymethyl-4- . iodophenyl)propionic acid (prepared in Exanple 12, 40.7 mg, 0.122 mmol.) and thiosalicylic acid (37.3 mg, 0.242 mmol.) . The resulting mixture was heated for 20 hours under reflux (temperature: approx. 100°C) after addition of 10 wg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry. Co., Ltd., hexane/ethyl acetate/acetic acid=s7/3/l, v/v/v) to obtain 40.6 mg (0.084 mmol., yield: 69%) of the de¬sired conpound.

This application is divided out of Indian Patent Application No.1862/MAS/97 which relates to a new process for the preparation of substituted propionic acid. The nain clain of said specification reads as follows:
A process for preparing 2-(10,ll-dihydro-10-oxodibenzo[b,f3thiepin-2-Yl) propionic acid comprising reacting 2-(3-carboxymethyl-4-halogenophenyl)propionic acid or its salt with thiophenol in a polar solvent, under basic conditions, in the presence of a known catalyst, to produce 2-(3-oarboxymethyl-4-phenylthiophenyl)propionic acid or its salt cyclizing the product in the presence of a known condensation agent under known conditions and recovering 2-(10,ll-dihydro-10-oxodibenzo[b,f]thiepin-2,Yl)propionic acid by a known manner.

WE CLAIM:
1. A process for preparing 2-(3-carboxymethyl-4-halogenophenyi) propionic acid having the following formula or its salt:

in which Hal is a halogen atom, the said process comprises subjecting 2-(4-amino-3-carboxymethyl-phenyl)propionic acid having the following formula or its salt:

to diazotization at –l0 C to 20°C under acidic conditions alkyl subsequent reaction with a halogenations agent, such as herein described, at -10**C to 100°C and thereafter recovering the 2-(3-carboxymethyl-4-ha]ogenophenyl) propionic acid in a known manner.

Documents:

662-mas-1999 abstract.pdf

662-mas-1999 claims.pdf

662-mas-1999 correspondence others.pdf

662-mas-1999 description (complete).pdf

662-mas-1999 form-1.pdf

662-mas-1999 form-26.pdf

662-mas-1999 form-3.pdf

662-mas-1999 form-4.pdf

662-mas-1999 form-5.pdf

662-mas-1999 petition.pdf

« Previous Patent

Next Patent »

Patent Number

189267

Indian Patent Application Number

662/MAS/1999

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

30-Jan-2004

Date of Filing

21-Jun-1999

Name of Patentee

M/S. NIPPON CHEMIPHAR CO. LTD

Applicant Address

2-3 LWAMOTO-OHO, 2-CHOME, CHIYODA-KU, TOKYO,

Inventors:

#	Inventor's Name	Inventor's Address
1	MASO YAMAMOTO,	7-5-2-204, WASEDA, MISATO-SHI, SAITAMA,

PCT International Classification Number

C07C 69/612

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA