(19) TZZ __T (11) EP 2 275 415 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 277/56 (2006.01) C07C 51/377 (2006.01) 27.11.2013 Bulletin 2013/48 (21) Application number: 10010620.2 (22) Date of filing: 23.08.2005 (54) Method for producing aminothiazole derivative and production intermediate Verfahren zur Herstellung eines Aminothiazolderivats und Zwischenprodukt Procédé de production de dérivé d’aminothiazole et production d’intermédiaire (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • DATABASE BEILSTEIN [Online] BEILSTEIN HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI INSTITUTE FOR ORGANIC CHEMISTRY, SK TR FRANKFURT-MAIN, DE; 1966, Capon et al: "2- Hydroxy-5-methoxy-benzoic acid phenyl ester", (30) Priority: 23.08.2004 JP 2004242759 XP002610770, Database accession no. 2698910 & CAPON ET AL: J. CHEM. SOC. B: PHYSICAL (43) Date of publication of application: ORGANIC, 1966, pages 472-473, 19.01.2011 Bulletin 2011/03 • DATABASE BEILSTEIN [Online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, (62) Document number(s) of the earlier application(s) in FRANKFURT-MAIN, DE; 1949, Pearl et al: "2- accordance with Art. 76 EPC: Hydroxy-3-methoxy-benzoic acid phenyl ester", 05774659.6 / 1 792 888 XP002610771, Database accession no. 3319124 &PEARL ET AL:J. AM. CHEM. SOC., vol. 71, 1949, (73) Proprietor: Zeria Pharmaceutical Co., Ltd. page 1066, Tokyo 103-8351 (JP) • DATABASE BEILSTEIN [Online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, (72) Inventors: FRANKFURT-MAIN, DE; 1971, Maugh et al: "2- • Nagasawa, Masaaki Hydroxy-4-methoxy-benzoic acid phenyl ester", Tokyo 103-8351 (JP) XP002610772, Database accession no. 2741847 • Asami, Kazuyasu & MAUGH ET AL: J. AM. CHEM. SOC., vol. 93, Honjyo-shi 1971, pages 3237-3248, Saitama 367-0042 (JP) • DATABASECA [Online] CHEMICAL ABSTRACTS • Nakao, Ryu SERVICE, COLUMBUS, OHIO, US; 1987, ELIX, Tokyo 103-8351 (JP) JOHN A. ET AL: "A novel synthesis of the lichen • Tanaka, Nobuyuki depsidones divaronic acid and stenosporonic Tokyo 103-8351 (JP) acid, and the biosynthetic implications", • Aida, Yoshiyuki XP002611288, retrieved from STN Database Tokyo 103-8351 (JP) accession no. 1988:131402 & ELIX, JOHN A. ET AL: "A novel synthesis of the lichen depsidones (74) Representative: Blodig, Wolfgang divaronic acid and stenosporonic acid, and the Wächtershäuser & Hartz biosynthetic implications", AUSTRALIAN Patentanwaltspartnerschaft JOURNAL OF CHEMISTRY , 40(8), 1451-64 Ottostrasse 4 CODEN: AJCHAS; ISSN: 0004-9425, 1987, 80333 München (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 275 415 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 275 415 B1 Description Technical Field 5 [0001] The present invention relates to an intermediate obtainable by a method for selectively demethylating a methoxy group present at the ortho position (2- position) of an aromatic carboxylic acid. A method for producing an aminothiazole derivative via the demethylation method and by using the intermediate is disclosed. Background Art 10 [0002] Beilstein Registry Number 2698910 relates to 2-hydroxy-5-methoxy-benzoic acid phenyl ester. [0003] It is known that compounds in which 2- hydroxybenzoic acids are amide-bonded to 2-aminothiazoles have an excellent enterokinesis-improving effect and are useful as prophylactic and therapeutic agents for epigastric indefinite complaints, nausea, vomiting, heartburn, anorexia, bloating sensation, reflux esophagitis, and the like (patent documents 15 1 to 3). Among these compounds, the compound represented by formula (7a) below: 20 25 [0004] , particularly, has a high safety as well as an excellent enterokinesis-improving effect and is useful as a pro- phylactic and therapeutic agent for the above-described various enterokinetic disorders. [0005] As a method for producing these 2- hydroxybenzoic acid amide derivatives, patent document 1 adopts a method 30 which involves reacting a 2-methoxybenzoic acid amide derivative with a demethylating reagent such as pyridine hy- drochloride to make a 2-hydroxybenzoic acid derivative. However, the demethoxylation reaction has been problematic to adopt industrially because the reaction produces many side reactions, making it difficult to selectively demethylate only a methoxy group selectively at the 2-position of the amide derivative. [0006] On the other hand, patent documents 2 and 3 describe that the reaction of 2-methoxybenzoic acid amide 35 derivatives with amines such as secondary and tertiary amines selectively demethylates methoxy groups selectively at the 2-position thereof. However, the yield of the demethylation reaction of methoxy groups at theposition 2- of the compounds is on the order of 64.6 to 86% and has not yet reached a satisfactory level in view of an industrial method. [Patent document 1]: WO96/36619 40 [Patent document 2]: WO98/58918 [Patent document 3]: Japanese Patent Laid-Open No. 2000-239224 Disclosure of the Invention 45 Problems to be Solved by the Invention [0007] An object of the present invention is to provide an intermediate for an industrial method for producing an aminothiazole derivative useful as a medicine via the demethylation method. 50 Means for Solving the Problems [0008] The present invention provides a compound as defined by the claim. [0009] Accordingly, as a result of various studies of a method for selectively demethylating the 2-methoxy group of an aromatic carboxylic acid having the methoxy group at the 2-position thereof, the present inventor has found that the 55 combination of a particular Lewis acid and a particular solvent enables the selective demethylation of only the 2- methoxy group of the aromatic carboxylic acid even when methoxy groups are present in the 3-, 4-, and 5-positions thereof. The present inventor has further found that when the amidation reaction of a 2-hydroxy aromatic carboxylic acid with a 2- aminothiazole is carried out, the use of the means involving reacting a phenyl ester of the 2- hydroxy aromatic carboxylic 2 EP 2 275 415 B1 acid with the 2-aminothiazole allows the reaction to proceed with an extremely high yield. [0010] The method wherein the compound of the present invention is used can be illustrated by the following reaction formula. 5 10 15 20 25 30 35 [0011] (wherein ring A represents a benzene ring or a 6- membered aromatic heterocycle; R1 represents a hydrogen atom; R2 and R3 represents a methoxy group; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a 40 specific electron-withdrawing group; and R6 represents an alkyl group.) [0012] Thus, a production method of a compound of formula (2), comprising reacting a compound of formula (1) with a Lewis acid selected from-the group consisting of BF3, TiCl4, and AlCl3 in esteric, ketonic or amidic solvents, with the proviso that an alkali metal bromide or an alkali metal iodide coexists in the case of BF 3 is disclosed. Moreover a production method of a compound of formula (3), comprising reacting a compound of formula (2) with a 45 phenol derivative or a triphenyl phosphite derivative is disclosed. In addition, a production method of a compound of formula (5), comprising reacting a compound of formula (3) with a compound of formula (4) under heating at 150°C or higher or in the presence of a boric acid ester is disclosed. Further, a production method of a compound represented by formula (7), comprising reacting a compound represented by formula (5) with N,N-diisopropylethylenediamine in the presence of toluene is disclosed. 50 [0013] In the above reaction formula showing the method of the present invention, a compound represented by formula (3) is a novel compound, and the compound is extremely important as an intermediate in the present method . [0014] In addition, of the compounds represented by formula (5), a compound wherein R 6is a methyl group, represented by formula (5a): 55 3 EP 2 275 415 B1 5 10 [0015] (wherein ring A and R1, R2, R3, and R4 are the same as defined above) is a novel compound, and the compound is also useful as an intermediate in the present method. [0016] It has been also found that the compound represented by formula (7a): 15 20 [0017] is converted to the hydrochloride thereof, followed by recrystallization from an isopropanol aqueous solution to provide the compound represented by formula (7c): 25 30 35 [0018] stably and efficiently. Effect of the Invention [0019] According to the present invention, a phenyl ester represented by formula (3) is used as an intermediate to 40 provide a compound represented by formula (7) useful as an enterokinesis-improving agent at a high yield and a high purity. Best Mode for Carrying Out the Invention 45 [0020] In the above reaction formula, ring A represents a benzene ring or a 6-membered aromatic heterocycle. The 6-membered aromatic heterocycle is preferably one containing one or two selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and specific examples thereof include a pyridine ring, a pyrimidine ring, a pyrazine ring, a oxazoline ring, and a thiazoline ring; a pyridine ring is preferable. Because these heterocycles have a methoxy group at the ortho position relative to the carboxyl group, for example, as in the formula (1), the ortho position relative to the 50 carboxyl group or carbonyl group comprises a carbon atom. Thus, when the position of the carboxyl group or carbonyl group is defined as the 1-position, specific examples of the heterocycle include a 3-pyridyl group, a 4-pyridyl group, a 5-pyridyl group, a 6-pyridyl group, a 3,5-pyrimidinyl group, and a 4,6- pyrimidinylgroup.