An Efficient Synthesis of 5-Bromo-2-methoxy-6-methylaminopyridine-3-carboxylic Acid

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概要

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• An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D_2 and D_3 and serotonin-3 (5-HT_3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide, is described. Reaction of methyl 2,6-difluoropyridine-3-carboxylate (12) with methylamine in EtOH at -25℃ gave a mixture of methyl 2-fluoro-6-methylaminopyridine-3-carboxylate (13) and the regioisomer 14 in a ratio of 57 : 43. On the other hand, reaction of 12 and methyl 2,6-dichloropyridine-3-carboxylate (16) with sodium methoxide in tetrahydrofuran (THF) and CH_2Cl_2 provided the 2-methoxypyridine-3-carboxylic esters 20 and 23,respectively, as main products. Similar reaction of 16 in N, N-dimethylformamide (DMF) and MeOH proved to be highly regioselective for the 6-position. A much greater regioselectivity for substitution at the 6-position (>97%) was observed when 16 was treated with 4-methylbenzenethiolate anion in DMF (quantitative yield). After methoxylation of methyl 2-chloro-6-(4-methylbenzenethio)pyridine-3-carboxylate (25b) and successive oxidation of the 6-benzenethio moiety, nucleophilic substitution of the sulfoxide derivative 28 with methylamine gave the 6-methylamino derivative 8. Finally, bromination of 8 and alkaline hydrolysis produced the desired product 1 in an overall yield of 67%.

• 社団法人日本薬学会の論文
• 2000-12-01

著者

• Kato Satoru

  Kanazawa Univ. Kanazawa Jpn

• 賀登 志朗

  大日本製薬株式会社創薬研究所

• HIROKAWA Yoshimi

  Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd.,

• KATO Shiro

  Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd.,

• Kato S

  Discovery Research Laboratories I Dainippon Pharmaceutical Co. Ltd.

• Kato S

  Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• HORIKAWA Tamaki

  Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• HORIKAWA Tamaki

  Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd.,

• Horikawa T

  Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Kato Shiro

  Discovery Research Laboratories I Dainippon Pharmaceutical Co. Ltd.

• Hirokawa Y

  Medicinal Chemistry Group Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Kato Satoru

  Department Of Molecular Neurobiology Graduate School Of Medicine University Of Kanazawa

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