An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) 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 degrees C 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 CH2Cl2 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%.

The optically active (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine (1) is the amine moiety of a novel and potent dopamine (D2 and D3) and 5-HT3 receptors antagonist AS-8112, which is a clinical candidate expected to be a broad antiemetic agent. Process development of an effective synthetic route to the optically active amine 1 from N-Cbz- and N-Ts-l-serine methyl esters was undertaken. In two potential scale-up processes, the route from N-Ts-l-serine methyl ester (21) was chosen because of its better overall yield (>30% yield for seven steps) and handling. The optically active amine 1 with high purity (>99.5% ee) was prepared via the reaction of the key intermediate N-Ts-aziridine 23 with EtNH2 and successive LiAlH4 reduction without racemization. Moderate scale-up synthesis of the amine 1 and AS-8112 by condensation of 1 and 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid is described.

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Potent and selective serotonin-3 (5-HT 3 ) receptor antagonists such as [(R)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide dihydrochloride], granisetron and ondansetron are known to be effective for the control of emesis induced by cancer chemotherapeutic agents.2) In addition, the traditional antiemetic agent domperidone, a peripheral dopamine D 2 receptor antagonist, has been shown to be effective for the treatment of symptoms of chronic upper gastrointestinal distress and for the prevention of nausea and vomiting resulting from a variety of causes.3) However, domperidone is only minimally effective against chemotherapy-or radiation-induced nausea and vomiting. 4) In the course of our studies on the structure-activity relationships of 5) novel benzamides with an alkyl group at the nitrogen atom in the hexahydro-1,4-diazepine ring such as, 1-ethyl-4-methylhexahydro-1,4-diazepine ring, were found to show dopamine D 2 receptor antagonistic activity along with a potent 5-HT 3 receptor antagonistic activity and to cause only weak central nervous system depression and extrapyramidal syndromes. 6)Thus, these compounds were expected to be broad antiemetic agents. These findings had led us to modify the benzoyl moiety and to prepare the optically active 6-aminohexahydro-1,4-diazepine ring, resulting in the discovery of (R)-5-bromo-N- (1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide difumarate (originally AS-8112), a potent dopamine D 2 and D 3 , 7) and 5-HT 3 receptors antagonist. AS-8112 was finally selected as a promising candidate in our search for broad antiemetic agents.1b) In order to obtain a large amount of AS-8112, an efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1) and 6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine was essential. This paper describes the efficient synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7), the key intermediate of 1, from the commercially available 2,6-dichloro-3-trifluoromethylpyridine (12). Results and DiscussionLarge-Scale Synthesis of 5-Bromo-2-methoxy-6-methylaminopyridine-3-carboxylic Acid (1) from 2,6-Dichloro-3-trifluoromethylpyridine (12) We have previously reported a novel synthetic route to 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1) from the commercially available 2,6-dichloropyridine-3-carboxylic acid with an overall yield of ca. 63% (Chart 1).8) The key reaction of this method is the selective nucleophilic substitution reaction of methyl 2,6-dichloropyridine-3-carboxylate (2) with 4-methylbenzenethiolate anion produced from 4-methylbenzenethiol and potassium tert-butoxide in N,N-dimethylformamide (DMF) at Ϫ30°C. The reaction gave a mixture of the desired 6-(4-methylbenzenethio)pyridine-3-carboxylic ester (3) and the regioisomer, 2-substituted pyridine derivative in a ratio of Ͼ97 : Ͻ3 in a quantitative yield. Treatment of the mixture containing 3 as a major product with sodium methoxide and purification by recr...