A practical preparation of methyl 2-methoxy-6-methylaminopyridine-3-carboxylate from 2,6-dichloro-3-trifluoromethylpyridine.
An effective and practical synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7), the key intermediate of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), from 2,6-dichloro-3-trifluoromethylpyridine (12) was undertaken. Process improvements were highlighted by regioselectivity of 12 with a nitrogen nucleophile and conversion of the 3-trifluoromethyl group into the methoxycarbonyl group. The reaction of 12 with N-benzylmethylamine provided the 6-(N-benzyl-N-methyl)aminopyridine 26a and the regioisomer 26b in >98:<2 ratio in a quantitative yield. Treatment of 2-methoxy-6-methylamino-3-trifluoropyridine (14a) with a large excess of sodium methoxide followed by acid hydrolysis gave the pyridine-3-carboxylic ester 7 in an excellent yield. The potential application of this reaction is also described.
Horikawa
T
T
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita, Osaka, Japan.
Hirokawa
Y
Y
Kato
S
S
D000932:Antiemetics / Q000138:chemical synthesis*; D001381:Azepines / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009539:Nicotinic Acids / Q000138:chemical synthesis*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared
C431510:5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide 2-fumarate; D000932:Antiemetics; D001381:Azepines; D007202:Indicators and Reagents; D009539:Nicotinic Acids; D011725:Pyridines; C423459:methyl 2-methoxy-6-methylaminopyridine-3-carboxylate; C454670:2,6-dichloro-3-trifluoromethylpyridine