methyl 5-bromo-2-methoxy-6-(methylamino)nicotinate -Drug Synthesis Database

【结构式】

【分子编号】17800

【品名】methyl 5-bromo-2-methoxy-6-(methylamino)nicotinate

【CA登记号】

【分子式】C₉H₁₁BrN₂O₃

【分子量】275.10202

【元素组成】C 39.29% H 4.03% Br 29.05% N 10.18% O 17.45%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

Esterification of 2,6-difluoronicotinic acid (I) with methanol and sulfuric acid afforded methyl ester (II). This was treated with methylamine in DMF at 5 C to give a 2:1 mixture of the desired 6-methylaminonicotinate (III) and its regioisomer (IV), which were separated by column chromatography. Reaction of (III) with potassium methoxide generated from methanol and potassium tert-butoxide yielded methyl ether (V). Then, bromination with N-bromosuccinimide in DMF gave bromoester (VI), which was subsequently hydrolyzed with aqueous NaOH to provide acid (VII). Finally, the target amide was prepared by condensation of acid (VII) with the chiral amine (VIII) in the presence of carbonyldiimidazole.

参考文献中间体

合成目标

【1】 Hirokawa, Y.; Yoshida, N.; Kato, S.; Synthesis of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamides and their affinities for 5-HT3 and dopamine D2 receptors. Bioorg Med Chem Lett 1998, 8, 12, 1551.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17795	2,6-difluoronicotinic acid	C₆H₃F₂NO₂	详情	详情
(II)	17796	methyl 2,6-difluoronicotinate	C₇H₅F₂NO₂	详情	详情
(III)	17797	methyl 2-fluoro-6-(methylamino)nicotinate	C₈H₉FN₂O₂	详情	详情
(IV)	17798	methyl 6-fluoro-2-(methylamino)nicotinate	C₈H₉FN₂O₂	详情	详情
(V)	17799	methyl 2-methoxy-6-(methylamino)nicotinate	C₉H₁₂N₂O₃	详情	详情
(VI)	17800	methyl 5-bromo-2-methoxy-6-(methylamino)nicotinate	C₉H₁₁BrN₂O₃	详情	详情
(VII)	17801	5-bromo-2-methoxy-6-(methylamino)nicotinic acid	C₈H₉BrN₂O₃	详情	详情
(VIII)	17802	(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine	C₈H₁₉N₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The intermediate 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (VII) has been obtained as follows: The reaction of 2,6-difluoropyridine (I) with BuLi and CO2 in THF gives 2,6-difluoropyridine-3-carboxylic acid (II), which is esterified with H2SO4 and methanol, yielding the methyl ester (III). The reaction of (III) with methylamine in ethanol affords 2-fluoro-6-(methylamino)pyridine-3-carboxylic acid ethyl ester (IV), which is treated with potassium tert-butoxide in refluxing methanol to provide 2-methoxy-6-(methylamino)pyridine-3-carboxylic acid methyl ester (V). The bromination of (V) with NBS in hot DMF gives the 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid methyl ester (VI), which is finally hydrolyzed with NaOH in refluxing methanol/water to yield the target carboxylic acid intermediate (VII).

参考文献中间体

合成目标

【1】 Kato, S.; Hirokawa, Y.; Morie, T.; Harada, H.; Yoshida, N. (Dainippon Pharmaceutical Co., Ltd.); (R)-5-Bromo-N-(1-ethyl-4-methylhexahydro-1H-1, 4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, process for producing the same and medicinal compsn. containing the same. EP 0855397; JP 1997100276; JP 1997118669; US 5945415; WO 9705129 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54008	2,6-Difluoropyridine	1513-65-1	C₅H₃F₂N	详情	详情
(II)	17795	2,6-difluoronicotinic acid		C₆H₃F₂NO₂	详情	详情
(III)	17796	methyl 2,6-difluoronicotinate		C₇H₅F₂NO₂	详情	详情
(IV)	17797	methyl 2-fluoro-6-(methylamino)nicotinate		C₈H₉FN₂O₂	详情	详情
(V)	17799	methyl 2-methoxy-6-(methylamino)nicotinate		C₉H₁₂N₂O₃	详情	详情
(VI)	17800	methyl 5-bromo-2-methoxy-6-(methylamino)nicotinate		C₉H₁₁BrN₂O₃	详情	详情
(VII)	17801	5-bromo-2-methoxy-6-(methylamino)nicotinic acid		C₈H₉BrN₂O₃	详情	详情

Extended Information