Zolpidem tartrate, SL-80-0750-23N, Myslee, Stilnoct, Ivadal, Ambien, Bikalm, Niotal, Stilnox, -Drug Synthesis Database

【结构式】

【药物名称】Zolpidem tartrate, SL-80-0750-23N, Myslee, Stilnoct, Ivadal, Ambien, Bikalm, Niotal, Stilnox

【化学名称】N,N,6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide L-(+)-tartrate (2:1)

【CA登记号】99294-93-6, 82626-48-0 (free base)

【分子式】C₂₃H₂₇N₃O₇

【分子量】457.48754

【开发单位】Sanofi-synthélabo (Originator), Altana Pharma (Licensee), Fujisawa (Licensee), Lorex (Licensee), Biovail (Formulation)

【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Benzodiazepines, GABA(A) BZ Site Receptor Agonists

合成路线1 合成路线2

合成路线1

A new and industrially viable synthesis of zolpidem has been described: The cyclization of 2-amino-5-methylpyridine (I) with 4-methylphenacyl bromide (II) gives 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (III), which is condensed with N,N-dimethylglyoxylamide (IV) to yield 2-hydroxy-N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyri din-3-yl]acetamide (V). The reaction of (V) with SOCl2 affords the corresponding chloroacetamide (VI), which is finally reduced to give zolpidem. This product is then converted into the hemitartrate salt. Via this synthesis, zolpidem is obtained in excellent yield and quality on an industrial scale.

参考文献中间体

【1】 Allen, J.; George, P.; Wick, A.; Mompon, B.; Depoortere, H.; Rossey, G.; Imidazopyridines: Towards novel hypnotic and anxiolytic drugs. Farmaco 1991, 46, 1, Suppl., 277-88.

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)	12752	5-Methyl-2-pyridinylamine; 2-Amino-5-methylpyridine; 5-Methyl-2-pyridinamine; 6-Amino-beta-picoline; 6-Amino-3-picoline	1603-41-4	C₆H₈N₂	详情	详情
(II)	12753	2-Bromo-1-(4-methylphenyl)-1-ethanone	619-41-0	C₉H₉BrO	详情	详情
(III)	12754	6-Methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine		C₁₅H₁₄N₂	详情	详情
(IV)	12755	N,N-Dimethyl-2-oxoacetamide		C₄H₇NO₂	详情	详情
(V)	12756	2-Hydroxy-N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide		C₁₉H₂₁N₃O₂	详情	详情
(VI)	12757	2-Chloro-N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide		C₁₉H₂₀ClN₃O	详情	详情

合成路线2

N,N-Dimethyl-4-(4-methylphenyl)-4-oxobutyramide (I) with Br2 in HOAc gives the 3-bromo derivative (II), which is cyclized with 5-methylpyridine-2-amine (III) in either hot acetonitrile or 1,3-dimethyl-2-imidazolidinone to afford the imidazo-pyridine derivative (IV). Finally, the semitartrate salt is obtained by treatment of (IV) with tartaric acid in MeOH. Alternatively, the conversion of N,N-Dimethyl-4-(4-methylphenyl)-4-oxobutyramide (I) into the imidazo-pyridine derivative (IV) can be directly performed by first refluxing of (I) with HBr in dichloromethane, followed by reaction with Br2 and final treatment with a solution of 5-methylpyridine-2-amine (III) in acetonitrile.

参考文献中间体

【1】 Wohlleben, W.; Sauter, M. (Boehringer Ingelheim Pharma KG); Method for the production of zolpidem. DE 10121638; WO 0290356 .

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)	57880	N,N-dimethyl-4-(4-methylphenyl)-4-oxobutanamide		C₁₃H₁₇NO₂	详情	详情
(II)	57881	3-bromo-N,N-dimethyl-4-(4-methylphenyl)-4-oxobutanamide		C₁₃H₁₆BrNO₂	详情	详情
(III)	12752	5-Methyl-2-pyridinylamine; 2-Amino-5-methylpyridine; 5-Methyl-2-pyridinamine; 6-Amino-beta-picoline; 6-Amino-3-picoline	1603-41-4	C₆H₈N₂	详情	详情
(IV)	57882	N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide		C₁₉H₂₁N₃O	详情	详情

Extended Information