5-Methyl-2-pyridinylamine; 2-Amino-5-methylpyridine; 5-Methyl-2-pyridinamine; 6-Amino-beta-picoline; 6-Amino-3-picoline -Drug Synthesis Database

【结构式】

【分子编号】12752

【品名】5-Methyl-2-pyridinylamine; 2-Amino-5-methylpyridine; 5-Methyl-2-pyridinamine; 6-Amino-beta-picoline; 6-Amino-3-picoline

【CA登记号】1603-41-4

【分子式】C₆H₈N₂

【分子量】108.143

【元素组成】C 66.64% H 7.46% N 25.9%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(II)

4-Methyl-2'-bromoacetophenone (I) is condensed with 2-amino-5-methyl pyridine (II) to give 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine (III). Compound (III) is condensed with formaldehyde and dimethylamine in a Mannich reaction to give the 3-dimethyl aminomethyl derivative (IV), which is quaternized on the side chain nitrogen to afford the quaternary iodide (V). Displacement of trimethylamine from the quaternary salt (V) with cyanide ion leads to 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetonitrile (VI). Acid hydrolysis of the nitrile then affords the corresponding acid (VII). Conversion of the acid to its acid chloride followed by condensation with dimethylamine then leads to zolpidem free base, which is converted to its L-(+)- tartrate (2:1) by treatment with L-(+)-tartaric acid.

参考文献中间体

合成目标

【1】 George, P.; Kaplan, J.-P. (Sanofi-Synthelabo ); Imidazo[1,2-a] pyridine derivs. and their applicat. EP 0050563; US 4382938 .
【2】 Prenez, A.; Sauvanet, J.P.; Thenot, J.P.; Friedmann, J.C.; Dimsdale, M.; Zivkovic, B.; Zolpidem Tartrate. Drugs Fut 1987, 12, 8, 777.

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)	12753	2-Bromo-1-(4-methylphenyl)-1-ethanone	619-41-0	C₉H₉BrO	详情	详情
(II)	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
(III)	12754	6-Methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine		C₁₅H₁₄N₂	详情	详情
(IV)	28210	N,N-dimethyl-N-[[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl]amine		C₁₈H₂₁N₃	详情	详情
(V)	28211	N,N,N-trimethyl[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methanaminium iodide		C₁₉H₂₄IN₃	详情	详情
(VI)	28212	2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile		C₁₇H₁₅N₃	详情	详情
(VII)	28213	2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid		C₁₇H₁₆N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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

合成目标

【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3

该中间体在本合成路线中的序号：(III)

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

合成目标

【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

合成路线4

该中间体在本合成路线中的序号：(XVIII)

The intermediate 6-amino-2-chloro-3-methylpyridine (XIII) is prepared by protection of 2-amino-5-methylpyridine (XVIII) with pivaloyl chloride in the presence of Et3N in CH2Cl2 to give the N-pyridyl pivalamide (XIX), which is converted to the corresponding N-oxide (XX) by treatment with H2O2 in AcOH at 80 °C. Rearrangement of the N-oxide (XX) by means of POCl3 and Et3N in refluxing CH2Cl2 leads to the chloropyridine (XXI), which is finally hydrolyzed with aqueous HCl at 80 °C .

参考文献中间体

合成目标

【1】 Hadida Rua, S., Hamilton, M., Miller, M., Grootenhuis, P.D.J., Bear, B., McCarthy, J., Zhou, J. (Vertex Pharmaceuticals, Inc.). Heterocyclic modulators of ATP-binding cassette transporters. EP 1945632, EP 2395002, EP 2404919, JP 2009514962, US 2008113985, US 7741321, US 7973038, US 2011172229, US 2011312958, US 2012232059, WO 2007056341.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	68639	6-amino-2-chloro-3-methylpyridine;2-Amino-6-chloro-5-methylpyridine;6-chloro-5-methyl-2-Pyridinamine	442129-37-5	C₆H₇ClN₂	详情	详情
(XVIII)	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
(XIX)	68643	N-(5-methylpyridin-2-yl)pivalamide		C₁₁H₁₆N₂O	详情	详情
(XX)	68644	5-methyl-2-pivalamidopyridine 1-oxide		C₁₁H₁₆N₂O₂	详情	详情
(XXI)	68645	N-(6-chloro-5-methylpyridin-2-yl)pivalamide		C₁₁H₁₅ClN₂O	详情	详情

Extended Information