3-chloropropanenitrile -Drug Synthesis Database

【结构式】

【分子编号】30744

【品名】3-chloropropanenitrile

【CA登记号】542-76-7

【分子式】C₃H₄ClN

【分子量】89.5242

【元素组成】C 40.25% H 4.5% Cl 39.6% N 15.65%

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：(II)

The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol - water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone - methanol - water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.

参考文献中间体

合成目标

【1】 Isomura, Y.; Ishii, Y.; Ito, N.; Takeda, M.; Yanagisawa, I.; Hirata, Y.; Tsukamoto, S. (Yamanouchi Pharmaceutical Co., Ltd.); Guanidinothiazole cpds., process for preparation and gastric inhibiting compsns. containing them. US 4283408 .
【2】 Hirata Y.; et al. (Yamanouchi Pharmaceutical Co., Ltd.); Novel amidine derivative and its preparation. BE 0882071; DE 2951675; DE 3008056; FR 2450827; GB 2052478; GB 2055800; JP 55118476; NL 7909321; NL 8001361 .
【3】 Blancafort, P.; Castaner, J.; Hillier, K.; Serradell, M.N.; Famotidine. Drugs Fut 1983, 8, 1, 14.

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)	30743	2-amino-4-([[amino(imino)methyl]sulfanyl]methyl)-1,3-thiazole		C₅H₈N₄S₂	详情	详情
(II)	30744	3-chloropropanenitrile	542-76-7	C₃H₄ClN	详情	详情
(III)	30745	3-[[(2-amino-1,3-thiazol-4-yl)methyl]sulfanyl]propanenitrile	76823-89-7	C₇H₉N₃S₂	详情	详情
(IV)	23530	benzoyl isothiocyanate	532-55-8	C₈H₅NOS	详情	详情
(V)	30746	N-benzoyl-N'-(4-[[(2-cyanoethyl)sulfanyl]methyl]-1,3-thiazol-2-yl)thiourea		C₁₅H₁₄N₄OS₃	详情	详情
(VI)	30747	N-(4-[[(2-cyanoethyl)sulfanyl]methyl]-1,3-thiazol-2-yl)thiourea		C₈H₁₀N₄S₃	详情	详情
(VII)	30748	4-[[(2-cyanoethyl)sulfanyl]methyl]-2-[[imino(methylsulfanyl)methyl]amino]-1,3-thiazole		C₉H₁₂N₄S₃	详情	详情
(VIII)	30749	N''-(4-[[(2-cyanoethyl)sulfanyl]methyl]-1,3-thiazol-2-yl)guanidine; 2-[4-(2-Cyanoethyl)methylthio]thioazolyl guanidine	76823-93-3	C₈H₁₁N₅S₂	详情	详情
(IX)	30750	methyl 3-[([2-[(diaminomethylene)amino]-1,3-thiazol-4-yl]methyl)sulfanyl]propanimidoate		C₉H₁₅N₅OS₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III), which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1). The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI), which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII). The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII), which is finally hydrolyzed with concentrated HCl in refluxing EtOH

参考文献中间体

合成目标

【1】 (Sumitomo Chemical Co., Ltd.); FR 2196153 .
【2】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); DE 2065311; JP 754670; JP 754671 .
【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Owen, R.T.; ID - 4708. Drugs Fut 1979, 4, 7, 492.
【4】 Honma, T.; et al.; The XIAP antisense compound AEG35156/GEM640 demonstrates significant antitumor activity in multiple human cancer xenograft models. Arzneim-Forsch 1974, 24, 9, 1248.
【5】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); 3-Hetero-substd.-N-benzyl-indoles. US 3907812 .

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)	61098	6-fluoro-2-methyl-1H-indole		C₉H₈FN	详情	详情
(II)	30744	3-chloropropanenitrile	542-76-7	C₃H₄ClN	详情	详情
(III)	61099	3-(6-fluoro-2-methyl-1H-indol-3-yl)propanenitrile		C₁₂H₁₁FN₂	详情	详情
(IV)	61100	3-(6-fluoro-2-methyl-1H-indol-3-yl)propanoic acid		C₁₂H₁₂FNO₂	详情	详情
(V)	61101	4-[3-(trifluoromethyl)phenyl]-4-piperidinol		C₁₂H₁₄F₃NO	详情	详情
(VI)	61102	3-(6-fluoro-2-methyl-1H-indol-3-yl)-1-{4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinyl}-1-propanone		C₂₄H₂₄F₄N₂O₂	详情	详情
(VII)	61103	1-[3-(6-fluoro-2-methyl-1H-indol-3-yl)propyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol		C₂₄H₂₆F₄N₂O	详情	详情
(VIII)	61104	N-[5-fluoro-2-(4-{4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinyl}butanoyl)phenyl]acetamide		C₂₄H₂₆F₄N₂O₃	详情	详情

Extended Information