1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate -Drug Synthesis Database

【结构式】

【分子编号】28068

【品名】1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate

【CA登记号】5130-24-5

【分子式】C₃H₃ClO₂

【分子量】106.50832

【元素组成】C 33.83% H 2.84% Cl 33.29% O 30.04%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XII)

The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II), which is submitted to optical resolution with (-)-dibenzoyltartaric acid, yielding the 3(S)-enantiomer (III). The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV), which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V). The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) , which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX). Finally, the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene. Alternatively, the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI), which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group. Alternatively, the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII), which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.

参考文献中间体

合成目标

【1】 Lynch, I.R.; Richardson, J.E.; Buxton, P.C.; Curzons, A.D.; Wood-Kaezmar, M.W.; Barnes, R.D. (Ferrosan A/S; SmithKline Beecham plc); Piperidine derivs., their preparation and their use as medicaments. EP 0223403; JP 1987129280; US 4721723 .
【2】 Sato, F.; Amano, T.; Kameo, K.; Tanami, T.; Muto, K.; Ono, N.; Goto, J. (Taisho Pharmaceutical Co., Ltd.); Prostaglandin derivs.. JP 1997286775 .
【3】 Lucas, E. (SmithKline Beecham plc); Process for the preparation of paroxetine and structurally related cpds.. WO 0078753 .
【4】 Christensen, J.A.; Squires, R.F. (Ferrosan A/S); 4-Phenylpiperidine compounds. DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743 .
【5】 Lemmens, J.M.; Peters, T.H.A.; Picha, F. (Synthon BV); Process to produce paroxetine. WO 0266466 .

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)	10989	4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine		C₁₂H₁₄FN	详情	详情
(II)	10990	[4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol		C₁₃H₁₆FNO	详情	详情
(III)	43486	[(3S)-4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol		C₁₃H₁₆FNO	详情	详情
(IV)	43487	[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol	105812-81-5	C₁₃H₁₈FNO	详情	详情
(V)	43488	(3S,4R)-3-(chloromethyl)-4-(4-fluorophenyl)-1-methylpiperidine		C₁₃H₁₇ClFN	详情	详情
(VI)	10985	1,3-Benzodioxol-5-ol; Sesamol	533-31-3	C₇H₆O₃	详情	详情
(VII)	10987	(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether		C₂₀H₂₂FNO₃	详情	详情
(VIII)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(IX)	13489	ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate		C₁₃H₂₀BrNO₃	详情	详情
(X)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(XI)	43490	ethyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate		C₂₂H₂₄FNO₅	详情	详情
(XII)	28068	1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate	5130-24-5	C₃H₃ClO₂	详情	详情
(XIII)	43491	vinyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate		C₂₂H₂₂FNO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

A synthesis of [11C]-granisetron has been published: The desmethylation of granisetron (I) with vinyl chloroformate in refluxing dichloroethane gives the intermediate vinyl ester (II), which is decarboxylated with dry HCl in dichloromethane yielding the desmethylgranisetron (III). Finally, this compound is methylated with [11C]-methyl iodide and NaOH in DMF at 145 C.

参考文献中间体

合成目标

【1】 Vandersteene, I.; Dierckx, R.A.; Slegers, G.; Audenaert, K.; Synthesis of [C-11]granisetron, a possible positron emission tomography ligand for 5-HT3 receptor studies. J Label Compd Radiopharm 1998, 41, 3, 171.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	28068	1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate	5130-24-5	C₃H₃ClO₂	详情	详情
(I)	28067	Granisetron; 1-Methyl-N-[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide		C₁₈H₂₄N₄O	详情	详情
(II)	28069	vinyl (1R,5S)-3-[[(1-methyl-1H-indazol-3-yl)carbonyl]amino]-9-azabicyclo[3.3.1]nonane-9-carboxylate		C₂₀H₂₄N₄O₃	详情	详情
(III)	28070	N-[(1R,5S)-9-azabicyclo[3.3.1]non-3-yl]-1-methyl-1H-indazole-3-carboxamide		C₁₇H₂₂N₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with vinyl chloroformate (II) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (95% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.

参考文献中间体

合成目标

【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640.
【2】 Cotrel, C.; Roussel, G. (Aventis Pharma SA); Optically active deriv. of 5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compsns. containing it. EP 0495717; EP 0609210; FR 2671800; JP 1994504548; WO 9212980 .
【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995.
【4】 Bayod Jasanada, M.S.; Brieva Collado, R.; Linares López, F.J.; García Campos, R.; Gotor Santamaría, V. (Asturpharma SA); (+)-6-(5-Chloropyrid-2-yl)-7-oxo-vinylcarbonyloxy-5,6-dihydropyrrolo[3,4b]pyrazine and their use in a process for the preparation of (+)-6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine. ES 2101653 .
【5】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(I)	32796	6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one		C₁₁H₇ClN₄O₂	详情	详情
(S)-(III)	32797	6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate		C₁₄H₉ClN₄O₄	详情	详情
rac-(III)	32798	(5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate		C₁₄H₉ClN₄O₄	详情	详情
(II)	28068	1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate	5130-24-5	C₃H₃ClO₂	详情	详情
(IV)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情

Extended Information