【结 构 式】 |
【分子编号】13235 【品名】Allyl chloride; 3-Chloro-1-propene 【CA登记号】107-05-1 |
【 分 子 式 】C3H5Cl 【 分 子 量 】76.5254 【元素组成】C 47.09% H 6.59% Cl 46.33% |
合成路线1
该中间体在本合成路线中的序号:(IV)The esterification of 2,4-dichloromandelic acid (I) with methanol and sulfuric acid gives the corresponding methyl ester (II), which by treatment with NH3 in methanol yields 2,4-dichloromandelamide (III). The alkylation of (III) with allyl chloride (IV) and NaH in THF affords 2-allyloxy-2-(2,4-dichlorophenyl)acetamide (V), which is hydrolyzed with refluxing aqueous HCl giving 2-allyloxy-2-(2,4-dichlorophenyl)acetic acid (VI). The reduction of (VI) with LiAlH4 in refluxing ether yields 2-allyloxy-2-(2,4-dichlorophenyl)ethanol (VII), which is esterified with methanesulfonyl chloride in pyridine to afford 2-allyloxy-2-(2,4-dichlorophenyl) ethanol methanesulfonate (VIII). Finally, this compound is condensed with 1H-imidazole (IX) in refluxing DMF.
【1】 GB 1522848 . |
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; de Angelis, L.; Imazalil. Drugs Fut 1982, 7, 4, 254. |
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) | 36400 | 2-(2,4-dichlorophenyl)-2-hydroxyacetic acid | C8H6Cl2O3 | 详情 | 详情 | |
(II) | 36401 | methyl 2-(2,4-dichlorophenyl)-2-hydroxyacetate | C9H8Cl2O3 | 详情 | 详情 | |
(III) | 36402 | 2-(2,4-dichlorophenyl)-2-hydroxyacetamide | C8H7Cl2NO2 | 详情 | 详情 | |
(IV) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
(V) | 36403 | 2-(allyloxy)-2-(2,4-dichlorophenyl)acetamide | C11H11Cl2NO2 | 详情 | 详情 | |
(VI) | 36404 | 2-(allyloxy)-2-(2,4-dichlorophenyl)acetic acid | C11H10Cl2O3 | 详情 | 详情 | |
(VII) | 36405 | 2-(allyloxy)-2-(2,4-dichlorophenyl)-1-ethanol | C11H12Cl2O2 | 详情 | 详情 | |
(VIII) | 36406 | 3-(allyloxy)-3-(2,4-dichlorophenyl)propyl methanesulfonate | C13H16Cl2O4S | 详情 | 详情 | |
(IX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)The bromination of 2,4-dichloroacetophenone (X) with Br2 in refluxing methanol gives 2,4-dichlorophenacyl bromide (XI), which is condensed with 1H-imidazole (IX) in methanol to yield 2,4-dichloro-alpha-(1-imidazolyl)acetophenone (XII). The reduction of (XII) with NaBH4 in refluxing methanol affords 1-(2,4-chlorophenyl)-2-(1-imidazolyl)ethanol (XIII), which is finally alkylated with allyl chloride (IV) and NaH in refluxing DMF.
【1】 Serradell, M.N.; Blancafort, P.; Castaner, J.; de Angelis, L.; Imazalil. Drugs Fut 1982, 7, 4, 254. |
【2】 Godefroi, E.F.; Schuermans, J.L.; US 3658813 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
(IX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
(X) | 36407 | 1-(2,4-dichlorophenyl)-1-ethanone; 2',4'-dichloroaetophenone | 2234-16-4 | C8H6Cl2O | 详情 | 详情 |
(XI) | 36408 | 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone | C8H5BrCl2O | 详情 | 详情 | |
(XII) | 32200 | 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanone | 46503-52-0 | C11H8Cl2N2O | 详情 | 详情 |
(XIII) | 14550 | 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanol; alpha-(2,4-Dichlorophenyl)-1H-imidazole-1-ethanol; 1-(2',4'-Dichlorophenyl)-2-(1-imidazolyl)ethanol | 24155-42-8 | C11H10Cl2N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XI)Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.
【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Iganidipine Hydrochloride. Drugs Fut 1997, 22, 1, 23. |
【2】 Matsui, H.; Fukata, F.M.; Mori, T.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); 1,4-Dihydropyridine derivs. and pharmaceutical compsn. Thereof. AU 8812519; EP 0289746; JP 1988225355; US 4937242 . |
【3】 Kakeya, N.; Fukada, F.; Nishizawa, S. (Kyoto Pharmaceutical Industries, Ltd.); 3-Aminocrotonic acid ester. JP 1991099064 . |
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) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
(II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
(III) | 13227 | tert-butyl 4-(2,2-dimethyl-3-oxopropyl)-1-piperazinecarboxylate | C14H26N2O3 | 详情 | 详情 | |
(IV) | 13228 | tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-1-piperazinecarboxylate | C14H28N2O3 | 详情 | 详情 | |
(V) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
(VI) | 13230 | tert-butyl 4-[3-(acetoacetoxy)-2,2-dimethylpropyl]-1-piperazinecarboxylate | C18H32N2O5 | 详情 | 详情 | |
(VII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
(VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
(IX) | 13233 | 3-[3-[4-(tert-butoxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C30H42N4O8 | 详情 | 详情 | |
(X) | 13234 | 3-[2,2-dimethyl-3-(1-piperazinyl)propyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C25H34N4O6 | 详情 | 详情 | |
(XI) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
(XII) | 13236 | 3-(4-Allyl-1-piperazinyl)-2,2-dimethyl-1-propanol | C12H24N2O | 详情 | 详情 | |
(XIII) | 13237 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl 3-oxobutanoate | C16H28N2O3 | 详情 | 详情 | |
(XIV) | 13238 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl (E)-3-amino-2-butenoate | C16H29N3O2 | 详情 | 详情 | |
(XV) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(IX)Reductive amination of N-Boc-4-piperidone (I) with allyl amine (II) in the presence of sodium triacetoxyborohydride gave aminopiperidine (III), which was condensed with 4-nitrobenzyl chloroformate (IV) to afford carbamate (V). The Boc group of (V) was then cleaved by treatment with methanolic HCl to produce intermediate piperidine (VI). Alternatively, the condensation of 1-Boc-piperidine-4-amine (VII) with chloroformate (IV) gives carbamate (VIII), which is allylated with allyl chloride (IX) and NaH in THF, yielding the already reported carbamate (V).
【1】 Chen, P.; Dorn, C.P. Jr.; Caldwell, C.G.; et al.; Synthesis and evaluation of CCR5 antagonists having potent in vitro antiviral activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 85. |
【2】 Finke, P.E.; Mills, S.G.; Caldwell, C.G.; MacCoss, M.; Wang, L.; Kothandaraman, S.; Kim, D.; Oates, B. (Merck & Co., Inc.); Cyclic amine modulators of chemokine receptor activity. EP 1052992; US 6140349; WO 9938514 . |
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) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
(II) | 13672 | Allylamine; 2-Propen-1-amine | 107-11-9 | C3H7N | 详情 | 详情 |
(III) | 43903 | tert-butyl 4-(allylamino)-1-piperidinecarboxylate | C13H24N2O2 | 详情 | 详情 | |
(IV) | 33055 | 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene | 4457-32-3 | C8H6ClNO4 | 详情 | 详情 |
(V) | 43904 | tert-butyl 4-(allyl[[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate | C21H29N3O6 | 详情 | 详情 | |
(VI) | 43905 | 4-nitrobenzyl allyl(4-piperidinyl)carbamate | C16H21N3O4 | 详情 | 详情 | |
(VII) | 28414 | 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine | 87120-72-7 | C10H20N2O2 | 详情 | 详情 |
(VIII) | 43906 | tert-butyl 4-([[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate | C18H25N3O6 | 详情 | 详情 | |
(IX) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(IV)When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with allyl chloride (IV) in alkaline medium afforded the required 2-(allylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
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) | 51787 | methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate | C12H14O3 | 详情 | 详情 | |
(II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(III) | 51801 | 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C12H12N2OS | 详情 | 详情 | |
(IV) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |