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【结 构 式】 
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【分子编号】36995 【品名】4-[2-(1-piperidinyl)ethoxy]benzoyl chloride 【CA登记号】 |
【 分 子 式 】C14H18ClNO2 【 分 子 量 】267.75516 【元素组成】C 62.8% H 6.78% Cl 13.24% N 5.23% O 11.95% |
合成路线1
该中间体在本合成路线中的序号：(V)Alkylation of ethyl 4-hydroxybenzoate (I) with 1-(2-chloroethyl)piperidine (II) provided adduct (III). After saponification of the ethyl ester group of (III), the resulting carboxylic acid (IV) was treated with oxalyl chloride to furnish the desired acid chloride (V).
| 【1】 Dantzig, A.H.; Grese, T.A.; Normal, B.H.; Palkowitz, A.D.; Sluka, J.P.; Starling, J.J. II; Winter, M.A. (Eli Lilly and Company); Methods for treating resistant tumors. EP 0773217; JP 2000500138; WO 9717069 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 36993 | ethyl 4-[2-(1-piperidinyl)ethoxy]benzoate | C16H23NO3 | 详情 | 详情 | |
| (IV) | 36994 | 4-[2-(1-piperidinyl)ethoxy]benzoic acid | C14H19NO3 | 详情 | 详情 | |
| (V) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Reaction of 4-bromoaniline (VI) with methanesulfonyl chloride afforded the bis sulfonamido derivative (VII). Palladium-catalyzed coupling of (VII) with 6-methoxybenzo[b]thiophene-2-boronic acid (VIII) then provided the 2-aryl benzothiophene (IX). Subsequent Friedel-Crafts acylation of (IX) with acid chloride (V) in the presence of AlCl3 gave rise to ketone (X). The methyl ether group of (X) was finally cleaved by treatment with ethanethiol and AlCl3.
| 【1】 Dantzig, A.H.; Grese, T.A.; Normal, B.H.; Palkowitz, A.D.; Sluka, J.P.; Starling, J.J. II; Winter, M.A. (Eli Lilly and Company); Methods for treating resistant tumors. EP 0773217; JP 2000500138; WO 9717069 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 | |
| (VI) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (VII) | 36996 | N-(4-bromophenyl)-N-(methylsulfonyl)methanesulfonamide | C8H10BrNO4S2 | 详情 | 详情 | |
| (VIII) | 25015 | 6-methoxy-1-benzothiophen-2-ylboronic acid | C9H9BO3S | 详情 | 详情 | |
| (IX) | 36997 | N-[4-(6-methoxy-1-benzothiophen-2-yl)phenyl]-N-(methylsulfonyl)methanesulfonamide | C17H17NO5S3 | 详情 | 详情 | |
| (X) | 36998 | N-[4-(6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenyl]-N-(methylsulfonyl)methanesulfonamide | C31H34N2O7S3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.
| 【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149. |
| 【2】 Sugita, K.; Makino, I.; Sugimoto, H.; et al.; Synthesis and biological activity of imidazole derivatives as a novel class of HIV-1 nonnucleoside reverse transcriptase inhibitors. Symp Med Chem 1999, Abst 2P-05. |
| 【3】 Aono, K.; Ichihashi, T.; Sugawara, T.; Hirano, K. (Shionogi & Co. Ltd.); Lymph-absorbable imidazole derivs.. EP 0893442; US 6054591; WO 9735843 . |
| 【4】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 | |
| (I) | 35840 | 2,2-dichloro-3-methylbutanal | C5H8Cl2O | 详情 | 详情 | |
| (II) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (III) | 17346 | Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde | 60656-87-3 | C9H10O2 | 详情 | 详情 |
| (IV) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 | |
| (V) | 63296 | 1-({[(Z)-4-(benzyloxy)-2-butenyl]oxy}methyl)benzene; benzyl (Z)-4-(benzyloxy)-2-butenyl ether | C18H20O2 | 详情 | 详情 | |
| (VI) | 35841 | benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole | C14H18N2O | 详情 | 详情 | |
| (VII) | 35842 | 2-[(benzyloxy)methyl]-5-iodo-4-isopropyl-1H-imidazole; benzyl (5-iodo-4-isopropyl-1H-imidazol-2-yl)methyl ether | C14H17IN2O | 详情 | 详情 | |
| (VIII) | 35843 | bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene | 137897-99-5 | C12H6Cl4S2 | 详情 | 详情 |
| (IX) | 35844 | benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole | C20H20Cl2N2OS | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 35845 | 4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether | C26H25Cl2N3OS | 详情 | 详情 | |
| (XII) | 35846 | [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol | C19H19Cl2N3OS | 详情 | 详情 |