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【结 构 式】 
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【药物名称】LY-329146 【化学名称】N-[4-[6-Hydroxy-3-[4-[2-(4-morpholinyl)ethoxy]benzoyl]-1-benzothien-2-yl]phenyl]-N-(methylsulfonyl)methanesulfonamide 【CA登记号】191043-78-4 【 分 子 式 】C30H32N2O7S3 【 分 子 量 】628.79074 |
【开发单位】Lilly (Originator) 【药理作用】Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, ONCOLYTIC DRUGS |
合成路线1
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
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 |