【结 构 式】 |
【分子编号】48584 【品名】2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone 【CA登记号】204205-33-4 |
【 分 子 式 】C11H10BrFO 【 分 子 量 】257.1022032 【元素组成】C 51.39% H 3.92% Br 31.08% F 7.39% O 6.22% |
合成路线1
该中间体在本合成路线中的序号:(IV)Reaction of the Grignard reagent prepared from 2-fluorobenzyl bromide (I) and Mg in ether with cyclopropyl cyanide (II) in the same solvent gives 1-cyclopropyl-2-(2-fluorophenyl)ethanone (III), which is brominated with Br2 in CCl4 to yield the a-bromoketone (IV). Condensation of ketone (IV) with 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridin-2-one hydrochloride (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally treated with acetic anhydride and NaH in DMF.
【2】 Koike, H.; Asai, F.; Sugidachi, A.; Kimura, T.; Inoue, T.; Nishino, S.; Tsuzaki, Y. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Tetrahydrothienopyridine derivs., furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation. EP 0542411; JP 1994041139; US 5288726; US 5436242 . |
【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835. |
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) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
(II) | 27238 | cyclopropanecarbonitrile | 5500-21-0 | C4H5N | 详情 | 详情 |
(III) | 48583 | 1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 150322-73-9 | C11H11FO | 详情 | 详情 |
(IV) | 48584 | 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 204205-33-4 | C11H10BrFO | 详情 | 详情 |
(V) | 48585 | 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one | 178688-48-7 | C7H9NOS | 详情 | 详情 |
(VI) | 48586 | 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one | 951380-42-0 | C18H18FNO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VI)Protection of 4-piperidone (I) with trityl chloride and TEA gives 1-tritylpiperidin-4-one (II), which is condensed with ethyl 2-oxoacetate (III) by means of pyrrolidine in refluxing benzene to yield 3-(ethoxycarbonylmethylene)-1-tritylpiperidin-4-one (IV). The deprotection and simultaneous reduction of compound (IV) with NaBH4 in methanol affords the 4-hydroxypiperidine derivative (V), which is condensed with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (VI) by means of K2CO3 in DMF to provide the adduct (VII). Reaction of the OH group of (VII) with CBr4 and PPh3 in dichloromethane gives the 4-bromopiperidine derivative (VIII), which by reaction with potassium thioacetate (IX) in ethanol provides the 4-(acetylthio)piperidine derivative (X). Selective hydrolysis of compound (X) with HCl in ethanol yields the 4-sulfanylpiperidine derivative (XI), which is finally submitted to a new hydrolysis with HCl in acetic acid.
【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835. |
【2】 Asai, F.; Sugidachi, A.; Ikeda, T.; Koike, H.; Inoue, T.; Takata, K.; Iwamura, R.; Kita, J.; Yoneda, K. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amine derivs.. EP 0934928; JP 1998120649; US 6087379; WO 9808811 . |
【3】 Shibakawa, N.; Iwabuchi, H.; Sugidachi, A.; Ikeda, T.; Iwamura, R.; Kuroki, Y.; Inoue, T.; Asai, F. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amino cpds.. EP 1063230; WO 9943648 . |
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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
(II) | 48590 | 1-trityl-4-piperidinone | C24H23NO | 详情 | 详情 | |
(III) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
(IV) | 48592 | ethyl 2-(4-oxo-1-trityl-3-piperidinylidene)acetate | C28H27NO3 | 详情 | 详情 | |
(V) | 48593 | ethyl 2-(4-hydroxy-3-piperidinylidene)acetate | C9H15NO3 | 详情 | 详情 | |
(VI) | 48584 | 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 204205-33-4 | C11H10BrFO | 详情 | 详情 |
(VII) | 48594 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-hydroxy-3-piperidinylidene]acetate | C20H24FNO4 | 详情 | 详情 | |
(VIII) | 48595 | ethyl 2-[4-bromo-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C20H23BrFNO3 | 详情 | 详情 | |
(IX) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
(X) | 48596 | ethyl 2-[4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C22H26FNO4S | 详情 | 详情 | |
(XI) | 48597 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanyl-3-piperidinylidene]acetate | C20H24FNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VI)
【1】 Wu XS, Cen JD, Guo H. 2008.2-methoxy -5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine by one-step reaction. CN 101250193. |
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) | 34011 | 4,5,6,7-tetrahydrothieno[3,2-c]pyridine | 54903-50-3 | C7H9NS | 详情 | 详情 |
(II) | 67366 | 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine | C14H15NS | 详情 | 详情 | |
(III) | 67367 | 5-benzyl-2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine | C14H14BrNS | 详情 | 详情 | |
(IV) | 67368 | 5-benzyl-2-methoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine | C15H17NOS | 详情 | 详情 | |
(V) | 67369 | 2-methoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride | C8H11NOS.HCl | 详情 | 详情 | |
(VI) | 48584 | 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 204205-33-4 | C11H10BrFO | 详情 | 详情 |
(VII) | 67370 | 1-cyclopropyl-2-(2-fluorophenyl)-2-(2-methoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone hydrochloride | C19H20FNO2S.HCl | 详情 | 详情 | |
(VIII) | 67371 | 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrochloride | C18H18ClFNO2S.HCl | 详情 | 详情 |