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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information