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【结 构 式】 
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【药物名称】Prasugrel, LY-640315, CS-747 【化学名称】Acetic acid 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl ester 【CA登记号】150322-43-3 【 分 子 式 】C20H20FNO3S 【 分 子 量 】373.4497 |
【开发单位】Ube (Originator), Lilly (Licensee), Sankyo (Licensee) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, P2Y12 (P2T) Antagonists |
合成路线1
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
Reaction of 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridin-2-one p-toluenesulfonate (VII) with TBDMS-Cl and TEA in dichloromethane gives the silylated enol ether (VIII), which is condensed with 1-cyclopropyl-2-chloro-2-(2-fluorophenyl)ethanone (IX) by means of TEA in the same solvent to provide the adduct (X). Finally, this compound is treated with TEA and DMAP and acetylated with Ac2O.
| 【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835. |
| 【2】 Yamamoto, Y.; Yokota, N.; Kohno, M.; Ataka, K.; Miyata, H. (Ube Industries, Ltd.); 2-Silyloxytetrahydrothienopyridine, salt thereof and process for preparing the same. US 5874581; WO 9611203 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 48585 | 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one | 178688-48-7 | C7H9NOS | 详情 | 详情 |
| (VIII) | 48587 | 2-[[tert-butyl(dimethyl)silyl]oxy]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine; tert-butyl(dimethyl)silyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl ether | C13H23NOSSi | 详情 | 详情 | |
| (IX) | 48588 | 2-chloro-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 178688-43-2 | C11H10ClFO | 详情 | 详情 |
| (X) | 48589 | 2-[2-[[tert-butyl(dimethyl)silyl]oxy]-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | C24H32FNO2SSi | 详情 | 详情 |
合成路线3
| 【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 |