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【结 构 式】 
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【分子编号】35253 【品名】2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine 【CA登记号】30433-91-1 |
【 分 子 式 】C6H9NS 【 分 子 量 】127.2102 【元素组成】C 56.65% H 7.13% N 11.01% S 25.21% |
合成路线1
该中间体在本合成路线中的序号：(I)A total synthesis of sufentanil has been described: The cyclization of 2-(2-thienyl)ethylamine (I) with allyltrimethylsilane (II) and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl)ethyl]piperidin-4-one (IV). The epoxidation of (IV) by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide (V), which is opened with aniline (VI) and boron trifluoride ethearate giving a 1.8:1 mixture of 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII) and 4-hydroxy-4-(phenylamino)piperidine (VIII) that are conveniently separated. The methylation of the OH group of (VII) with diazomethane and SiO2 affords the methoxymethyl compound (IX), which is finally acylated with propionic anhydride to provide sufentanil.
| 【1】 Park, H.J.; Jeon, R.O.; Ryu, J.S.; Hyun, S.S.; Suh, Y.G.; Shin, D.Y.; Total synthesis of sufentanil. Arch Pharmacal Res 1999, 22, 4, 398. |
| 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) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
| (II) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (III) | 35254 | 1-[2-(2-thienyl)ethyl]-4-piperidinol | C11H17NOS | 详情 | 详情 | |
| (IV) | 35255 | 1-[2-(2-thienyl)ethyl]-4-piperidinone | C11H15NOS | 详情 | 详情 | |
| (V) | 35256 | 6-[2-(2-thienyl)ethyl]-1-oxa-6-azaspiro[2.5]octane | C12H17NOS | 详情 | 详情 | |
| (VI) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VII) | 35257 | [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol | C18H24N2OS | 详情 | 详情 | |
| (VIII) | 35258 | 4-(anilinomethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinol | C18H24N2OS | 详情 | 详情 | |
| (IX) | 35259 | N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylamine; 4-(methoxymethyl)-N-phenyl-1-[2-(2-thienyl)ethyl]-4-piperidinamine | C19H26N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Reaction of 2-amino-5-bromopyridine (I) with thiocarbonyl diimidazole (II) provided the thioimidazolide (III). This was then coupled with 2-(2-thienyl)ethyl amine (IV) to furnish the target thiourea.
| 【1】 Maher, D.; Mao, C.; Tuel-Ahlgren, L.; Uckun, F.M.; Zhu, D.; Pendergrass, S.; Venkatachalam, T.K.; N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett 1999, 9, 24, 3411. |
| 【2】 Ventatachalam, T.K.; Uckun, F.M. (Parker Hughes Institute); Thiophene-ethyl thiourea cpds. and use. US 6124324; WO 0078755 . |
| 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) | 12123 | 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine | 1072-97-5 | C5H5BrN2 | 详情 | 详情 |
| (II) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (III) | 24645 | N-(5-bromo-2-pyridinyl)-1H-imidazole-1-carbothioamide | C9H7BrN4S | 详情 | 详情 | |
| (IV) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)2-(2-Thienyl)ethylamine (I) was protected as the N-Boc derivative (II) with Boc2O in CHCl3. Regioselective halogenation of the thiophene ring of (II) with concomitant Boc group cleavage by means of bromine in cold HOAc yielded the 5-bromothiophene (III). The thioimidazolide (VI) was prepared by reaction of 2-amino-5-chloropyridine (IV) with thiocarbonyl diimidazole (V). Finally, condensation of (VI) with amine (III) in hot DMF furnished the target thiourea.
| 【1】 Uckun, F.M.; Sudbeck, E.A.; Venkatachalam, T.K.; Regiospecific synthesis, X-ray crystal structure and biological activities of 5-bromothiophenethyl thioureas. Tetrahedron Lett 2001, 42, 38, 6629. |
| 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) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
| (II) | 52887 | tert-butyl 2-(2-thienyl)ethylcarbamate | C11H17NO2S | 详情 | 详情 | |
| (III) | 52888 | 2-(5-bromo-2-thienyl)-1-ethanamine; 2-(5-bromo-2-thienyl)ethylamine | C6H8BrNS | 详情 | 详情 | |
| (IV) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (V) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (VI) | 36903 | C9H7ClN4S | 详情 | 详情 |