【结 构 式】 |
【分子编号】16270 【品名】N-(tert-butyl)-1,4,5,6-tetrahydro-2-pyrazinecarboxamide 【CA登记号】 |
【 分 子 式 】C9H17N3O 【 分 子 量 】183.2536 【元素组成】C 58.99% H 9.35% N 22.93% O 8.73% |
合成路线1
该中间体在本合成路线中的序号:(XXXIII)6) The chiral piperazine (VII) can be obtained by several different ways: 6a) The sequential protection of piperazine-2(S)-carboxylic acid (XXIX) gives 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2(S)-carboxylic acid (XXX), which is condensed with tert-butylamine by means of EDC and HOBt to afford the tert-butylamide (XXXI). Finally, this compound is selectively deprotected by hydrogenation with H2 over Pd/C in methanol, yielding the chiral piperazine (VII). 6b) The partial hydrogenation of N-tert-butylpyrazine-2-carboxamide (XXXII) with H2 over Pd/C gives the tetrahydro derivative (XXXIII), which is sequentially protected as usual to the 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrazin e -2-carboxamide (XXXIV). Finally, this compound is hydrogenated using the chiral catalyst [R-BINAP(COD)Rh]OTf to afford the chiral piperazine (XXXI), already obtained. 6c) The N-tert-butylpyrazine-2-carboxamide (XXXII) is fully reduced with H2 over Pd/C in propanol, giving the racemic N-tert-butylpiperazine-2-carboxamide (XXXV), which is submitted to optical resolution with (S)-(+)-camphosulfonic acid, yielding the (S)-isomer (XXXVI), which is then selectively protected with tert-butoxycarbonyl anhydride to give the desired chiral amide (VII).
【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
【2】 Rossen, K.; Weissman, S.A.; Sager, J.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir. Tetrahedron Lett 1995, 36, 36, 6419-22. |
【3】 Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 . |
【4】 Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 . |
【5】 Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 . |
【6】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 . |
【7】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51. |
【8】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6. |
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) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
(XXIX) | 16266 | (2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
(XXX) | 16267 | (2S)-1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)hexahydro-2-pyrazinecarboxylic acid | C18H24N2O6 | 详情 | 详情 | |
(XXXI) | 16268 | 1-benzyl 4-(tert-butyl) (2S)-2-[(tert-butylamino)carbonyl]tetrahydro-1,4-pyrazinedicarboxylate | C22H33N3O5 | 详情 | 详情 | |
(XXXII) | 16269 | N-(tert-butyl)-2-pyrazinecarboxamide | 121885-10-7 | C9H13N3O | 详情 | 详情 |
(XXXIII) | 16270 | N-(tert-butyl)-1,4,5,6-tetrahydro-2-pyrazinecarboxamide | C9H17N3O | 详情 | 详情 | |
(XXXIV) | 16271 | 4-benzyl 1-(tert-butyl) 5-[(tert-butylamino)carbonyl]-2,3-dihydro-1,4-pyrazinedicarboxylate | C22H31N3O5 | 详情 | 详情 | |
(XXXV) | 16272 | N-(tert-butyl)-2-piperazinecarboxamide; Piperazine-2-carboxylic acid tert-butylamide | C9H19N3O | 详情 | 详情 | |
(XXXVI) | 16273 | (2S)-N-(tert-butyl)hexahydro-2-pyrazinecarboxamide | C9H19N3O | 详情 | 详情 |