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【结 构 式】 
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【分子编号】63560 【品名】2-bromo-5-chlorobenzoic acid 【CA登记号】21739-93-5 |
【 分 子 式 】C7H4BrClO2 【 分 子 量 】235.46426 【元素组成】C 35.71% H 1.71% Br 33.93% Cl 15.06% O 13.59% |
合成路线1
该中间体在本合成路线中的序号：(XX)2-Bromo-4-chlorobenzoic acid (XX) is esterified to (XXI) employing methanolic HCl. Displacement of the 2-bromo group of (XXI) with Zn(CN)2 produces nitrile (XXII). Simultaneous reduction of both ester and cyano groups of (XXII) by means of LiAlH4 leads to amino alcohol (XXIII), which is further protected as the N-Boc derivative (XXIV) with di-tert-butyl dicarbonate. Treatment of the benzylic alcohol (XXIV) with diphenylphosphoryl azide affords the alkyl azide (XXV). After reduction of (XXV) to the corresponding amine (XXVI) by means of PPh3 in THF/H2O, coupling with carboxylic acid (XIX) with EDC, HOAt and Et3N furnishes amide (XXVII). The N-Boc group of (XXVII) is finally cleaved under acidic conditions to provide the title compound (1,2).
| 【1】 Rittle, K.E.; Barrow, J.C.; Cutrona, K.J.; Dier, D.L.; Glass, K.L.; Krueger, J.A.; Kuo, L.C.; Lewis, S.D.; Lucas Jr., B.J.; McMasters, D.R.; Morrissette, M.M.; Nantermet, P.G.; Newton, C.L.; Sanders, W.M.; Yan, Y.; Vacca, J.P.; Selnick, H.G.; Unexpected enhancement of thrombin inhibitor potency with O-aminoalkylbenzylamides in the P1 position. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 229. |
| 【2】 Selnick, H.G.; Rittle, K.E.; Barrow, J.C.; Morrissette, M.M.; Nantermet, P.G.; Staas, D. (Merck & Co., Inc.); Thrombin inhibitors. WO 0257225 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 63222 | 2-(2-{[4-(carboxymethyl)-5-chloro-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate | C13H11ClF2N4O4 | 详情 | 详情 | |
| (XX) | 63560 | 2-bromo-5-chlorobenzoic acid | 21739-93-5 | C7H4BrClO2 | 详情 | 详情 |
| (XXI) | 63561 | methyl 2-bromo-5-chlorobenzoate | C8H6BrClO2 | 详情 | 详情 | |
| (XXII) | 63562 | methyl 5-chloro-2-cyanobenzoate | C9H6ClNO2 | 详情 | 详情 | |
| (XXIII) | 63563 | [2-(aminomethyl)-5-chlorophenyl]methanol | C8H10ClNO | 详情 | 详情 | |
| (XXIV) | 63564 | tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate | C13H18ClNO3 | 详情 | 详情 | |
| (XXV) | 63565 | tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate | C13H17ClN4O2 | 详情 | 详情 | |
| (XXVI) | 63566 | tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate | C13H19ClN2O2 | 详情 | 详情 | |
| (XXVII) | 63567 | 2-{2-[(4-{2-[(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)amino]-2-oxoethyl}-5-chloro-3-oxo-3,4-dihydro-2-pyrazinyl)amino]-1,1-difluoroethyl}-1-pyridiniumolate | C26H28Cl2F2N6O5 | 详情 | 详情 |