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【结 构 式】 
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【分子编号】63222 【品名】2-(2-{[4-(carboxymethyl)-5-chloro-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate 【CA登记号】 |
【 分 子 式 】C13H11ClF2N4O4 【 分 子 量 】360.7044064 【元素组成】C 43.29% H 3.07% Cl 9.83% F 10.53% N 15.53% O 17.74% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Lithiation of 2-bromopyridine (VI), followed by addition to diethyl oxalate leads to ketoester (VII). Subsequent fluorination of (VII) by means of diethylaminosulfur trifluoride gives rise to the difluoro ester (VIII). Reduction of ester (VIII) by using NaBH4 yields alcohol (IX), which is then activated as the triflate (X) with trifluoromethanesulfonic anhydride. Displacement of triflate (X) with NaN3 in hot DMF produces azide (XI). The pyridine ring of (XI) is converted into the corresponding N-oxide (XII) by treatment with m-chloroperbenzoic acid. Reduction of azide (XII) by means of triphenylphosphine in moist THF leads to amine (XIII). Coupling of amine (XIII) with the bromopyrazinone (XIV) provides the aminopyrazinone adduct (XV), which is further chlorinated to (XVI) employing N-chlorosuccinimide. Saponification of the ethyl ester group of (XVI) provides carboxylic acid (XVII). This is finally coupled to the benzylic amine (V) in the presence of EDC/HOAt to furnish the title amide.
| 【1】 Williams, P.D.; Selnick, H.G.; Young, M.B.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. EP 1359913; WO 0264140 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 63212 | [5-chloro-2-(1H-1,2,3,4-tetraazol-1-yl)phenyl]methanamine; 5-chloro-2-(1H-1,2,3,4-tetraazol-1-yl)benzylamine | C8H8ClN5 | 详情 | 详情 | |
| (VI) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (VII) | 29952 | ethyl 2-oxo-2-(2-pyridinyl)acetate | C9H9NO3 | 详情 | 详情 | |
| (VIII) | 63213 | ethyl 2,2-difluoro-2-(2-pyridinyl)acetate | C9H9F2NO2 | 详情 | 详情 | |
| (IX) | 63214 | 2,2-difluoro-2-(2-pyridinyl)-1-ethanol | C7H7F2NO | 详情 | 详情 | |
| (X) | 63215 | 2,2-difluoro-2-(2-pyridinyl)ethyl trifluoromethanesulfonate | C8H6F5NO3S | 详情 | 详情 | |
| (XI) | 63216 | 2,2-difluoro-2-(2-pyridinyl)ethyl azide; 2-(2-azido-1,1-difluoroethyl)pyridine | C7H6F2N4 | 详情 | 详情 | |
| (XII) | 63217 | 2-(2-azido-1,1-difluoroethyl)-1-pyridiniumolate | C7H6F2N4O | 详情 | 详情 | |
| (XIII) | 63218 | 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate | C7H8F2N2O | 详情 | 详情 | |
| (XIV) | 63219 | ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate | C8H9BrN2O3 | 详情 | 详情 | |
| (XV) | 63220 | 2-(2-{[4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate | C15H16F2N4O4 | 详情 | 详情 | |
| (XVI) | 63221 | 2-(2-{[5-chloro-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate | C15H15ClF2N4O4 | 详情 | 详情 | |
| (XVII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Acylation of glycine ethyl ester (X) with ethyl oxalyl chloride (XI) provides the oxalic acid mono-amide (XII). Subsequent condensation of (XII) with aminoacetaldehyde dimethylacetal (XIII) affords the diamide (XIV). Cyclization of (XIV) under acetal hydrolysis conditions leads to pyrazinone (XV). This is then brominated to (XVI) employing POBr3 in refluxing dichloroethane. Condensation of the bromopyrazinone (XVI) with amine (IX) at 120 C in a sealed vessel furnishes the aminopyrazinone (XVII). After chlorination of (XVII) with N-chlorosuccinimide, the resultant chloropyrazine ester (XVIII) is hydrolyzed to acid (XIX) under alkaline conditions
| 【1】 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 |
|---|---|---|---|---|---|---|
| (IX) | 63218 | 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate | C7H8F2N2O | 详情 | 详情 | |
| (X) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (XI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XII) | 63556 | ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate | C8H13NO5 | 详情 | 详情 | |
| (XIII) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XIV) | 63557 | ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate | C10H18N2O6 | 详情 | 详情 | |
| (XV) | 63558 | ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate | C8H10N2O4 | 详情 | 详情 | |
| (XVI) | 63219 | ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate | C8H9BrN2O3 | 详情 | 详情 | |
| (XVII) | 63220 | 2-(2-{[4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate | C15H16F2N4O4 | 详情 | 详情 | |
| (XVIII) | 63221 | 2-(2-{[5-chloro-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate | C15H15ClF2N4O4 | 详情 | 详情 | |
| (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 |
合成路线3
该中间体在本合成路线中的序号：(XIX)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 |