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【结 构 式】

【分子编号】63221

【品名】2-(2-{[5-chloro-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate

【CA登记号】

【 分 子 式 】C15H15ClF2N4O4

【 分 子 量 】388.7581664

【元素组成】C 46.34% H 3.89% Cl 9.12% F 9.77% N 14.41% O 16.46%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XVI)

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:(XVIII)

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
Extended Information