|
【结 构 式】 
|
【分子编号】63218 【品名】2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate 【CA登记号】 |
【 分 子 式 】C7H8F2N2O 【 分 子 量 】174.1502064 【元素组成】C 48.28% H 4.63% F 21.82% N 16.09% O 9.19% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(IX)2-Bromopyridine (I) is metalated by means of butyllithium and subsequently condensed with diethyl oxalate (II) to produce the keto ester adduct (III). Reaction of (III) with hot diethylaminosulfur trifluoride gives rise to the difluoro ester (IV), which is further reduced to alcohol (V) employing NaBH4 in EtOH. Treatment of (V) with triflic anhydride and 2,6-di-t-butyl-4-methylpyridine in CH2Cl2 yields the corresponding triflate (VI), which is then converted into azide (VII) by reaction with NaN3 in DMF. The pyridine ring of (VII) is oxidized by means of m-chloroperbenzoic acid to produce the N-oxide (VIII). Then, azido group reduction with PPh3 in moist THF leads to the primary amine (IX)
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (II) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (III) | 29952 | ethyl 2-oxo-2-(2-pyridinyl)acetate | C9H9NO3 | 详情 | 详情 | |
| (IV) | 63213 | ethyl 2,2-difluoro-2-(2-pyridinyl)acetate | C9H9F2NO2 | 详情 | 详情 | |
| (V) | 63214 | 2,2-difluoro-2-(2-pyridinyl)-1-ethanol | C7H7F2NO | 详情 | 详情 | |
| (VI) | 63215 | 2,2-difluoro-2-(2-pyridinyl)ethyl trifluoromethanesulfonate | C8H6F5NO3S | 详情 | 详情 | |
| (VII) | 63216 | 2,2-difluoro-2-(2-pyridinyl)ethyl azide; 2-(2-azido-1,1-difluoroethyl)pyridine | C7H6F2N4 | 详情 | 详情 | |
| (VIII) | 63217 | 2-(2-azido-1,1-difluoroethyl)-1-pyridiniumolate | C7H6F2N4O | 详情 | 详情 | |
| (IX) | 63218 | 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate | C7H8F2N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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 |