-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2-[6-Chloro-3-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethylamino]-2-oxo-1,2-dihydropyrazin-1-yl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]acetamide

【CA登记号】450415-35-7

【分子式】C₂₁H₁₇Cl₂F₂N₉O₃

【分子量】552.33094

【开发单位】Merck & Co. (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1 合成路线2

合成路线1

The precursor 5-chloro-2-tetrazol-1-yl-benzylamine (V) is prepared as follows. Cyclization of 5-chloroanthranilic acid (I) with sodium azide and trimethyl orthoformate gives rise to the tetrazole derivative (II). Subsequent coupling of acid (II) with ammonium chloride in the presence of EDC and HOAt affords amide (III). This is then dehydrated to the nitrile (IV) employing the Burgess reagent in THF. Nitrile (IV) is reduced to the target amine (V) by catalytic hydrogenation over Raney nickel.

参考文献中间体

【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
(I)	10285	2-Amino-5-chlorobenzoic acid	635-21-2	C₇H₆ClNO₂	详情	详情
(II)	63209	5-chloro-2-(1H-1,2,3,4-tetraazol-1-yl)benzoic acid		C₈H₅ClN₄O₂	详情	详情
(III)	63210	5-chloro-2-(1H-1,2,3,4-tetraazol-1-yl)benzamide		C₈H₆ClN₅O	详情	详情
(IV)	63211	5-chloro-2-(1H-1,2,3,4-tetraazol-1-yl)benzonitrile		C₈H₄ClN₅	详情	详情
(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

合成路线2

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.

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)