ethyl 2-oxo-2-(2-pyridinyl)acetate -Drug Synthesis Database

【结构式】

【分子编号】29952

【品名】ethyl 2-oxo-2-(2-pyridinyl)acetate

【CA登记号】

【分子式】C₉H₉NO₃

【分子量】179.1754

【元素组成】C 60.33% H 5.06% N 7.82% O 26.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

This compound can be obtained in three different ways: 1) Condensation of pyridine-2-carboxylic acid (Ia, R = H), with 1-phenyl methylpiperazine (II) at 160 C. 2) Condensation of methyl pyridine-2-carboxylate (Ib, R = CH3) with 1-phenylmethylpiperazine (II) at 140 C. 3) Reaction of 1-phenylmethylpiperazine (II) with a mixed anhydride (III) formed from (Ia) and ethyl chloroformate (IV).

参考文献中间体

合成目标

【1】 Budai, Z.; Zolyomi, G.; Synthesis of 14C and 3H specifically labelled 1-benzyl-4-picolinoylpiperazine. J Label Compd Radiopharm 1981, 18, 427-432.
【2】 Budai, Z.; Mezei, T.; Lay, A.; A novel synthesis of pyridinecarboxylic acid piperazides. Acta Chim Acad Sci Hung 1980, 105, 241-246.
【3】 Budai, Z.; Mezei, T.; Lay, A. (Egis Pharmaceuticals Ltd.); Preparation of pyridinecaboxylic acid piperazides. DE 2828888; GB 2001062; HU 175075 .
【4】 Korosi, J.; et al. (Egis Pharmaceuticals Ltd.); Pyridine derivatives. DE 2215545; GB 1378964; HU 162396; JP 7644957 .
【5】 Nogradi, M.; Piberaline. Drugs Fut 1984, 9, 1, 30.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ia)	29950	2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid	98-98-6	C₆H₅NO₂	详情	详情
(Ib)	29951	methyl 2-pyridinecarboxylate	2459-07-6	C₇H₇NO₂	详情	详情
(II)	28542	N-Benzylpiperazine; 1-Benzylpiperazine	2759-28-6	C₁₁H₁₆N₂	详情	详情
(III)	29952	ethyl 2-oxo-2-(2-pyridinyl)acetate		C₉H₉NO₃	详情	详情
(IV)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

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

合成目标

【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3

该中间体在本合成路线中的序号：(III)

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)

参考文献中间体

合成目标

【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

Extended Information