ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate -Drug Synthesis Database

【结构式】

【分子编号】63219

【品名】ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate

【CA登记号】

【分子式】C₈H₉BrN₂O₃

【分子量】261.07514

【元素组成】C 36.8% H 3.47% Br 30.61% N 10.73% O 18.38%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XIV)

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2

该中间体在本合成路线中的序号：(XVI)

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

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
(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：(VII)

Acylation of glycine ethyl ester (I) with ethyl oxalyl chloride (II) affords amide (III). Subsequent reaction of (III) with aminoacetaldehyde dimethyl acetal (IV) produces the oxalic acid diamide (V). Cyclization of (V) under acidic conditions furnishes the pyrazine dione (VI), which is further brominated to (VII) employing phosphorus oxybromide.

参考文献中间体

合成目标

【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .

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)	10309	ethyl 2-aminoacetate; Glycine ethyl ester	459-73-4	C₄H₉NO₂	详情	详情
(II)	11043	Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride	4755-77-5	C₄H₅ClO₃	详情	详情
(III)	63556	ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate		C₈H₁₃NO₅	详情	详情
(IV)	34158	aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine	22483-09-6	C₄H₁₁NO₂	详情	详情
(V)	63557	ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate		C₁₀H₁₈N₂O₆	详情	详情
(VI)	63558	ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate		C₈H₁₀N₂O₄	详情	详情
(VII)	63219	ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate		C₈H₉BrN₂O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Mitsunobu coupling of N-Boc-L-phenylglycinol (VIII) with hydrazoic acid affords azide (IX). Subsequent acidic cleavage of the N-Boc protecting group of (IX) furnishes amino azide (X). This is then condensed with the bromopyrazinone (VII) upon heating at 110 C in a pressure vessel to furnish adduct (XI). Treatment of (XI) with N-chlorosuccinimide in hot dichloroethane gives rise to the chloropyrazinone (XII). The azido group of (XII) is then reduced to the corresponding amine (XIII) employing SnCl2 in MeOH/THF (1,2).

参考文献中间体

合成目标

【1】 Nantermet, P.G.; Barrow, J.C.; Newton, C.L.; Pellicore, J.M.; Young, M.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; McMasters, D.R.; Youwei, Y.; Kuo, L.C.; Vacca, J.P.; Selnick, H.G.; Design and synthesis of potent and selective macrocyclic thrombin inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 168.
【2】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	63219	ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate	C₈H₉BrN₂O₃	详情	详情
(VIII)	54624	tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate	C₁₄H₂₁NO₃	详情	详情
(IX)	63851	tert-butyl (1S)-2-azido-1-benzylethylcarbamate	C₁₄H₂₀N₄O₂	详情	详情
(X)	63852	(1S)-2-azido-1-benzylethylamine; (2S)-1-azido-3-phenyl-2-propanamine	C₉H₁₂N₄	详情	详情
(XI)	64204	ethyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₂₀N₆O₃	详情	详情
(XII)	64205	ethyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₁₉ClN₆O₃	详情	详情
(XIII)	64206	ethyl 2-[3-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₂₁ClN₄O₃	详情	详情

Extended Information