benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】47070

【品名】benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate

【CA登记号】

【分子式】C₃₃H₂₅N₃O₃S

【分子量】543.64592

【元素组成】C 72.91% H 4.64% N 7.73% O 8.83% S 5.9%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

7-Aminocephalosporanic acid (I) was esterified with diphenyldiazomethane to produce the benzhydryl ester (II). Diazotization of (II) with isopropyl nitrite in the presence of trifluoroacetic acid, followed by treatment of the resulting diazo compound with propylene oxide and a catalytic amount of rhodium (II) octanoate, gave the corresponding 7-oxocephalosporanate (III). Wittig reaction of ketone (III) with the ylide resulting from 2-picolyltriphenylphosphonium chloride (IV) and NaNH2 in cold THF yielded olefin (V). Cephem double-bond isomerization upon treatment with triethylamine produced the 2-cephem derivative (VI) as the major compound, which was separated from the unreacted 3-cephem by flash chromatography. Acid hydrolysis of acetate ester (VI) gave rise to the corresponding alcohol (VII), which was further oxidized to aldehyde (VIII) by using pyridinium dichromate. Condensation of aldehyde (VIII) with the Wittig reagent (III) produced adduct (IX).

参考文献中间体

合成目标

【1】 Adam, G.; Doppalapudi, V.R.; Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; New cephalosporin-derived beta-lactamase inhibitors. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F403.
【2】 Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; Doppalapudi, V.R.; Adam, G.C. (Research Corporation Technologies, Inc.); beta-Lactamase inhibiting cpds.. WO 0063213 .

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)	22747	(6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₀H₁₂N₂O₅S	详情	详情
(II)	39849	benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₃H₂₂N₂O₅S	详情	详情
(III)	47065	benzhydryl (6R)-3-[(acetoxy)methyl]-7,8-dioxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₃H₁₉NO₆S	详情	详情
(IV)	35151	triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride	73870-25-4	C₂₄H₂₁ClNP	详情	详情
(V)	47066	benzhydryl (6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₉H₂₄N₂O₅S	详情	详情
(VI)	47067	benzhydryl (2R,6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate		C₂₉H₂₄N₂O₅S	详情	详情
(VII)	47068	benzhydryl (2R,6R)-3-(hydroxymethyl)-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate		C₂₇H₂₂N₂O₄S	详情	详情
(VIII)	47069	benzhydryl (2R,6R)-3-formyl-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate		C₂₇H₂₀N₂O₄S	详情	详情
(IX)	47070	benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate		C₃₃H₂₅N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Oxidation of (IX) with concomitant double-bond isomerization by means of meta-chloroperbenzoic acid furnished sulfone (X). The benzhydryl ester of (X) was then cleaved using trifluoroacetic acid in anisole to produce the corresponding carboxylic acid, which was finally converted to the title sodium salt by treatment with NaHCO3.

参考文献中间体

合成目标

【1】 Adam, G.; Doppalapudi, V.R.; Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; New cephalosporin-derived beta-lactamase inhibitors. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F403.
【2】 Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; Doppalapudi, V.R.; Adam, G.C. (Research Corporation Technologies, Inc.); beta-Lactamase inhibiting cpds.. WO 0063213 .

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)	47070	benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate		C₃₃H₂₅N₃O₃S	详情	详情
(X)	47071	2-((E)-2-[(6R)-2-[(benzhydryloxy)carbonyl]-5,5,8-trioxo-7-[(Z)-2-pyridinylmethylidene]-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]ethenyl)-1-pyridiniumolate		C₃₃H₂₅N₃O₆S	详情	详情

Extended Information