E-1010, ER-35786, -Drug Synthesis Database

【结构式】

【药物名称】E-1010, ER-35786

【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxymethyl]-2-[2(S)-[1(R)-hydroxy-1-[pyrrolidin-3(R)-yl]methyl]pyrrolidin-4(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid monohydrochloride

【CA登记号】186319-97-1

【分子式】C₁₉H₃₀ClN₃O₅S

【分子量】447.98505

【开发单位】Eisai (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2

合成路线1

The condensation of the enolphosphate (I) (1) and the thiol (II) in the presence of diisopropylethylamine gives the protected compound (III), which is deprotected by hydrogenolysis with H2 over Pd(OH)2 on carbon, purified by reverse-phase silica gel chromatography and treated with HCl to afford ER-35786 (2), as shown in Scheme 22662001a.

参考文献中间体

【1】 Kaneda, S.; Hayasi, K.; Kumagai, T.; Crystalline 1-methyl-2-diphenylphosphoryloxy-carbapenem compounds. JP 92330085 .
【2】 Sato, N.; Ohba, F.; ER-35786. Drugs Fut 1996, 21, 4, 361.
【3】 Sato, N.; Sasho, M.; Kamada, A.; Suzuki, T.; Ashizawa, K.; Sugiyama, I.; ER-35786, a new antipseudomonal carbapenem: I. Synthesis and structure-activity relations of 2-substituted 1beta-methyl carbapenems. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F151.

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)	13224	4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	90776-59-3	C₂₉H₂₇N₂O₁₀P	详情	详情
(II)	17113	(R)-[(2S,4S)-1-methyl-4-sulfanyltetrahydro-1H-pyrrol-2-yl][(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methanol		C₁₁H₂₂N₂OS	详情	详情
(III)	17114	methyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[((3S,5S)-5-[(R)-hydroxy[(3R)-1-methylpyrrolidinyl]methyl]-1-methylpyrrolidinyl)sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₂H₃₅N₃O₅S	详情	详情

合成路线2

The thiol (II) has been obtained as follows: The aldehyde (V), which is synthesized from trans-4-hydroxy-L-proline in several steps (3), reacts with the lithium enolate of the pyrrolidone (IV) to afford the alcohol (VI) and its diastereomeric isomers. After purification on a silica gel column, reduction of (VI) by borane-dimethylsulfide in refluxing THF gives (VII). Removal of the amino protecting groups of (VII) by TFA, followed by reprotection with PNZ groups and then removal of the tert-butyldimethylsilyl group with Bu4NF gives the diol (VIII). Selective mesylation of (VIII), followed by reaction with potassium thioacetate, gives (IX), which is treated with aqueous 1 N NaOH in methanol to afford the thiol (II).

参考文献中间体

【1】 Sato, N.; Ohba, F.; ER-35786. Drugs Fut 1996, 21, 4, 361.
【2】 Nakagawa, S.; Ohtake, N.; Nakano, F.; Yamada, K.; Ushijima, R.; Murase, S.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); 2-(Substd. pyrrolidinylthio)carbapenem derivs. EP 0449191; JP 1992321688; US 5373002; US 5374720; US 5438054; WO 9114687 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	17113	(R)-[(2S,4S)-1-methyl-4-sulfanyltetrahydro-1H-pyrrol-2-yl][(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methanol		C₁₁H₂₂N₂OS	详情	详情
(IV)	17115	1-Methyl-2-pyrrolidinone	872-50-4	C₅H₉NO	详情	详情
(V)	17116	(2S,4R)-4-hydroxy-1-methyltetrahydro-1H-pyrrole-2-carbaldehyde		C₆H₁₁NO₂	详情	详情
(VI)	17117	(3S)-3-[(R)-hydroxy[(2S,4R)-4-hydroxy-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1-methyltetrahydro-2H-pyrrol-2-one		C₁₁H₂₀N₂O₃	详情	详情
(VII)	17118	(R)-((2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpyrrolidinyl)[(3R)-1-methylpyrrolidinyl]methanol		C₁₁H₂₂N₂O₂	详情	详情
(VIII)	17119	(3R,5S)-5-[(R)-hydroxy[(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl]-1-methyltetrahydro-1H-pyrrol-3-ol		C₁₁H₂₂N₂O₂	详情	详情
(IX)	17120	S-((3S,5S)-5-[(R)-hydroxy[(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl]-1-methyltetrahydro-1H-pyrrol-3-yl) ethanethioate		C₁₃H₂₄N₂O₂S	详情	详情

Extended Information