MEN-10700, -Drug Synthesis Database

【结构式】

【药物名称】MEN-10700

【化学名称】(+)-(5R,6S)-2-[N-(Carbamoylmethyl)-N-methylaminomethyl]-6-[1(R)-hydroxyethyl]-2-penem-3-carboxylic acid

【CA登记号】156662-18-9, 156662-23-6 (monoNa salt)

【分子式】C₁₂H₁₇N₃O₅S

【分子量】315.35039

【开发单位】Lusofarmaco (Originator), Menarini (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Penems

合成路线1 合成路线2

合成路线1

The 2-(hydroxymethyl)penem (I) is transformed into the corresponding mesylate (II), which is then condensed with sarcosinamide (III), to afford adduct (IV). The O-silyl group of (IV) is removed by treatment with tetrabutylammonium fluoride, yielding alcohol (V). Finally, the allyl ester group of (V) is cleaved in the presence of palladium and triphenylphosphine to furnish the target carboxylic acid.

参考文献中间体

【3】 Altamura, M.; Arcamone, F.M.; Perrotta, E.; Pestellini, V.; Sbraci, P.; Cascio, G. (Lusofarmaco; Menarini Industrie Farma Riunite Srl); Penem derivs., their preparation and pharmaceutical compsns. containing them. EP 0660837; JP 1996501543; WO 9406803 .
【1】 Pestellini, V.; Perrotta, E.; Arcamone, F.; Sbraci, P.; Altamura, M.; 2-Substituted penems with amino acid-related side chains: Synthesis and antibacterial activity of a new series of beta-lactam antibiotics. J Med Chem 1995, 38, 21, 4244.
【2】 Altamura, M.; et al.; Synthesis and antibacterial activity of MEN 10700, a new penem antibiotic. Bioorg Med Chem Lett 1995, 5, 6, 555.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	58252	allyl (5R,6S)-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₈H₂₉NO₅SSi	详情	详情
(II)	58253	allyl (5R,6S)-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-{[(methylsulfonyl)oxy]methyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₉H₃₁NO₇S₂Si	详情	详情
(III)	54572	2-(methylamino)acetamide	C₃H₈N₂O	详情	详情
(IV)	58254	allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₁H₃₅N₃O₅SSi	详情	详情
(V)	58255	allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₅H₂₁N₃O₅S	详情	详情

合成路线2

In a related method, the 4-acetoxy-azetidinone (I) is reacted with 2-chlorothioacetic acid (II) in the presence of ZnI2 to give the (chloroacetylthio)azetidinone (III). Nitrogen acylation in (III) by means of allyl oxalyl chloride produces (IV), which undergoes ring closure to the penem (V) in the presence of triethyl phosphite in boiling toluene. Displacement of chloride (V) with sarcosinamide (VI) yields adduct (VII). After desilylation of (VII) to (VIII) by means of tetrabutylammonium fluoride, palladium-catalyzed allyl ester cleavage leads to the title compound.

参考文献中间体

【1】 Arcamone, F.M.; et al.; Synthesis and biological activity of the penem antibiotic MEN 10700 and its orally absorbed ester MEN 11505. J Antibiot 2000, 53, 10, 1086.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate	C₁₃H₂₅NO₄Si	详情	详情
(II)	58256	2-chloroethanethioic S-acid	C₂H₃ClOS	详情	详情
(III)	58257	S-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl] 2-chloroethanethioate	C₁₃H₂₄ClNO₃SSi	详情	详情
(IV)	58258	allyl 2-{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[(2-chloroacetyl)sulfanyl]-4-oxoazetidinyl}-2-oxoacetate	C₁₈H₂₈ClNO₆SSi	详情	详情
(V)	58259	allyl (5R,6S)-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(chloromethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₈H₂₈ClNO₄SSi	详情	详情
(VI)	54572	2-(methylamino)acetamide	C₃H₈N₂O	详情	详情
(VII)	58254	allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₁H₃₅N₃O₅SSi	详情	详情
(VIII)	58255	allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₅H₂₁N₃O₅S	详情	详情

Extended Information