benzhydryl (1S,8R)-8-amino-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】55358

【品名】benzhydryl (1S,8R)-8-amino-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate

【CA登记号】

【分子式】C₂₁H₁₉NO₃S

【分子量】365.4528

【元素组成】C 69.02% H 5.24% N 3.83% O 13.13% S 8.77%

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：(X)

The fermentation of cephalosporin C (I) with immobilized Rhodoturula gracilis gives 3-(acetoxymethyl)-7(R)-(glutaroylamino)-3-cephem-4-carboxylic acid (II), which is oxidized to the corresponding sulfoxide (III). The electrochemical reduction of (II) yields the exo-methylene derivative (IV), which is esterified with diphenyldiazomethane to afford the diphenylmethyl diester (V). The ozonolysis of (V) provides the enol (VI), which is reduced with NaBH4 to the secondary alcohol (VII). The reaction of (VII) with Ms-Cl and TEA gives the mesylate (VIII), which by treatment with DEA, yields the 3-cephem derivative (IX). The cleavage of the amido group of (IX) with PCl5 and pyridine affords 7(R)-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (X).

参考文献中间体

合成目标

【1】 Chai, D.; et al.; Ceftibuten: Development of a commercial process based on cephalosporin C. Part IV. Pilot-plant scale electrochemical reduction of 3Acetoxymethyl-7(S)-glytaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 178.
【2】 Bernasconi, E.; et al.; Deftibuten: Development of a commercial process based on cephalosporin C. Part I. Process for the manufacture of 3-acetoxymethyl-7(R-glutaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 152.
【3】 Bernasconi, E.; et al.; Ceftibuten: Development of a commercial process based on cephalosporin C. Part III. Process for the conversion of 3-exomethylene-7(S)-glytaroylaminocepham-4-carboxylic acid 1(S)-oxide to ceftibuten. Org Process Res Dev 2002, 6, 2, 169.
【4】 Bernasconi, E.; et al.; Ceftibuten: Development of commerci I process B sed on ceph losporin C. Part II. Process for the Manufacture of 3-exomethylene-7(R)-glutaroyllaminoceph m-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 158.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	55349	(1S,8R)-4-[(acetyloxy)methyl]-8-{[(5R)-5-amino-5-carboxypentanoyl]amino}-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylic acid	C₁₇H₂₂N₂O₈S	详情	详情
(II)	55350	(1S,8R)-4-[(acetyloxy)methyl]-8-[(4-carboxybutanoyl)amino]-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylic acid	C₁₆H₁₉NO₈S	详情	详情
(III)	55351	(1S,8R)-4-[(acetyloxy)methyl]-8-[(4-carboxybutanoyl)amino]-2,7-dioxo-2lambda~4~-thiabicyclo[4.2.0]oct-4-ene-5-carboxylic acid	C₁₆H₁₉NO₉S	详情	详情
(IV)	55352	(1S,8R)-8-[(4-carboxybutanoyl)amino]-4-methylene-2,7-dioxo-2lambda~4~-thiabicyclo[4.2.0]octane-5-carboxylic acid	C₁₄H₁₇NO₇S	详情	详情
(V)	55353	benzhydryl (1S,8R)-8-{[5-(benzhydryloxy)-5-oxopentanoyl]amino}-4-methylene-2,7-dioxo-2lambda~4~-thiabicyclo[4.2.0]octane-5-carboxylate	C₄₀H₃₇NO₇S	详情	详情
(VI)	55354	benzhydryl (1S,8R)-8-{[5-(benzhydryloxy)-5-oxopentanoyl]amino}-4-hydroxy-2,7-dioxo-2lambda~4~-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate	C₃₉H₃₅NO₈S	详情	详情
(VII)	55355	benzhydryl (1S,8R)-8-{[5-(benzhydryloxy)-5-oxopentanoyl]amino}-4-hydroxy-7-oxo-2-thiabicyclo[4.2.0]octane-5-carboxylate	C₃₉H₃₇NO₇S	详情	详情
(VIII)	55356	benzhydryl (1S,8R)-8-{[5-(benzhydryloxy)-5-oxopentanoyl]amino}-4-{[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}-7-oxo-2-thiabicyclo[4.2.0]octane-5-carboxylate	C₄₂H₄₃NO₇S₂	详情	详情
(IX)	55357	benzhydryl (1S,8R)-8-{[5-(benzhydryloxy)-5-oxopentanoyl]amino}-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate	C₃₉H₃₅NO₆S	详情	详情
(X)	55358	benzhydryl (1S,8R)-8-amino-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate	C₂₁H₁₉NO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The condensation of the 7(R)-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (X) with 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(3-methyl-2-butenyloxycarbonyl)-2-butenoic acid (XI) by means of POCl3 and TEA gives the corresponding amide (XII), which is finally deprotected by means of AlCl3 and anisole to afford the target ceftibuten.

参考文献中间体

合成目标

【1】 Chai, D.; et al.; Ceftibuten: Development of a commercial process based on cephalosporin C. Part IV. Pilot-plant scale electrochemical reduction of 3Acetoxymethyl-7(S)-glytaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 178.
【2】 Bernasconi, E.; et al.; Ceftibuten: Development of commerci I process B sed on ceph losporin C. Part II. Process for the Manufacture of 3-exomethylene-7(R)-glutaroyllaminoceph m-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 158.
【3】 Bernasconi, E.; et al.; Ceftibuten: Development of a commercial process based on cephalosporin C. Part III. Process for the conversion of 3-exomethylene-7(S)-glytaroylaminocepham-4-carboxylic acid 1(S)-oxide to ceftibuten. Org Process Res Dev 2002, 6, 2, 169.
【4】 Bernasconi, E.; et al.; Deftibuten: Development of a commercial process based on cephalosporin C. Part I. Process for the manufacture of 3-acetoxymethyl-7(R-glutaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide. Org Process Res Dev 2002, 6, 2, 152.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	55358	benzhydryl (1S,8R)-8-amino-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate	C₂₁H₁₉NO₃S	详情	详情
(XI)	55359	(E)-2-(2-{[(benzyloxy)carbonyl]amino}-1,3-thiazol-5-yl)-5-[(3-methyl-2-butenyl)oxy]-5-oxo-2-pentenoic acid	C₂₁H₂₂N₂O₆S	详情	详情
(XII)	55360	benzhydryl (1S,8R)-8-({(E)-2-(2-{[(benzyloxy)carbonyl]amino}-1,3-thiazol-5-yl)-5-[(3-methyl-2-butenyl)oxy]-5-oxo-2-pentenoyl}amino)-7-oxo-2-thiabicyclo[4.2.0]oct-4-ene-5-carboxylate	C₄₂H₃₉N₃O₈S₂	详情	详情

Extended Information