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【结 构 式】

【分子编号】25496

【品名】(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester

【CA登记号】

【 分 子 式 】C38H42N4O8S

【 分 子 量 】714.83964

【元素组成】C 63.85% H 5.92% N 7.84% O 17.91% S 4.49%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

The cyclization of 3(R)-aminopyrrolidine-1-carboxylic acid allyl ester (I) with 2-bromo-4-chlorobutyryl chloride (II) by means of aqueous NaOH in dichloromethane gives the bipyrrolidine (III), which is treated with triphenylphosphine in dichloromethane yielding the phosphonium salt (IV). The condensation of (IV) with (R,R,R)-7-(tert-butoxycarbonylamino)-3-formyl-2-cephem-4-carboxylic acid diphenylmethyl ester (V) in refluxing THF affords the expected condensation product (VI), which is oxidized at the sulfur atom with triphenylphosphine oxide and meta-chloroperbenzoic acid (MCPBA) in dichloromethane to provide the sulfoxide (VII). Rearrangement of (VII) with simultaneous deoxygenation of the sulfur atom by means of PBr3 in dichloromethane/DMF provides the 3-cephem isomer (VIII).

1 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
2 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .
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) 25489 allyl (3R)-3-amino-1-pyrrolidinecarboxylate C8H14N2O2 详情 详情
(II) 25490 2-bromo-4-chlorobutanoyl chloride C4H5BrCl2O 详情 详情
(III) 25491 3(R)-(3-Bromo-2-oxopyrrolidin-1-yl)pyrrolidine-1-carboxylic acid allyl ester C12H17BrN2O3 详情 详情
(IV) 25492 1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-yl]triphenylphosphonium bromide C30H33N2O3P 详情 详情
(V) 25493 benzhydryl (2R,6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate C26H26N2O6S 详情 详情
(VI) 25494 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情
(VII) 25495 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester S-oxide C38H42N4O9S 详情 详情
(VIII) 25496 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

Intermediate (VIII) is treated with TFA and anisole in dichloromethane to deprotect the 7-amino group giving (IX). The condensation of (IX) with 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(trityloxyimino)thioacetic acid S-(benzothiazol-2-yl)ester (XII) in DMF gives the expected 4-acetamido derivative (XIII), which is finally deprotected first with bis (trimethylsilyl)acetamide (BSA) and bis(triphenylphosphine)palladium dichloride in dichloromethane to eliminate the allyloxycarbonyl group, and then with TFA and triethylsilane to eliminate the trityl group.

1 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
2 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 25496 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情
(IX) 25497 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-amino-3-cephem-4-carboxylic acid C20H24N4O6S 详情 详情
(X) 25498 S-(1,3-benzothiazol-2-yl) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]ethanethioate C30H21N5O2S3 详情 详情
(XI) 25499 1-allyl-1-methylpyrrolidinium 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]acetate C31H33N5O3S 详情 详情
(XII) 25500 1,3-benzothiazol-2-ylsulfide C7H4NS2 详情 详情
(XIII) 25501 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(triphenylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid C43H40N8O8S2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VIII)

The cyclization of 3(R)-aminopyrrolidine-1-carboxylic acid allyl ester (I) with 2-bromo-4-chlorobutyryl chloride (II) by means of aqueous NaOH in dichloromethane gives the bipyrrolidine (III), which is treated with triphenylphosphine in dichloromethane yielding the phosphonium salt (IV). The condensation of (IV) with (R,R,R)-7-(tert-butoxycarbonylamino)-3-formyl-2-cephem-4-carboxylic acid diphenylmethyl ester (V) in refluxing THF affords the expected condensation product (VI), which is oxidized at the sulfur atom with triphenylphosphine oxide and meta-chloroperbenzoic acid (MCPBA) in dichloromethane to provide the sulfoxide (VII). Rearrangement of (VII) with simultaneous deoxygenation of the sulfur atom by means of PBr3 in dichloromethane/DMF provides the 3-cephem isomer (VIII).

1 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
2 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .
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) 25489 allyl (3R)-3-amino-1-pyrrolidinecarboxylate C8H14N2O2 详情 详情
(II) 25490 2-bromo-4-chlorobutanoyl chloride C4H5BrCl2O 详情 详情
(III) 25491 3(R)-(3-Bromo-2-oxopyrrolidin-1-yl)pyrrolidine-1-carboxylic acid allyl ester C12H17BrN2O3 详情 详情
(IV) 25492 1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-yl]triphenylphosphonium bromide C30H33N2O3P 详情 详情
(V) 25493 benzhydryl (2R,6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate C26H26N2O6S 详情 详情
(VI) 25494 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情
(VII) 25495 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester S-oxide C38H42N4O9S 详情 详情
(VIII) 25496 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VIII)

Intermediate (VIII) is treated with TFA and anisole in dichloromethane to deprotect the 7-amino group giving (IX). The condensation of (IX) with 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(trityloxyimino)thioacetic acid S-(benzothiazol-2-yl)ester (XII) in DMF gives the expected 4-acetamido derivative (XIII), which is deprotected first with bis(trimethylsilyl)acetamide (BSA) and bis(triphenylphosphine)palladium dichloride in dichloromethane to eliminate the allyloxycarbonyl group, and then with TFA and triethylsilane to eliminate the trityl group affording Ro-63-9141 (XIV).

1 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
2 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 25496 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester C38H42N4O8S 详情 详情
(IX) 25497 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-amino-3-cephem-4-carboxylic acid C20H24N4O6S 详情 详情
(X) 25498 S-(1,3-benzothiazol-2-yl) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]ethanethioate C30H21N5O2S3 详情 详情
(XI) 25499 1-allyl-1-methylpyrrolidinium 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]acetate C31H33N5O3S 详情 详情
(XII) 25500 1,3-benzothiazol-2-ylsulfide C7H4NS2 详情 详情
(XIII) 25501 (6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(triphenylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid C43H40N8O8S2 详情 详情
(XIV) 25502 (6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)acetamido]-3-[2-oxo-1-(3(R)-pyrrolidinyl)pyrrolidin-3-ylidenemethyl]-3-cephem-4-carboxylic acid C20H22N8O6S2 详情 详情
Extended Information