【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% |
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 |