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【结 构 式】 
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【分子编号】25493 【品名】benzhydryl (2R,6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C26H26N2O6S 【 分 子 量 】494.56832 【元素组成】C 63.14% H 5.3% N 5.66% O 19.41% S 6.48% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(V)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 |