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【结 构 式】 
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【分子编号】33017 【品名】(3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione 【CA登记号】75172-31-5 |
【 分 子 式 】C11H11NO4 【 分 子 量 】221.21268 【元素组成】C 59.73% H 5.01% N 6.33% O 28.93% |
合成路线1
该中间体在本合成路线中的序号：(II)L-Tartaric acid (I) was converted to succinimimide (II) upon treatment with benzylamine in refluxing xylene with azeotropic removal of water. Subsequent reduction of (II) with borane, generated from NaBH4 and BF3, afforded pyrrolidine (III). Removal of the N-benzyl group of (III) was effected by hydrogenolysis over Pd/C, and the resulting secondary amine (IV) was coupled with the N-protected 3-thioacetylproline (V) to furnish amide (VI). Deacetylation of (VI) under basic conditions provided thiol (VII). Condensation of thiol (VII) with carbapenem enolphosphate (VIII) afforded thioether (IX). The 4-nitrobenzyl protecting groups of (IX) were finally removed by hydrogenolysis over Pd/C.
| 【1】 Park, S.W.; Park, S.Y.; Kim, D.J.; Shin, K.J.; Kang, Y.K.; Yoo, K.H.; Jae Seo, K.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2. Bioorg Med Chem Lett 1999, 9, 16, 2385. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 33017 | (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione | 75172-31-5 | C11H11NO4 | 详情 | 详情 |
| (III) | 33018 | (3S,4S)-1-benzyl-3,4-pyrrolidinediol | C11H15NO2 | 详情 | 详情 | |
| (IV) | 33019 | (3S,4S)-3,4-pyrrolidinediol | C4H9NO2 | 详情 | 详情 | |
| (V) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (VI) | 33020 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate | C19H23N3O8S | 详情 | 详情 | |
| (VII) | 33021 | 4-nitrobenzyl (2S,4S)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C17H21N3O7S | 详情 | 详情 | |
| (VIII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (IX) | 33022 | 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H37N5O13S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIXb)Stereospecific methods to prepare aminopyrrolidine (X) have been developed starting from both enantiomers of trans-N-benzyl-2,3-dihydroxysuccinimide (XXIXa) and (XXIXb), generated respectively from D- and L-tartaric acid. Monoprotection of the (S,S)-diol (XXIXa) with one equivalent of TBDMSCl in the presence of imidazole in cold DMF followed by imide reduction with borane-THF complex leads to the pyrrolidine (XXXa), which after debenzylation with H2 and Pd/C and reprotection with Boc2O provides the tert-butyl carbamate (XXXIa). Alcohol (XXXIa) is then converted to the corresponding mesylate, which undergoes nucleophilic displacement by NaN3 in DMF to give the cis-azide (XXXII). Azide (XXXII) is then reduced by catalytic hydrogenation over Pd/C to afford the corresponding amine, which is protected with Boc2O, followed by desilylation with tetrabutylammonium fluoride to give the cis-alcohol (XXXIII). Inversion of the configuration of alcohol (XXXIII) to the trans-isomer (XXVIII) is then accomplished by mesylation with MsCl and Et3N followed by displacement with potassium acetate in DMF and acetate hydrolysis with K2CO3 in MeOH. Finally, compound (XXVIII) is methylated with iodomethane and NaH and subsequently deprotected with p-TsOH in i-PrOH .
Alternatively, the (R,R)-imide (XXIXb) is converted to the trans-diol derivative (XXXb) as before, and the N-benzyl group is then exchanged for a Boc group, giving alcohol (XXXIb). Alkylation of compound (XXXIb) with iodomethane and NaH affords the corresponding methyl ether, which is desilylated to alcohol (XXXIV) by means of TBAF in THF. Mesylation of alcohol (XXXIV), followed by displacement with lithium acetate produces the methoxy acetate (XXXV), which is hydrolyzed to the cis-alcohol (XXXVI) using K2CO3 in MeOH. Mesylation of alcohol (XXXVI) followed by displacement with NaN3 provides the azide (XXXVII). After reduction with H2 and Pd/C, the resulting amine is protected as the Boc derivative (XXXVIII) with Boc2O in EtOH. Finally, amine (XXXVIII) is alkylated with iodomethane and NaH, followed by deprotection with p-TsOH (X) .
| 【1】 Tsuzuku, Y., Chiba, K., Hino, K. Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Asymmetry 2001, 12(12): 1793-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIXa) | 69222 | trans-N-benzyl-2,3-dihydroxysuccinimide; (3S,4S)-3,4-dihydroxy-1-(phenylmethyl)-2,5-Pyrrolidinedione; (3S-trans)-3,4-dihydroxy-1-(phenylmethyl)-2,5-Pyrrolidinedione | 187032-53-7 | C11H11NO4 | 详情 | 详情 |
| (XXIXb) | 33017 | (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione | 75172-31-5 | C11H11NO4 | 详情 | 详情 |
| (XXXa) | 69223 | (3S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-3-ol | C17H29NO2Si | 详情 | 详情 | |
| (XXXb) | 69224 | (3R,4R)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-3-ol | C17H29NO2Si | 详情 | 详情 | |
| (XXXIa) | 69226 | (3S,4S)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-4-hydroxypyrrolidine-1-carboxylate | C15H31NO4Si | 详情 | 详情 | |
| (XXXIb) | 69225 | (3R,4R)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-4-hydroxypyrrolidine-1-carboxylate | C15H31NO4Si | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XXVIII) | 69221 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 | |
| (XXXII) | 69228 | (3R,4S)-tert-butyl 3-azido-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate | C15H30N4O3Si | 详情 | 详情 | |
| (XXXIII) | 69229 | (3R,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 | |
| (XXXIV) | 69227 | (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate | C10H19NO4 | 详情 | 详情 | |
| (XXXV) | 69230 | (3S,4R)-tert-butyl 3-acetoxy-4-methoxypyrrolidine-1-carboxylate | C12H21NO5 | 详情 | 详情 | |
| (XXXVI) | 69231 | (3S,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate | C10H19NO4 | 详情 | 详情 | |
| (XXXVII) | 69232 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate;trans-3-Azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester;TRANS-3-AZIDO-1-BOC-4-METHOXYPYRROLIDINE | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (XXXVIII) | 69233 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 |