【结 构 式】 |
【分子编号】63989 【品名】N-methoxy-2-[methoxy(methyl)amino]-N-methyl-2-oxoacetamide 【CA登记号】 |
【 分 子 式 】C6H12N2O4 【 分 子 量 】176.17236 【元素组成】C 40.91% H 6.87% N 15.9% O 36.33% |
合成路线1
该中间体在本合成路线中的序号:(XII)Condensation of oxalyl chloride (XI) with N,O-dimethylhydroxylamine produces N,N'-dimethyl-N,N'-dimethoxy oxamide (XII). This is then condensed with cyclobutylmethylmagnesium bromide (XIII) to afford the ketoamide (XIV). Asymmetric keto group reduction employing (R)-alpine borane leads to the (S)-alcohol (XV) in 91% enantiomeric excess. Hydrolysis of the N-methoxyamide function of (XV) to provide hydroxyacid (XVI) is then accomplished employing potassium tert-butoxide in the presence of the equimolecular amount of H2O in THF. Alkylation of hydroxyacid (XVI) with benzyl bromide and Et3N furnishes the corresponding benzyl ester (XVII). Treatment of (XVII) with trifluoromethanesulfonic anhydride gives rise to triflate (XVIII), which is further condensed with pyrrolidine (X) to produce (XIX). After desilylation of (XIX) with tetrabutylammonium fluoride, the resultant alcohol (XX) is oxidized to aldehyde (XXI) under Swern conditions.
【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Kim, R.M. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6498161; WO 0059498 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 63988 | (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine; tert-butyl(dimethyl)silyl [(3R,4S)-4-(3-fluorophenyl)pyrrolidinyl]methyl ether | C17H28FNOSi | 详情 | 详情 | |
(XI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
(XII) | 63989 | N-methoxy-2-[methoxy(methyl)amino]-N-methyl-2-oxoacetamide | C6H12N2O4 | 详情 | 详情 | |
(XIII) | 63990 | bromo(cyclobutylmethyl)magnesium | C5H9BrMg | 详情 | 详情 | |
(XIV) | 63991 | 3-cyclobutyl-N-methoxy-N-methyl-2-oxopropanamide | C9H15NO3 | 详情 | 详情 | |
(XV) | 63992 | (2S)-3-cyclobutyl-2-hydroxy-N-methoxy-N-methylpropanamide | C9H17NO3 | 详情 | 详情 | |
(XVI) | 63993 | (2S)-3-cyclobutyl-2-hydroxypropanoic acid | C7H12O3 | 详情 | 详情 | |
(XVII) | 63994 | benzyl (2S)-3-cyclobutyl-2-hydroxypropanoate | C14H18O3 | 详情 | 详情 | |
(XVIII) | 63995 | benzyl (2S)-3-cyclobutyl-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate | C15H17F3O5S | 详情 | 详情 | |
(XIX) | 63997 | benzyl (2R)-2-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidinyl]-3-cyclobutylpropanoate | C31H44FNO3Si | 详情 | 详情 | |
(XX) | 63996 | benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidinyl]propanoate | C25H30FNO3 | 详情 | 详情 | |
(XXI) | 63998 | benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate | C25H28FNO3 | 详情 | 详情 |