|
【结 构 式】 
|
【药物名称】 【化学名称】6-[5-Imino-3(R)-(trifluoromethyl)pyrrolidin-2(R)-yl]-L-norleucine 【CA登记号】 【 分 子 式 】C11H18F3N3O2 【 分 子 量 】281.28021 |
【开发单位】Pfizer (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Inducible Nitric Oxide Synthase (NOS-2) Inhibitors |
合成路线1
Michael addition of ethyl trifluorocrotonate (I) to 3-nitropropionaldehyde dimethyl acetal (II) gave adduct (III). Reductive cyclization of nitro ester (III) furnished a mixture of cis- (IV) and trans- (V) pyrrolidinones. The desired cis-isomer (IV) was protected by N-alkylation with p-methoxybenzyl chloride, yielding (VI). After acid hydrolysis of the acetal function of (VI), the resulting aldehyde (VII) was subjected to a Wittig reaction with ethoxycarbonylmethylene triphenylphosphorane to afford the unsaturated ester (VIII), which was further hydrogenated over of Pd/C to the saturated ester (IX). The ester function of (IX) was then converted to aldehyde (X) by either reduction with DIBAL or by reduction to alcohol, followed by Swern oxidation.
| 【1】 Hagen, T.J.; et al.; 2-Imino-pyrrolidine amino acids as inhibitors of human nitric oxide synthase. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 249. |
| 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) | 25555 | ethyl (E)-4,4,4-trifluoro-2-butenoate | 74499-23-3 | C6H7F3O2 | 详情 | 详情 |
| (II) | 50482 | 1,1-dimethoxy-3-nitropropane; 1-methoxy-3-nitropropyl methyl ether | C5H11NO4 | 详情 | 详情 | |
| (III) | 50483 | ethyl 6,6-dimethoxy-4-nitro-3-(trifluoromethyl)hexanoate | C11H18F3NO6 | 详情 | 详情 | |
| (IV) | 50484 | (4R,5R)-5-(2,2-dimethoxyethyl)-4-(trifluoromethyl)-2-pyrrolidinone | C9H14F3NO3 | 详情 | 详情 | |
| (V) | 50485 | (4S,5R)-5-(2,2-dimethoxyethyl)-4-(trifluoromethyl)-2-pyrrolidinone | C9H14F3NO3 | 详情 | 详情 | |
| (VI) | 50486 | (4R,5R)-5-(2,2-dimethoxyethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-2-pyrrolidinone | C17H22F3NO4 | 详情 | 详情 | |
| (VII) | 50487 | 2-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]acetaldehyde | C15H16F3NO3 | 详情 | 详情 | |
| (VIII) | 50488 | ethyl (E)-4-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]-2-butenoate | C19H22F3NO4 | 详情 | 详情 | |
| (IX) | 50489 | ethyl 4-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]butanoate | C19H24F3NO4 | 详情 | 详情 | |
| (X) | 50490 | 4-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]butanal | C17H20F3NO3 | 详情 | 详情 |
合成路线2
Horner-Emmons condensation of aldehyde (X) with Z-alpha-phosphonoglycine trimethyl ester (XI) furnished the unsaturated amino ester (XII). The required saturated compound (XIII) was then prepared by asymmetric hydrogenation of (XII) in the presence of a rhodium chiral catalyst. Removal of the p-methoxybenzyl protecting group of (XIII) was achieved by treatment with cerium ammonium nitrate yielding pyrrolidinone (XIV). Treatment of (XIV) with triethyloxonium tetrafluoroborate produced the cyclic imidate (XV), which was converted to amidine (XVI) by reaction with ammonium chloride. Finally, acid hydrolysis of the ester and carbamate groups of (XVI) provided the title compound.
| 【1】 Hagen, T.J.; et al.; 2-Imino-pyrrolidine amino acids as inhibitors of human nitric oxide synthase. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 249. |
| 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) | 50490 | 4-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]butanal | C17H20F3NO3 | 详情 | 详情 | |
| (XI) | 50491 | N-(Benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester | C13H18NO7P | 详情 | 详情 | |
| (XII) | 50492 | methyl (Z)-2-[[(benzyloxy)carbonyl]amino]-6-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]-2-hexenoate | C28H31F3N2O6 | 详情 | 详情 | |
| (XIII) | 50493 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(2R,3R)-1-(4-methoxybenzyl)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]hexanoate | C28H33F3N2O6 | 详情 | 详情 | |
| (XIV) | 50494 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(2R,3R)-5-oxo-3-(trifluoromethyl)pyrrolidinyl]hexanoate | C20H25F3N2O5 | 详情 | 详情 | |
| (XV) | 50495 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(2R,3R)-5-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-2-yl]hexanoate | C21H27F3N2O5 | 详情 | 详情 | |
| (XVI) | 50496 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(2R,3R)-5-imino-3-(trifluoromethyl)pyrrolidinyl]hexanoate | C20H26F3N3O4 | 详情 | 详情 |