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【结 构 式】 
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【分子编号】45844 【品名】(1R,5S,7S)-4-[(3R)-3-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)-3-[4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]propanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione 【CA登记号】 |
【 分 子 式 】C42H48F10N2O7SSi 【 分 子 量 】942.987932 【元素组成】C 53.5% H 5.13% F 20.15% N 2.97% O 11.88% S 3.4% Si 2.98% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The diastereoselective addition of the Grignard reagent prepared from bromide (III) to the chiral acylsultam Michael acceptor (XIII) afforded the triarylpropanoylsultam intermediate (XIV). Removal of the chiral auxiliary of (XIV) by means of lithium propanethiolate, followed by decarboxylation with NaOH and then acidic treatment gave (XV). Deprotection of the SEM group of (XV) with tetrabutylammonium fluoride provided the tertiary alcohol (XVI). The pyridine ring of (XVI) was finally oxidized to the N-oxide to furnish the desired chiral compound.
| 【1】 Guay, D.; Ducharme, Y.; Blouin, M.; Hamel, P.; Girard, M. (Merck Frosst Canada Inc.); Tri-aryl ethane derivs. as PDE IV inhibitors. EP 0873311; JP 2000501742; US 5710170; WO 9722586 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 45835 | [1-(4-bromophenyl)-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether; (2-[[1-(4-bromophenyl)-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methoxy]ethyl)(trimethyl)silane | C15H19BrF6O2Si | 详情 | 详情 | |
| (XIII) | 45843 | (1R,5S,7S)-4-[(E)-3-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)-2-propenoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C27H28F4N2O5S | 详情 | 详情 | |
| (XIV) | 45844 | (1R,5S,7S)-4-[(3R)-3-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)-3-[4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]propanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C42H48F10N2O7SSi | 详情 | 详情 | |
| (XV) | 45845 | [1-[4-[(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)ethyl]phenyl]-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether; 4-[(2R)-2-[3,4-bis(difluoromethoxy)phenyl]-2-[4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]ethyl]-3-methylpyridine | C31H33F10NO4Si | 详情 | 详情 | |
| (XVI) | 45846 | 2-[4-[(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)ethyl]phenyl]-1,1,1,3,3,3-hexafluoro-2-propanol | C25H19F10NO3 | 详情 | 详情 |