【结 构 式】 |
【分子编号】59755 【品名】3-(2-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-1-(ethoxycarbonyl)-2-{2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-5-yl}ethyl)-1-pyridiniumolate 【CA登记号】 |
【 分 子 式 】C26H22F8N2O6S 【 分 子 量 】642.5237856 【元素组成】C 48.6% H 3.45% F 23.65% N 4.36% O 14.94% S 4.99% |
合成路线1
该中间体在本合成路线中的序号:(XVIII)Lithiation of thiazole (X) with butyllithium, and then addition to hexafluoroacetone (XI) in cold Et2O gives the carbinol adduct (XII), which is subsequently protected with 2-(trimethylsilyl)ethoxymethyl chloride (XIII), yielding the SEM ether (XIV). A further metalation of (XIV) with butyllithium, followed by addition to aldehyde (IX) provides alcohol (XV). Bromination of (XV), with simultaneous SEM group cleavage to afford (XVI), is accomplished by treatment with thionyl bromide and pyridine. Alkylation of the potassium enolate of ethyl 3-pyridylacetate N-oxide (XVII) with bromide (XVI) gives ester (XVIII). Finally, decarboethoxylation of (XVIII) by means of LiOH, followed by resolution of the racemic mixture using chiral HPLC furnishes the title enantiomer.
【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IX) | 59749 | 3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde | C11H10F2O3 | 详情 | 详情 | |
(X) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
(XI) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
(XII) | 59750 | 1,1,1,3,3,3-hexafluoro-2-(1,3-thiazol-2-yl)-2-propanol | C6H3F6NOS | 详情 | 详情 | |
(XIII) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
(XIV) | 59751 | 2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazole; [2,2,2-trifluoro-1-(1,3-thiazol-2-yl)-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether | C12H17F6NO2SSi | 详情 | 详情 | |
(XV) | 59752 | [3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl][2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazol-5-yl]methanol | C23H27F8NO5SSi | 详情 | 详情 | |
(XVI) | 59753 | 2-(5-{bromo[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methyl}-1,3-thiazol-2-yl)-1,1,1,3,3,3-hexafluoro-2-propanol | C17H12BrF8NO3S | 详情 | 详情 | |
(XVII) | 59754 | 3-(2-ethoxy-2-oxoethyl)-1-pyridiniumolate | C9H11NO3 | 详情 | 详情 | |
(XVIII) | 59755 | 3-(2-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-1-(ethoxycarbonyl)-2-{2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-5-yl}ethyl)-1-pyridiniumolate | C26H22F8N2O6S | 详情 | 详情 |