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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information