【结 构 式】 |
【分子编号】59748 【品名】[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methanol 【CA登记号】 |
【 分 子 式 】C11H12F2O3 【 分 子 量 】230.2112864 【元素组成】C 57.39% H 5.25% F 16.51% O 20.85% |
合成路线1
该中间体在本合成路线中的序号:(VIII)The preparation of the precursor aldehyde (IX) is illustrated in Scheme 1. Alkylation of 3-hydroxy-4-(difluoromethoxy)benzaldehyde (I) with 1-bromo-2-chloroethane (II) affords the chloroethyl ether (III). After reduction of the aldehyde function of (III) with NaBH4, the resulting alcohol (IV) is protected as the corresponding silyl ether (V) with triisopropylsilyl triflate and 2,6-lutidine. Dehydrohalogenation of the chloroethyl ether moiety of (V) with NaOH under phase-transfer conditions, followed by resilylation with triisopropylsilyl triflate, leads to the vinyl ether (VI). This is converted into the cyclopropyl derivative (VII) following the Simmons-Smith procedure in the presence of chloroiodomethane and diethylzinc. Desilylation of (VII) with tertbutylammonium fluoride yields the benzylic alcohol (VIII), which is again oxidized to aldehyde (IX) employing MnO2 in CH2Cl2.
【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 |
---|---|---|---|---|---|---|
(I) | 59742 | 4-(difluoromethoxy)-3-hydroxybenzaldehyde | C8H6F2O3 | 详情 | 详情 | |
(II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
(III) | 59743 | 3-(2-chloroethoxy)-4-(difluoromethoxy)benzaldehyde | C10H9ClF2O3 | 详情 | 详情 | |
(IV) | 59744 | [3-(2-chloroethoxy)-4-(difluoromethoxy)phenyl]methanol | C10H11ClF2O3 | 详情 | 详情 | |
(V) | 59745 | 3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl triisopropylsilyl ether; {[3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane | C19H31ClF2O3Si | 详情 | 详情 | |
(VI) | 59746 | {[4-(difluoromethoxy)-3-(vinyloxy)benzyl]oxy}(triisopropyl)silane; 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl vinyl ether | C19H30F2O3Si | 详情 | 详情 | |
(VII) | 59747 | cyclopropyl 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl ether; {[3-(cyclopropyloxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane | C20H32F2O3Si | 详情 | 详情 | |
(VIII) | 59748 | [3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methanol | C11H12F2O3 | 详情 | 详情 | |
(IX) | 59749 | 3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde | C11H10F2O3 | 详情 | 详情 |