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【结 构 式】 
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【药物名称】L-869298 【化学名称】2-[5-[1(S)-[3-(Cyclopropyloxy)-4-(difluoromethoxy)phenyl]-2-(1-oxidopyridin-3-yl)ethyl]thiazol-2-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol 【CA登记号】362718-74-9 ((-)-enantiomer), 362718-73-8 ((+)-enantiomer), 362718-66-9 (undefined isomer) 【 分 子 式 】C23H18F8N2O4S 【 分 子 量 】570.46211 |
【开发单位】Merck Frosst (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors |
合成路线1
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 |
合成路线2
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 |