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【结 构 式】 
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【药物名称】EMIXUSTAT HYDROCHLORIDE 【化学名称】3-Amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1(R)-ol hydrochloride 【CA登记号】1141934-97-5;1141777-14-1 (as free base) 【 分 子 式 】C16H25NO2.HCl 【 分 子 量 】299.836 |
【开发单位】Originated by Acucela, Inc. (US); in codevelopment with Otsuka Pharmaceutical Co., Ltd. (JP). 【药理作用】Retinoid isomerohydrolase (RPE65) inhibitor;Treatment of age-related macular degeneration |
合成路线1
Reaction of 3-(tetrahydropyranyloxy)benzaldehyde (I) with acetonitrile (II) in the presence of t-BuOK in THF gives the b-hydroxypropionitrile (III), which by reduction with LiAlH4 in THF/Et2O yields the primary amine (IV). N-Protection of amine (IV) with ethyl trifluoroacetate (V) in THF affords the carbamate (VI), whose secondary hydroxyl group is oxidized with MnO2 in CH2Cl2 to yield the ketone (VII). Enantioselective reduction of ketone (VII) with (–)-DIP-Cl and DIEA in THF provides the (R)-alcohol (VIII), which is O-alkylated at its phenolic hydroxyl group with cyclohexylmethyl bromide (IX) and K2CO3 in DMF to give ether (X). Finally, compound (X) is N-deprotected by means of K2CO3 in MeOH/H2O and treated with HCl in i-PrOH .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 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) | 67832 | 3-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde | C12H14O3 | 详情 | 详情 | |
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (III) | 67833 | 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propanenitrile | C14H17NO3 | 详情 | 详情 | |
| (IV) | 67834 | 3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propan-1-ol | C14H21NO3 | 详情 | 详情 | |
| (V) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (VI) | 67835 | 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H20F3NO4 | 详情 | 详情 | |
| (VII) | 67836 | 2,2,2-trifluoro-N-(3-oxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H18F3NO4 | 详情 | 详情 | |
| (VIII) | 67837 | (R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-hydroxyphenyl)propyl)acetamide | C11H12F3NO3 | 详情 | 详情 | |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (X) | 67838 | (R)-N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide | C18H24F3NO3 | 详情 | 详情 |
合成路线2
Mitsunobu reaction of 3-hydroxybenzaldehyde (XI) with cyclohexylmethanol (XII) using PPh3 and DEAD in THF or condensation of 3-hydroxybenzaldehyde (XI) with cyclohexylmethyl bromide (IX) using K2CO3 and NMP in DMF at 75 °C give ether (XIII), which by reaction with acetonitrile (II) by means of LDA in THF at –78 °C or t-BuOK in THF yields the b-hydroxynitrile (XIV). Reduction of nitrile (XIV) with LiAlH4 or BH3·Me2S in THF affords the primary amine (XV), which by N-protection with Fmoc-Cl and DIEA in CH2Cl2 provides carbamate (XVI). Oxidation of secondary alcohol (XVI) with MnO2 in CH2Cl2 leads to the ketone (XVII), which is finally submitted to enantioselective reduction using (–)-DIP-Cl (prepared in situ by treating (–)-a-pinene with chloroborane-methyl sulfide complex in hexane) and DIEA in THF, followed by deprotection of the obtained N-Fmoc protected compound with DBU in THF. Alternatively, resolution of racemic emixustat (XV) can be performed using D-mandelic acid .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (XI) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XII) | 28360 | cyclohexylmethanol | 100-49-2 | C7H14O | 详情 | 详情 |
| (XIII) | 67839 | 3-(cyclohexylmethoxy)benzaldehyde | C14H18O2 | 详情 | 详情 | |
| (XIV) | 67840 | 3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile | C16H21NO2 | 详情 | 详情 | |
| (XV) | 67841 | 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol | C16H25NO2 | 详情 | 详情 | |
| (XVI) | 67842 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)carbamate | C31H35NO4 | 详情 | 详情 | |
| (XVII) | 67843 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-oxopropyl)carbamate | C31H33NO4 | 详情 | 详情 |