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【结 构 式】 
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【药物名称】olodaterol Hydrochloride 【化学名称】6-Hydroxy-8-[1(R)-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-3,4-dihydro-2H-1,4-benzoxazin-3-one hydrochloride 【CA登记号】868049-49-4;869477-96-3 (hydrochloride) 【 分 子 式 】C21H26N2O5.HCl 【 分 子 量 】422.902 |
【开发单位】Boehringer Ingelheim (DE) 【药理作用】β2-Adrenoceptor Agonist;Treatment of COPD;Treatment of Asthma |
合成路线1
oxidation of 8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one (I) with Seo2 in refluxing dioxane/water yields the arylglyoxal hydrate (II) (1), which is subjected to reductive amination with 2-(4-methoxyphenyl)-1,1-dimethylethylamine (III) using either LiBH4 in THF or naBH4 in EtoH to give benzyl-protected racemic olodaterol (IV). Debenzylation of intermediate (IV) using H2So4 in the presence of t-Buono in MeoH or by catalytic hydrogenolysis over Pd/C in MeoH affords racemic olodaterol (V) , which is finally resolved by means of chiral HPLC and the (R)-enantiomer (VI) treated with hydrochloric acid in i-ProH .
In an alternative procedure, a-halogenation of ketone (I) with benzyltrimethylammonium chloroiodate (BTMA-ICl) or dichloroiodate (BTMA-ICl2) in DCE/AcoH/H2o , or with tetrabutylammonium tribromide (TBATB) in dioxane , yields the respective 8-(halo acetyl)-1,4-benzoxazin-3-ones (VIIa) and (VIIb) . Enantio selective transfer hydrogenation of the chloroacetophenone derivative (VIIa) with HCooH and Et3n in the presence of RhCl[(S,S)-TsDPEn(p-cymene)] or RuCl[(S,S)-TsDPEn(p-cymene)] in DMF , or chiral reduction of bromoacetophenone derivative (VIIb) with (–)-DIPCl in THF , provides the corresponding (R)-halohydrins (VIIIa) or (VIIIb) . Cyclization of these halohydrins by means of naoH in DMF results in the chiral epoxide (IX) , which then couples with 2-(4-methoxyphenyl)-1,1-dimethylethylamine (III) in refluxing i-ProH or dioxane to produce the benzyl-protected (R)-olodaterol (X) . Finally, compound (X) is debenzylated by means of H2 over Pd/C in MeoH to afford olodaterol (VI) , and then treated with HCl in i-ProH .
| 【1】 Bouyssou, T., Hoenke, C., Rudolf, K. et al. Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett 2010, 20(4): 1410-4. |
| 【2】 Bouyssou, T., Buettner, F., Konetzki, I. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Novel medicaments for the treatment of chronic obstructive pulmonary diseases. Cn 10187800, DE 10253282, EP 2025338, JP 2006508140, US 2004147513, US 2006106213, US 7056916, US 2007155741, US 2008167298, US 2009092558, US 7786111, Wo 2004045618. |
| 【3】 Konetzki, I., Lustenberger, P., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Novel enantiomerically pure beta-agonists, method for the production and the use thereof in the form of a drug. EP 1789405, JP 2007537196, US 2005267106, US 2007027148, US 7220742, US 7491719, US 2009137578, US 8034809, Wo 2005111005. |
| 【4】 Krueger, T., Ries, U., Schnaubelt, J., Rall, W., Leuter, Z.A., Duran, A., Soyka, R. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 1917253, JP 2009504708, US 201114859, Wo 2007020227. |
| 【5】 Rodriguez Dehli, J.M., Hagenkoetter, R., Schul, M., Stange, C. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 2125759, JP 2010516739, US 2010022770, Wo 2008090193. |
| 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) | 68013 | 6-(benzyloxy)-8-(2,2-dihydroxyacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H15NO6 | 详情 | 详情 | |
| (VIIa) | 68018 | 6-(benzyloxy)-8-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H14ClNO4 | 详情 | 详情 | |
| (VIIb) | 68019 | 6-(benzyloxy)-8-(2-bromoacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H14BrNO4 | 详情 | 详情 | |
| (VIIIa) | 68021 | (R)-6-(benzyloxy)-8-(2-chloro-1-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H16ClNO4 | 详情 | 详情 | |
| (VIIIb) | 68020 | (R)-6-(benzyloxy)-8-(2-bromo-1-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H16BrNO4 | 详情 | 详情 | |
| (I) | 68012 | 8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one | C17H15NO4 | 详情 | 详情 | |
| (III) | 68014 | 2-(4-methoxyphenyl)-1,1-dimethylethylamine | C11H17NO | 详情 | 详情 | |
| (IV) | 68015 | 6-(benzyloxy)-8-(1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C28H32N2O5 | 详情 | 详情 | |
| (V) | 68016 | 6-hydroxy-8-(1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C21H26N2O5 | 详情 | 详情 | |
| (VI) | 68017 | (R)-6-hydroxy-8-(1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C21H26N2O5 | 详情 | 详情 | |
| (IX) | 68022 | (R)-6-(benzyloxy)-8-(oxiran-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C17H15NO4 | 详情 | 详情 | |
| (X) | 68023 | (R)-6-(benzyloxy)-8-(1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one | C28H32N2O5 | 详情 | 详情 |
合成路线2
Selective O-protection of 2,5-dihydroxyacetophenone (XI) with benzyl bromide by means of K2Co3 in acetone or methylisobutylketone yields 2’-hydroxy-5’-benzyloxyacetophenone (XII) , which is then nitrated with fuming Hno3 in AcoH to give the 3’-nitroacetophenone derivative (XIII) . Reduction of the nitro group in compound (XIII) by catalytic hydrogenation over Rh/C in MeoH or Pto2 in 2-MeTHF (4, 5) provides the corresponding aniline (XIV) , which finally undergoes cyclization with chloroacetyl chloride (XV) in the presence of K2Co3 in refluxing acetonitrile or 2-MeTHF .
| 【1】 Bouyssou, T., Hoenke, C., Rudolf, K. et al. Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett 2010, 20(4): 1410-4. |
| 【2】 Konetzki, I., Lustenberger, P., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Novel enantiomerically pure beta-agonists, method for the production and the use thereof in the form of a drug. EP 1789405, JP 2007537196, US 2005267106, US 2007027148, US 7220742, US 7491719, US 2009137578, US 8034809, Wo 2005111005. |
| 【3】 Krueger, T., Ries, U., Schnaubelt, J., Rall, W., Leuter, Z.A., Duran, A., Soyka, R. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 1917253, JP 2009504708, US 201114859, Wo 2007020227. |
| 【4】 Rodriguez Dehli, J.M., Hagenkoetter, R., Schul, M., Stange, C. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 2125759, JP 2010516739, US 2010022770, Wo 2008090193. |
| 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) | 68012 | 8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one | C17H15NO4 | 详情 | 详情 | |
| (XI) | 38479 | 1-(2,5-dihydroxyphenyl)-1-ethanone | 490-78-8 | C8H8O3 | 详情 | 详情 |
| (XII) | 20133 | 1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone | C15H14O3 | 详情 | 详情 | |
| (XIII) | 68024 | 1-(5-(benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone | C15H13NO5 | 详情 | 详情 | |
| (XIV) | 68025 | 1-(3-amino-5-(benzyloxy)-2-hydroxyphenyl)ethanone | C15H15NO3 | 详情 | 详情 | |
| (XV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
合成路线3
N-Protection of 4-(2-amino-2-methylpropyl)phenol (XVI) with CbzCl by means of na2Co3 in CH2Cl2/H2o yields the benzyl carbamate (XVII), which is then O-alkylated with MeI using K2Co3 in DMF to give the methyl ether (XVIII). Finally, compound (XVIII) is N-deprotected by means of H2 over Pd/C in MeoH .
In an alternative method, addition of MeMgCl to 1-(4-methoxyphenyl) acetone (XIX) in toluene produces 1-(4-methoxyphenyl)-2-methyl-2-propanol (XX), which then undergoes Ritter reaction with acetonitrile in the presence of H2So4 in AcoH to afford the N-substituted acetamide (XXI) . Finally, amide (XXI) is hydrolyzed with naoH or KoH in ethoxyethanol/ethylene glycol at 150 °C (III) .
| 【1】 Bouyssou, T., Hoenke, C., Rudolf, K. et al. Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett 2010, 20(4): 1410-4. |
| 【2】 Krueger, T., Ries, U., Schnaubelt, J., Rall, W., Leuter, Z.A., Duran, A., Soyka, R. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 1917253, JP 2009504708, US 201114859, Wo 2007020227. |
| 【3】 Rodriguez Dehli, J.M., Hagenkoetter, R., Schul, M., Stange, C. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 2125759, JP 2010516739, US 2010022770, Wo 2008090193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 68014 | 2-(4-methoxyphenyl)-1,1-dimethylethylamine | C11H17NO | 详情 | 详情 | |
| (XVI) | 29476 | 4-(2-amino-2-methylpropyl)phenol | 51706-55-9 | C10H15NO | 详情 | 详情 |
| (XVII) | 68026 | benzyl (1-(4-hydroxyphenyl)-2-methylpropan-2-yl)carbamate | C18H21NO3 | 详情 | 详情 | |
| (XVIII) | 68027 | benzyl (1-(4-methoxyphenyl)-2-methylpropan-2-yl)carbamate | C19H23NO3 | 详情 | 详情 | |
| (XIX) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (XX) | 68028 | 1-(4-methoxyphenyl)-2-methylpropan-2-ol | C11H16O2 | 详情 | 详情 | |
| (XXI) | 68029 | N-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)acetamide | C13H19NO2 | 详情 | 详情 |