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【结 构 式】

【分子编号】68017

【品名】(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

【CA登记号】 

【 分 子 式 】C21H26N2O5

【 分 子 量 】386.44792

【元素组成】C 65.27% H 6.78% N 7.25% O 20.7%

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:(VI)

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
Extended Information