2-(4-methoxyphenyl)-1,1-dimethylethylamine -Drug Synthesis Database

【结构式】

【分子编号】68014

【品名】2-(4-methoxyphenyl)-1,1-dimethylethylamine

【CA登记号】　

【分子式】C₁₁H₁₇NO

【分子量】179.26212

【元素组成】C 73.7% H 9.56% N 7.81% O 8.93%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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 .

参考文献中间体

合成目标

【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	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

该中间体在本合成路线中的序号：(III)

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) .

参考文献中间体

合成目标

【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

Extended Information