4-(2-amino-2-methylpropyl)phenol -Drug Synthesis Database

【结构式】

【分子编号】29476

【品名】4-(2-amino-2-methylpropyl)phenol

【CA登记号】51706-55-9

【分子式】C₁₀H₁₅NO

【分子量】165.23524

【元素组成】C 72.69% H 9.15% N 8.48% O 9.68%

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：(IV)

By condensation of substituted nicotinamide (VI) with the carbazolyoxymethyl-oxirane (XII) in hot methanol/water. The intermediates the nicotinamide (VI) and the oxirane (XII) have been obtained as follows: 1.- Nicotinamide (VI): The reaction of 4-hydroxybenzyl alcohol (I) with 2-nitropropane (II) by means of potassium tert-butoxide in hot diglyme gives 4-(2-methyl-2-nitropropyl)phenol (III), which is reduced to the corresponding amino derivative (IV) with H2 over Pd/C in methanol/ethanol/acetic acid. Finally, this compound is condensed with 6-chloronicotinamide (V) by means of K2CO3 in dimethylacetamide/isooctane. 2.- Oxirane (XII): The reaction of phenylhydrazine (VII) with cyclohexane-1,3-dione (VIII) by means of NaHCO3 in isopropanol/water gives the monohydrazone (IX), which is cyclized with hotpolyphosphoric acid yielding the 4-hydroxycarbazole (X). Finally, this compound is condensed with the glycidyl 3-nitrophenylsulfonate (XI) by means of K2CO3 in refluxing acetone.

参考文献中间体

合成目标

【1】 Crowell, T.A.; Evrard, D.A.; Jones, C.D.; Muehl, B.S.; Rito, C.J.; Shuker, A.J.; Thorpe, A.J.; Thrasher, K.J. (Eli Lilly and Company); Carbazole analogues as selective B3 adrenergic agonists. EP 0827746; WO 9809625 .

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)	29474	4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol	623-05-2	C₇H₈O₂	详情	详情
(II)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(III)	29475	4-(2-methyl-2-nitropropyl)phenol		C₁₀H₁₃NO₃	详情	详情
(IV)	29476	4-(2-amino-2-methylpropyl)phenol	51706-55-9	C₁₀H₁₅NO	详情	详情
(V)	29477	6-chloronicotinamide	6271-78-9	C₆H₅ClN₂O	详情	详情
(VI)	29478	6-[4-(2-amino-2-methylpropyl)phenoxy]nicotinamide		C₁₆H₁₉N₃O₂	详情	详情
(VII)	11818	Phenyl hydrazine; 1-Phenylhydrazine	100-63-0	C₆H₈N₂	详情	详情
(VIII)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(IX)	29479	3-hydroxy-2-cyclohexen-1-one N-phenylhydrazone		C₁₂H₁₄N₂O	详情	详情
(X)	29480	4-Hydroxycarbazole; 9H-carbazol-4-ol	52602-39-8	C₁₂H₉NO	详情	详情
(XI)	16259	(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate	115314-14-2	C₉H₉NO₆S	详情	详情
(XII)	29481	9H-carbazol-4-yl (2S)oxiranylmethyl ether; 4-[(2S)oxiranylmethoxy]-9H-carbazole		C₁₅H₁₃NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

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