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【结 构 式】

【分子编号】31141

【品名】4-Hydroxy-3,5-dimethylbenzonitrile; 2,6-Dimethyl-4-hydroxybenzonitrile

【CA登记号】4198-90-7

【 分 子 式 】C9H9NO

【 分 子 量 】147.1766

【元素组成】C 73.45% H 6.16% N 9.52% O 10.87%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(V)

The condensation of 3,5-dimethylisoxazole (I) with ethylene oxide (II) by means of butyllithium in THF gives 3-(3-methylisoxazol-5-yl)-1-propanol (III), which by reaction with refluxing SOCl2 yields the corresponding propyl chloride (IV). The condensation of (IV) with 4-hydroxy-3,5-dimethylbenzonitrile (V) [obtained by reaction of 4-bromo-2,6-dimethylphenol (VI) with Cu2CN2 in refluxing DMF] by means of K2CO3 and KI in hot N-methylpyrrolidone affords 3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]benzonitrile (VII). The reaction of (VII) with hydroxylamine (VIII) and K2CO3 in refluxing ethanol gives the corresponding benzohydroxamic acid (IX), which is finally cyclized with refluxing trifluoroacetic anhydride and pyridine.

1 Diana, G.D.; Rudewicz, P.; Pevear, D.C.; et al.; Picornavirus inhibitors: Trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J Med Chem 1995, 38, 1355-71.
2 Fromtling, R.A.; Castañer, J.; VP-63843. Drugs Fut 1997, 22, 1, 40.
3 Diana, G.D.; Nitz, T.J. (Sanofi-Synthelabo); 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents. EP 0566199; JP 1994049066; US 5349068 .
4 Diana, G.D.; Nitz, T.J. (Sanofi-Synthelabo); 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents. US 5464848 .
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) 31138 3,5-dimethylisoxazole 300-87-8 C5H7NO 详情 详情
(II) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情
(III) 31139 3-(3-methyl-5-isoxazolyl)-1-propanol C7H11NO2 详情 详情
(IV) 31140 5-(3-chloropropyl)-3-methylisoxazole 130800-76-9 C7H10ClNO 详情 详情
(V) 31141 4-Hydroxy-3,5-dimethylbenzonitrile; 2,6-Dimethyl-4-hydroxybenzonitrile 4198-90-7 C9H9NO 详情 详情
(VI) 31142 4-bromo-2,6-dimethylphenol 2374-05-2 C8H9BrO 详情 详情
(VII) 31143 3,5-dimethyl-4-[3-(3-methyl-5-isoxazolyl)propoxy]benzonitrile C16H18N2O2 详情 详情
(IX) 31144 N-hydroxy-3,5-dimethyl-4-[3-(3-methyl-5-isoxazolyl)propoxy]benzenecarboximidamide C16H21N3O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

The reaction of 5-bromo-2,4,6-trichloropyrimidine (I) with 4-aminobenzonitrile (II) by means of DIEA in refluxing dioxane gives the diarylamine (III), which is condensed with 4-hydroxy-3,5-dimethylbenzonitrile (IV) by means of NaH in NMP to yield the corresponding adduct (V). Finally, this compound is treated with ammonia in dioxane at 150 C in a pressure vessel.

1 Heeres, J.; De Corte, B.; Kukla, M.J.; Van Aken, K.J.A.; Janssen, P.A.J.; Ludovici, D.W.; De Jonge, M.R.; Kavash, R.W.; Ho, C.Y.; Koymans, L.M.H. (Janssen Pharmaceutica NV); HIV replication inhibiting pyrimidines. EP 1002795; WO 0027825 .
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) 46616 5-bromo-2,4,6-trichloropyrimidine C4BrCl3N2 详情 详情
(II) 15361 4-Aminobenzonitrile 873-74-5 C7H6N2 详情 详情
(III) 46617 4-[(5-bromo-4,6-dichloro-2-pyrimidinyl)amino]benzonitrile C11H5BrCl2N4 详情 详情
(IV) 31141 4-Hydroxy-3,5-dimethylbenzonitrile; 2,6-Dimethyl-4-hydroxybenzonitrile 4198-90-7 C9H9NO 详情 详情
(V) 46618 4-[[5-bromo-6-chloro-2-(4-cyanoanilino)-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile C20H13BrClN5O 详情 详情

合成路线3

该中间体在本合成路线中的序号:(II)

 

1 Shashikant J, Golak CM, Shyam T, et al. 2010. An improved synthesis of etravirine. Orangic Process Research & Development, 14: 657~660.
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) 43734 2,4,6-trichloropyrimidine 3764-01-0 C4HCl3N2 详情 详情
(II) 31141 4-Hydroxy-3,5-dimethylbenzonitrile; 2,6-Dimethyl-4-hydroxybenzonitrile 4198-90-7 C9H9NO 详情 详情
(III) 67127 4-((2,6-dichloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4198-90-7 C13H9Cl2N3O 详情 详情
(IV) 15361 4-Aminobenzonitrile 873-74-5 C7H6N2 详情 详情
(V) 67128 4-((4-(4-(aminomethyl)-2,6-dimethylphenoxy)-6-chloropyrimidin-2-yl)amino)benzonitrile   C20H14ClN5O 详情 详情
(VI) 67129 4-((6-((4-(aminomethyl)phenyl)amino)-2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile    C20H14ClN5O 详情 详情
Extended Information