【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% |
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 |