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【结 构 式】 
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【药物名称】Rilpivirine, R-278474，TMC-278 【化学名称】4-[4-[4-[(E)-2-Cyanovinyl]-2,6-dimethylphenylamino]pyrimidin-2-ylamino]benzonitrile 【CA登记号】500287-72-9, 700361-47-3 (monohydrochloride), 877817-88-4 (fumarate salt [1:1]) 【 分 子 式 】C22H18N6 【 分 子 量 】366.4188 |
【开发单位】Tibotec (BE, IE, US). 【药理作用】Reverse transcriptase inhibitor, Anti-HIV agent. |
合成路线1
Rilpivirine can be synthesized as follows. Chlorination of 2-(p-cyanophenylamino)-4-pyrimidinone (I) with refluxing POCl3 gives the chloropyrimidine (II), which is condensed with ethyl 4-amino-3,5-dimethylbenzoate (III) by heating at 150 °C to afford the diamino pyrimidine (IV). Reduction of ester (IV) with LiAlH4 in THF followed by reoxidation of the obtained alcohol (V) utilizing MnO2 in CH2Cl2 gives the aldehyde (VI). Then, Wittig reaction of aldehyde (VI) with cyanomethyl triphenylphosphonium chloride (VII) in the presence of t-BuOK provides the target cyanovinyl derivative (1, 2). In a related method, chloropyrimidine (II) is condensed with either 4-bromo-(VIIIa) or 4-iodo-2,6-dimethylaniline (VIIIb) at 150 °C to yield the corresponding diaminopyrimidines (IXa) and (IXb). Subsequent Heck coupling of aryl halides (IXa) and (IXb) with acrylonitrile (X) by means of palladium acetate and tri-o-tolylphosphine provides the title compound rilpivirine (1, 3). Scheme 1.
| 【1】 Guillemont, J., Pasquier, E., Palandjian, P. et al. Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1. J Med Chem 2005, 48(6): 2072-9. |
| 【2】 Guillemont, J.E.G., Palandjian, P., De Jonge, M.R. et al. (Janssen Pharmaceutica NV). HIV inhibiting pyrimidines derivatives. EP 1419152, JP 2005507380, US 2004198739, US 2006252764, US 7125879, WO 03016306. |
| 【3】 Guillemont, J.E.G., Schils, D.P.R., Willems, J.J.M. et al. (Janssen Pharmaceutica NV). Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. EP 1529032, JP 2005537303, US 2006167253, WO 2004016581. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIb) | 65540 | 4-Iodo-2,6-dimethylaniline | 4102-53-8 | C8H10IN | 详情 | 详情 |
| (Ixa) | 65541 | 4-[[4-[(4-Bromo-2,6-Dimethylphenyl)Amino]-2-Pyridinyl]Amino]Benzonitrile | 374067-85-3 | C19H16BrN5 | 详情 | 详情 |
| (Ixb) | 65542 | 4-[[4-[(4-Iodo-2,6-Dimethylphenyl)Amino]-2-Pyridinyl]Amino]Benzonitrile | C19H16IN5 | 详情 | 详情 | |
| (VIIIa) | 65539 | 4-Bromo-2,6-dimethylaniline; 4-Bromo-2,6-xylidine | 24596-19-8 | C8H10BrN | 详情 | 详情 |
| (I) | 54375 | 4-[(4-hydroxy-2-pyrimidinyl)amino]benzonitrile; 4-[(1,4-Dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile | 189956-45-4 | C11H8N4O | 详情 | 详情 |
| (II) | 54376 | 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile | 244768-32-9 | C11H7ClN4 | 详情 | 详情 |
| (III) | 65534 | ethyl 4-amino-3,5-dimethylbenzoate | C11H15NO2 | 详情 | 详情 | |
| (IV) | 65535 | C21H22N5O2 | 详情 | 详情 | ||
| (V) | 65536 | C20H19N5O | 详情 | 详情 | ||
| (VI) | 65537 | C20H17N5O | 详情 | 详情 | ||
| (VII) | 65538 | (Cyanomethyl)Triphenylphosphonium Chloride; Cyanomethyl-Triphenyl-Phosphonium Chloride; Cyanomethyl-Triphenylphosphonium Chloride; Cyanomethyl-Triphenyl-Phosphanium Chloride | 4336-70-3 | C20H17ClNP | 详情 | 详情 |
| (X) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |