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【结 构 式】

【分子编号】65535

【品名】 

【CA登记号】 

【 分 子 式 】C21H22N5O2

【 分 子 量 】376.43818

【元素组成】C 67% H 5.89% N 18.6% O 8.5%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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
Extended Information