4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile -Drug Synthesis Database

【结构式】

【分子编号】54376

【品名】4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile

【CA登记号】244768-32-9

【分子式】C₁₁H₇ClN₄

【分子量】230.65624

【元素组成】C 57.28% H 3.06% Cl 15.37% N 24.29%

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：(II)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(IV)

The synthesis can be performed by two related ways: 1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding chloro derivative (IV). Finally, this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative. 2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane, followed by chromatographic purification furnishes intermediate (VIII), which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.

参考文献中间体

合成目标

【2】 Heeres, J.; Kukla, M.J.; Andries, K.J.L.M.; Janssen, P.A.J.; Ho, C.Y.; Janssen, M.A.C.; Ludovici, D.W.; de Corte, B.; de Jonge, M.R.; Koymans, L.M.H.; van Aken, K.J.A. (Janssen Pharmaceutica NV); HIV inhibiting pyrimidine derivs.. EP 0945442; EP 0945443; US 6197779; US 6440986; WO 9950250 .
【1】 Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; et al.; Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001, 11, 17, 2235.

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)	54374	2-Methylsulfanylpyrimidin-4-ol; 2-Methylthio-4-hydroxy pyrimidine	124700-70-5	C₅H₆N₂OS	详情	详情
(II)	15361	4-Aminobenzonitrile	873-74-5	C₇H₆N₂	详情	详情
(III)	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
(IV)	54376	4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile	244768-32-9	C₁₁H₇ClN₄	详情	详情
(V)	28804	2,4,6-trimethylaniline	88-05-1	C₉H₁₃N	详情	详情
(VII)	54377	2,4-Dichloropyrimidine	3934-20-1	C₄H₂Cl₂N₂	详情	详情
(VIII)	54378	2-chloro-N-mesityl-4-pyrimidinamine; N-(2-chloro-4-pyrimidinyl)-N-mesitylamine		C₁₃H₁₄ClN₃	详情	详情

Extended Information