Vicriviroc, Sch-417690, SCH-D, -Drug Synthesis Database

【结构式】

【药物名称】Vicriviroc, Sch-417690, SCH-D

【化学名称】1-(4,6-Dimethylpyrimidin-5-yl)-1-[4-[4-[2-methoxy-1(R)-[4-(trifluoromethyl)phenyl]ethyl]-3(S)-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone
　　　　　　5-[4-[4-[2-methoxy-1(R)-[4-(trifluoromethyl)phenyl]ethyl]-3(S)-methylpiperazin-1-yl]-4-methylpiperidin-1-ylcarbonyl]-4,6-dimethylpyrimidine

【CA登记号】306296-47-9, 599179-03-0 (maleate salt (1:1))

【分子式】C₂₈H₃₈F₃N₅O₂

【分子量】533.64256

【开发单位】Schering-Plough (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemokine CCR5 Antagonists

合成路线1 合成路线2

合成路线1

The reaction of 4-(trifluoromethyl)styrene (I) with mCPBA in dichloromethane gives the epoxide (II), which is treated with MeONa in methanol to yield the benzyl alcohol (III). The reaction of (III) with MsCl and TEA affords the mesylate (IV), which is condensed with the monoprotected piperazine (V) in refluxing acetonitrile to provide a diastereomeric mixture of compounds (VI) + (VII) that is resolved by flash chromatography. The desired isomer (VII) is deprotected by means of HCl or TFA to give piperazine (VIII), which is condensed with N-Boc-4-piperidone (IX) with simultaneous alkylation by means of Ti(OiPr)4 and Et2Al-CN in refluxing dichloromethane to yield the intermediate (X). The reaction of (X) with MeMgBr in THF affords the methylated compound (XI), which is deprotected by means of TFA to provide the substituted piperidine derivative (XII). Finally, this compound is acylated by means of 4,6-dimethylpyrimidine-5-carbonyl chloride (XIII) and aqueous NaOH in dichloromethane to provide the target compound. (1-3)

参考文献中间体

【1】 Imamura, S.; Baba, M.; Ishihara, Y.; Hashiguchi, S.; Kanzaki, N.; Nishimura, O. (Takeda Chemical Industries, Ltd.); Cyclic amide cpds., process for the preparation of the same and uses thereof. EP 1180513; JP 2001011073; WO 0066551 .
【2】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 .
【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Laughlin, M.A.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 2003069252; US 6689765 .

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)	64940	1-ethenyl-4-(trifluoromethyl)benzene		C₉H₇F₃	详情	详情
(II)	64941	2-[4-(trifluoromethyl)phenyl]oxirane		C₉H₇F₃O	详情	详情
(III)	64942	2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]-1-ethanol		C₁₀H₁₁F₃O₂	详情	详情
(IV)	64943	2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate		C₁₁H₁₃F₃O₄S	详情	详情
(V)	51868	tert-butyl (3S)-3-methyl-1-piperazinecarboxylate		C₁₀H₂₀N₂O₂	详情	详情
(VI)	64944	1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate		C₂₀H₂₉F₃N₂O₃	详情	详情
(VII)	64945	1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate		C₂₀H₂₉F₃N₂O₃	详情	详情
(VIII)	64946	2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether		C₁₅H₂₁F₃N₂O	详情	详情
(IX)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(X)	64947	1,1-dimethylethyl 4-cyano-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate		C₂₆H₃₇F₃N₄O₃	详情	详情
(XI)	64948	1,1-dimethylethyl 4-methyl-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate		C₂₆H₄₀F₃N₃O₃	详情	详情
(XII)	64949	methyl 2-[2-methyl-4-(4-methyl-4-piperidinyl)-1-piperazinyl]-2-[4-(trifluoromethyl)phenyl]ethyl ether; 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-4-(4-methyl-4-piperidinyl)piperazine		C₂₁H₃₂F₃N₃O	详情	详情
(XIII)	64950	4,6-dimethyl-5-pyrimidinecarbonyl chloride		C₇H₇ClN₂O	详情	详情

合成路线2

The reaction of the chiral benzyl alcohol (I) with 4-chlorobenzenesulfonyl chloride (II) and DABCO in toluene gives the sulfonate (III), which is condensed with the monoprotected piperazine (IV) by means of K2CO3 in hot toluene/acetonitrile to yield the adduct (V). The deprotection of (V) by means of hot aqueous HCl affords the piperazine derivative (VI), which is condensed with the acyl piperidine (VII) --obtained by condensation of 4,6-dimethylpyrimidine-5-carboxylic acid (VIII) with 4-piperidone (IX) --by means of acetone cyanohydrin or NaCN/AcOH to provide the cyano adduct (X). Finally, this compound is treated with AlMe3 and Me-MgCl in THF/toluene to yield the target compound.

参考文献中间体

【1】 Gala, D.; Leong, W.; Jones, A.D.; Shi, X.; Chen, M.; D'sa, B.A.; Zhu, M.; Xiao, T.; Tang, S.; Goodman, A.J.; Nielsen, C.M.; Lee, G.M.; Gamboa, J.A. (Schering Corp.); Synthesis of piperidine and piperazine cpds. as CCR5 antagonists. WO 0384950 .

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)	64951	(1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]-1-ethanol		C₁₀H₁₁F₃O₂	详情	详情
(II)	15787	4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride	98-60-2	C₆H₄Cl₂O₂S	详情	详情
(III)	64952	(1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl 4-chlorobenzenesulfonate		C₁₆H₁₄ClF₃O₄S	详情	详情
(IV)	50647	benzyl (3R)-3-methyl-1-piperazinecarboxylate		C₁₃H₁₈N₂O₂	详情	详情
(V)	64953	benzyl (3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate		C₂₃H₂₇F₃N₂O₃	详情	详情
(VI)	64946	2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether		C₁₅H₂₁F₃N₂O	详情	详情
(VII)	64954	1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-piperidinone		C₁₂H₁₅N₃O₂	详情	详情
(VIII)	64955	4,6-dimethyl-5-pyrimidinecarboxylic acid		C₇H₈N₂O₂	详情	详情
(IX)	27115	4-piperidinone	40064-34-4	C₅H₉NO	详情	详情
(X)	64956	1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-((3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazinyl)-4-piperidinecarbonitrile		C₂₈H₃₅F₃N₆O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)