Casopitant Mesilate, GW-579769, Rezonic, Zunrisa, -Drug Synthesis Database

【结构式】

【药物名称】Casopitant Mesilate, GW-579769, Rezonic, Zunrisa

【化学名称】4(S)-(4-Acetylpiperazin-1-yl)-N-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2(R)-(4-fluoro-2-methylphenyl)-N-methylpiperidine- 1-carboxamide methanesulfonate

【CA登记号】414910-30-8, 414910-27-3 (free base)

【分子式】C₁₃H₃₉F₇N₄O₅S

【分子量】712.719

【开发单位】GlaxoSmithKline.

【药理作用】Tachykinin NK1 Antagonist, Treatment of Nausea/Vomiting

合成路线1 合成路线2

合成路线1

Casopitant can be prepared by two related methods starting from either racemic 2-(4-fluoro-2-methylphenyl)-4-piperidinone (I) or from the corresponding (R)-enantiomer (II). Optically pure piperidinone (II), obtained either by asymmetric synthesis or by resolution of (I) with L-mandelic acid, is treated with triphosgene and NaHCO3 to give the carbamoyl chloride (III), which is then coupled with N-methyl-1(R)-[3,5-(bis-trifluoromethyl)phenyl]ethylamine (IV) to afford the urea adduct (V). Alternatively, reaction of racemic piperidinone (I) with triphosgene and DIEA followed by coupling of the resulting carbamoyl chloride (VI) with the 1-aryl-ethylamine (IV) leads to a diastereomeric mixture of urea adducts, from which the target (R,R)-diastereoisomer (V) can be isolated using flash column chromatography. The N-carbamoyl piperidone (V) is then subjected to reductive amination with N-acetylpiperazine (VII) in the presence of NaBH(OAc)3 to generate a mixture of epimeric 4-piperazinylpiperidines, from which the 4(S)-isomer casopitant is finally obtained through recrystallization as the corresponding methanesulfonate salt (1, 2). Scheme 1.

参考文献中间体

【1】 Alvaro, G., Di Fabio, R., Tranquillini, M.E., Tampieri, M., Maragni, P. (GlaxoSmithKline plc). Chemical compounds. EP 1326832, EP 1524266, EP 1752449, EP 1921064, JP 2004511544, US 2004014770, US 2005137208, US 2006142302, US 2008021041, US 7060702, US 7119092, US 7294630, WO 2002032867.
【2】 Christensen, S.R., Merlo Pich, E., Ratti, E., Yamada, T. (Glaxo Group Ltd.). Novel use. WO 2008046882.

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)	65727	2-(4-Fluoro-2-methylphenyl)-4-piperidinone		C₁₂H₁₄FNO	详情	详情
(II)	65728	(2R)-(4-Fluoro-2-methylphenyl)-4-piperidinone		C₁₂H₁₄FNO	详情	详情
(III)	65729			C₁₃H₁₃ClFNO₂	详情	详情
(IV)	65730	(R)-N-Methyl-1-[3,5-bis(trifluoromethyl)phenyl]ethylamine	334477-60-0	C₁₁H₁₁F₆N	详情	详情
(V)	65731			C₂₄H₂₃F₇N₂O₂	详情	详情
(VI)	65732			C₁₃H₁₃ClFNO₂	详情	详情
(VII)	20674	N-Acetyl piperazine; 1-(1-piperazinyl)-1-ethanone	13889-98-0	C₆H₁₂N₂O	详情	详情

合成路线2

The intermediate 2-aryl-4-piperidinones (I) and (II) can be obtained by the following methods. Condensation of 2-methyl-4-fluorobenzaldehyde (VIII) with 4-amino-2-butanone ethylene ketal (IX) gives the imine ketal (X), which undergoes Mannich-type cyclization to the 4,4-ethylenedioxy piperidine (XI) upon refluxing in benzene in the presence of anhydrous p-TsOH. Subsequent acidic hydrolysis of the ethylene ketal (XI) yields the racemic piperidone (I). In a different strategy, condensation of 4-fluoro-2-methylphenylmagnesium bromide (XII) with 4-methoxypyridine (XIII) in the presence of benzyl chloroformate followed by acidic hydrolysis of the intermediate enol ether provides 1-(benzyloxycarbonyl)-2-(4-fluoro-2-methylphenyl)-2,3-dihydro-4-pyridone (XIV). After reduction of (XIV) to the corresponding piperidinone (XV) by means of L-selectride in cold THF, the protecting group is removed by hydrogenolysis over Pd/C to provide the deprotected amine (I) (1, 2). Similarly, condensation of the Grignard reagent (XII) with 4-methoxypyridine (XIII) in the presence of (–)-menthyl chloroformate followed by acidic enol ether hydrolysis gives the dihydropyridone menthyl carbamate (XVIa-b) as a mixture of diastereoisomers, which can be separated by flash column chromatography. The minor 2(R)-isomer is then hydrolyzed employing methanolic NaOMe to provide 2(R)-(4-fluoro-2-methylphenyl)-2,3-dihydro-4-pyridone (XVII), which is reduced to the chiral piperidinone (II) by catalytic hydrogenation over Pd/C (1). Scheme 2.

参考文献中间体

【1】 Alvaro, G., Di Fabio, R., Tranquillini, M.E., Tampieri, M., Maragni, P. (GlaxoSmithKline plc). Chemical compounds. EP 1326832, EP 1524266, EP 1752449, EP 1921064, JP 2004511544, US 2004014770, US 2005137208, US 2006142302, US 2008021041, US 7060702, US 7119092, US 7294630, WO 2002032867.
【2】 Christensen, S.R., Merlo Pich, E., Ratti, E., Yamada, T. (Glaxo Group Ltd.). Novel use. WO 2008046882.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVIa-b)	65741			C₂₃H₃₀FNO₃	详情	详情
(I)	65727	2-(4-Fluoro-2-methylphenyl)-4-piperidinone		C₁₂H₁₄FNO	详情	详情
(II)	65728	(2R)-(4-Fluoro-2-methylphenyl)-4-piperidinone		C₁₂H₁₄FNO	详情	详情
(VIII)	65733	4-Fluoro-2-methylbenzaldehyde	63082-45-1	C₈H₇FO	详情	详情
(IX)	65734	(2-Methyl-1,3-dioxolan-2-yl)methanamine	3289-19-8	C₆H₁₃NO₂	详情	详情
(X)	65735			C₁₄H₁₈FNO₂	详情	详情
(XI)	65736			C₁₄H₁₈FNO₂	详情	详情
(XII)	65737	4-Fluoro-2-Methylphenylmagnesium Bromide	30897-90-6	C₇H₆BrFMg	详情	详情
(XIII)	65738	4-Methoxypyridine	620-08-6	C₆H₇NO	详情	详情
(XIV)	65739	benzyl 2-(4-fluoro-2-methylphenyl)-4-oxo-2,3-dihydropyridine-1-carboxylate	414909-98-1	C₂₀H₁₈FNO₃	详情	详情
(XV)	65740	benzyl 2-(4-fluoro-2-methylphenyl)-4-oxo-2,3,5,6-tetrahydroyridine-1-carboxylate		C₂₀H₂₀FNO₃	详情	详情
(XVII)	65742			C₁₂H₁₂FNO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)