Letermovir；AIC-246, -Drug Synthesis Database

【结构式】

【药物名称】Letermovir；AIC-246

【化学名称】2-[8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4(S)-yl]acetic acid

【CA登记号】917389-32-3

【分子式】C₂₉H₂₈F₄N₄O₄

【分子量】572.5506

【开发单位】AiCuris GmbH & Co. KG (GE); the product has been licensed on a worldwide basis to Merck & Co., Inc. (US)

【药理作用】Treatment of Human Cytomegalovirus Infection;Antiinfective Agent

合成路线1 合成路线2

合成路线1

Heck coupling of 2-bromo-6-fluoroaniline (I) with methyl acrylate (II) by means of Pd(oAc)2, (o-tol)3P and Et3n in refluxing acetonitrile yields the (E)-cinnamate (III), which is then treated with PPh3 in the presence of CCl4 and Et3n in acetonitrile to give the iminophosphorane (IV). Compound (IV) is then condensed with 2-methoxy-5-(trifluoromethyl) phenyl isocyanate (V) [prepared by treatment of 2-methoxy-5-(trifluoromethyl)aniline (VI) with diphosgene in the presence of proton sponge] in CH2Cl2 to provide the carbodiimide (VII). Cyclocondensation of carbodiimide (VII) with 1-(3-methoxyphenyl)-piperazine (VIII) in the presence of Sio2 in refluxing CH2Cl2 affords the 3,4-dihydroquinazoline derivative (IX) (1), which is then subjected to ester hydrolysis with naoH in H2o/dioxane to produce the racemic carboxylic acid (X) . Finally, racemate (X) is resolved through chiral HPLC .
In an alternative procedure, chlorination of the dihydroquinazolinone derivative (XI) with PoCl3 and DBU in refluxing chlorobenzene, followed by coupling of the resulting 2-chloro-3,4-dihydroquinazoline (XII) with 1-(3-methoxyphenyl)piperazine (VIII) in the presence of DBU in refluxing dioxane produces the 3,4-dihydroquinazoline derivative (IX). Resolution of the racemic ester (IX) using di-p-toluoyl-D-tartaric acid in EtoAc provides the corresponding (S)-enantiomer (XIII), which is finally hydrolyzed with naoH in H2O/dioxane .

参考文献中间体

【1】 Wunberg, T., Jeske, M., Lampe, T. et al. (Bayer HealthCare AG). Substituted dihydrochinazolines having antiviral properties. DE 10319612, EP 1622880, JP 2006525249, US 2005065160, US 7196086, US 2007191387, Wo 2004096778.
【2】 Goossen, K., Kuhn, o., Berwe, M., Krueger, J., Militzer, H.-C. (Bayer HealthCare AG). Method for producing dihydroquinazolines. Cn 101863843, DE 10227517, EP 1893587, JP 2008543797, US 2009221822, US 8084604, US 2012130072, US 8372972, Wo 2006133822.

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)	68030	2-bromo-6-fluoroaniline	65896-11-9	C₆H₅BrFN	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	68031	(E)-methyl 3-(2-amino-3-fluorophenyl)acrylate		C₁₀H₁₀FNO₂	详情	详情
(IV)	68032	(E)-methyl 3-(3-fluoro-2-((triphenylphosphoranylidene)amino)phenyl)acrylate		C₂₈H₂₃FNO₂P	详情	详情
(V)	68033	2-methoxy-5-(trifluoromethyl)phenyl isocyanate	16588-75-3	C₉H₆F₃NO₂	详情	详情
(VI)	27669	2-methoxy-5-(trifluoromethyl)aniline	349-65-5	C₈H₈F₃NO	详情	详情
(VII)	68034	(E)-methyl 3-(3-fluoro-2-((((2-methoxy-4-(trifluoromethyl)phenyl)imino)methylene)amino)phenyl)acrylate		C₁₉H₁₄F₄N₂O₃	详情	详情
(VIII)	14853	methyl 3-piperazinophenyl ether; 1-(3-methoxyphenyl)piperazine	16015-71-7	C₁₁H₁₆N₂O	详情	详情
(IX)	68035	methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate		C₃₀H₃₀F₄N₄O₄	详情	详情
(X)	68036	2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid		C₂₉H₂₈F₄N₄O₄	详情	详情
(XI)	68037	methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate		C₁₉H₁₆F₄N₂O₄	详情	详情
(XII)	68038	methyl 2-(2-chloro-8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-4-yl)acetate		C₁₉H₁₅ClF₄N₂O₃	详情	详情
(XIII)	68039	(S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate		C₃₀H₃₀F₄N₄O₄	详情	详情

合成路线2

Condensation of 2-fluoroaniline (XIV) or 2-bromo-6-fluoroaniline (I) with 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (V) in refluxing acetonitrile yields the corresponding diaryl ureas (XV) or (XVI), respec-tively. The N-(2-Fluorophenyl)urea derivative (XV) is then condensed with methyl acrylate (II) by means of Pd(OAc)2 and H2S2O7 in AcoH to give the corresponding (E)-cinnamate (XVII), which finally undergoes intramolecular Michael addition in the presence of DBU in refluxing acetone .
Alternatively, intermediate (XI) is obtained by Heck coupling of aryl bromide (XVI) with methyl acrylate (II) in the presence of Pd(MeCn)2Cl2, (o-tol)3P and Et3n in isobutyronitrile at 90-102 °C .

参考文献中间体

【1】 Goossen, K., Kuhn, o., Berwe, M., Krueger, J., Militzer, H.-C. (Bayer HealthCare AG). Method for producing dihydroquinazolines. Cn 101863843, DE 10227517, EP 1893587, JP 2008543797, US 2009221822, US 8084604, US 2012130072, US 8372972, Wo 2006133822.

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)	68030	2-bromo-6-fluoroaniline	65896-11-9	C₆H₅BrFN	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(V)	68033	2-methoxy-5-(trifluoromethyl)phenyl isocyanate	16588-75-3	C₉H₆F₃NO₂	详情	详情
(XI)	68037	methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate		C₁₉H₁₆F₄N₂O₄	详情	详情
(XIV)	22296	2-fluorophenylamine; 2-fluoroaniline	348-54-9	C₆H₆FN	详情	详情
(XV)	68040	1-(2-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea		C₁₅H₁₂F₄N₂O₂	详情	详情
(XVI)	68041	1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea		C₁₅H₁₁BrF₄N₂O₂	详情	详情
(XVII)	68042	(E)－methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)ureido)phenyl)acrylate		C₁₉H₁₆F₄N₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)