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【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

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 .

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 .

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