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【结 构 式】 
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【分子编号】68037 【品名】methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate 【CA登记号】 |
【 分 子 式 】C19H16F4N2O4 【 分 子 量 】412.341 【元素组成】C 55.34% H 3.91% F 18.43% N 6.79% O 15.52% |
合成路线1
该中间体在本合成路线中的序号：(XI)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
该中间体在本合成路线中的序号：(XI)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 |