• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】DPC-963, DMP-963

【化学名称】4(S)-(2-Cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-one

【CA登记号】214287-90-8

【 分 子 式 】C14H9F5N2O

【 分 子 量 】316.23263

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors

合成路线1

Condensation of 6'-amino-2,2,2,2',3'-pentafluoroacetophenone (I) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine, followed by desilylation with tetrabutylammonium fluoride provided the quinazoline derivative (II). Dehydration of the tertiary alcohol of (II) to afford imine (III) was carried out employing molecular sieves in refluxing xylene. Subsequent addition of lithium cyclopropylacetylide (IV) to (III) in the presence of BF3-Et2O yielded the racemic adduct (V). The desired (S)-enantiomer was isolated by means of chiral HPLC.

1 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
2 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
3 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .
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) 36614 1-(6-amino-2,3-difluorophenyl)-2,2,2-trifluoro-1-ethanone C8H4F5NO 详情 详情
(II) 36615 5,6-difluoro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone C9H5F5N2O2 详情 详情
(III) 36616 5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone C9H3F5N2O 详情 详情
(IV) 36611 (2-cyclopropylethynyl)lithium C5H5Li 详情 详情
(V) 36617 4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone C14H9F5N2O 详情 详情

合成路线2

The condensation of 5,6-difluoro-4-(trifluoromethyl)quinazolin-2(1H)-one (V) with lithium cyclopropylacetylene (VI) (LiHMDS is used as strong base) catalyzed by the chiral moderator (IV) in toluene/THF gives the target compound with an enantiomeric excess of 94%, which increases up to 99.6% after working up (crystallization in heptane). The chiral moderator (IV) has been obtained as follows: The epoxidation of (+)-3-carene (I) with MCPBA in dichloromethane gives the corresponding epoxide (II), which is then condensed with morpholine (III) using MgBr as a catalyst.

1 Kauffman, G.S.; et al.; An efficient chiral moderator prepared for inexpensive (+)-3-carene: Synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2000, 2, 20, 3119.
2 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .
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) 47239 (1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene 13466-78-9 C10H16 详情 详情
(II) 47240 (1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane C10H16O 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 47241 (1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol C14H25NO2 详情 详情
(V) 36616 5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone C9H3F5N2O 详情 详情
(VI) 36611 (2-cyclopropylethynyl)lithium C5H5Li 详情 详情
Extended Information