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【结 构 式】 
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【分子编号】36616 【品名】5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone 【CA登记号】 |
【 分 子 式 】C9H3F5N2O 【 分 子 量 】250.127716 【元素组成】C 43.22% H 1.21% F 37.98% N 11.2% O 6.4% |
合成路线1
该中间体在本合成路线中的序号：(III)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
该中间体在本合成路线中的序号：(V)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 |
合成路线3
该中间体在本合成路线中的序号：(III)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 (VI) was then isolated by means of chiral HPLC. Finally, reduction of the triple bond of (VI) with LiAlH4 furnished the corresponding olefin.
| 【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 | |
| (VI) | 36618 | (4S)-4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H9F5N2O | 详情 | 详情 |