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【结 构 式】 
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【药物名称】DPC-083 【化学名称】(E)-6-Chloro-4(S)-(2-cyclopropylvinyl)-4-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-one 【CA登记号】214287-99-7 【 分 子 式 】C14H12ClF3N2O 【 分 子 量 】316.71274 |
【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 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (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 toluene. 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) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (II) | 36609 | 6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C9H6ClF3N2O2 | 详情 | 详情 | |
| (III) | 36610 | 6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone | C9H4ClF3N2O | 详情 | 详情 | |
| (IV) | 36611 | (2-cyclopropylethynyl)lithium | C5H5Li | 详情 | 详情 | |
| (V) | 36612 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 | |
| (VI) | 36613 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 |
合成路线2
DPC-083 is directly obtained by reduction of ()-6-chloro-4(S)-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-one (I), DPC-961, with lithium aluminum hydride in 1,2-dichlorobenzene/THF.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331. |
| 【2】 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. |
| 【3】 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. |
| 【4】 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) | 36613 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 |
合成路线3
DPC-961 (I) can be obtained by several different related ways: 1) Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (II) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine in THF, followed by desilylation with tetrabutylammonium fluoride in THF, provides the quinazoline derivative (III), which is dehydrated employing molecular sieves in refluxing toluene to yield the imine (IV). Treatment of compound (IV) with lithium cyclopropylacetylide (V) in THF in the presence of BF3.Et2O gives the racemic adduct (VI). Finally, the desired (S)-enantiomer (I) is isolated by means of chiral HPLC . 2) Condensation of 6-chloro-4-(trifluoromethyl)quinazolin-2(1H)-one (IV) with lithium cyclopropylacetylide (V) catalyzed by the chiral auxiliary (X) in toluene/THF gives directly DPC-961. The chiral auxiliary (X) can be synthesized as follows: Epoxidation of (+)-3-carene (VII) with MCPBA in dichloromethane gives the corresponding epoxide (VIII), which is then condensed with morpholine (IX) by means of MgBr2 as catalyst.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331. |
| 【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.; 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. |
| 【4】 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 . |
| 【5】 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) | 36613 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 | |
| (II) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (III) | 36609 | 6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C9H6ClF3N2O2 | 详情 | 详情 | |
| (IV) | 36610 | 6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone | C9H4ClF3N2O | 详情 | 详情 | |
| (V) | 36611 | (2-cyclopropylethynyl)lithium | C5H5Li | 详情 | 详情 | |
| (VI) | 47241 | (1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol | C14H25NO2 | 详情 | 详情 | |
| (VII) | 47239 | (1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene | 13466-78-9 | C10H16 | 详情 | 详情 |
| (VIII) | 47240 | (1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane | C10H16O | 详情 | 详情 | |
| (IX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线4
DPC-961 (I) can be obtained by several different related ways: 3) Condensation of 4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)aniline (XI) with (R)-1-phenylethyl isocyanate (XII) by means of HCl at low temperature gives a mixture of the urea (XIII) and tetrahydroquinazolinone (XIV). Without isolation, urea (XIII) is cyclized to the tetrahydroquinazolinone (XIV) by heating at 60 C. Dehydration of (XIV) by means of SOCl2 and Et3N in toluene affords the quinazolinone (XV), which, without isolation, is condensed with the Grignard reagent bromomagnesium cyclopropylacetylide (XVI) in THF to provide the alkylated tetrahydroquinazolinone (XVII). Finally, compound (XVII) is deprotected from the chiral auxiliary by means of TFA or formic acid. 4) Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (II) with (R)-1-phenylethyl isocyanate (XII) by means of either HCl in THF or TMSCl/THF in toluene, followed by heating at 60-65 C, provides the tetrahydroquinazolinone (XIX). Dehydration of (XIX) with SOCl2 and Et3N or NMM in toluene affords quinazolinone (XV), which, without isolation, is condensed with the Grignard reagent chloromagnesium cyclopropylacetylide (XX) to give the tetrahydroquinazoline (XVII). Finally, this compound is treated with TFA or formic acid as before.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331. |
| 【2】 Magnus, N.A.; et al.; A new asymmetric 1,4-addition method: Application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961. Tetrahedron Lett 2000, 41, 17, 3015. |
| 【3】 Confalone, P.N.; Magnus, N.A.; Storace, L. (DuPont Pharmaceuticals Co.); Process for the preparation of quinazolinones. WO 0029391 . |
| 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) | 36613 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 | |
| (II) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (X) | 50015 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1,1-ethanediol | C8H7ClF3NO2 | 详情 | 详情 | |
| (XI) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |
| (XII) | 50016 | N-[4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)phenyl]-N'-[(1R)-1-phenylethyl]urea | C17H16ClF3N2O3 | 详情 | 详情 | |
| (XIII) | 50017 | (4S)-6-chloro-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C17H14ClF3N2O2 | 详情 | 详情 | |
| (XIV) | 50018 | 6-chloro-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-2(3H)-quinazolinone | C17H12ClF3N2O | 详情 | 详情 | |
| (XV) | 50019 | bromo(2-cyclopropylethynyl)magnesium | C5H5BrMg | 详情 | 详情 | |
| (XVI) | 50020 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C22H18ClF3N2O | 详情 | 详情 | |
| (XVII) | 52671 | N-[4-chloro-2-(2,2,2-trifluoroacetyl)phenyl]-N'-(1-phenylethyl)urea | C17H14ClF3N2O2 | 详情 | 详情 | |
| (XVIII) | 52670 | chloro(2-cyclopropylethynyl)magnesium | C5H5ClMg | 详情 | 详情 | |
| (XIX) | 52672 | 6-chloro-4-hydroxy-3-(1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C17H14ClF3N2O2 | 详情 | 详情 |