DPC-961, DMP-961, -Drug Synthesis Database

【结构式】

【药物名称】DPC-961, DMP-961

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

【CA登记号】214287-88-4

【分子式】C₁₄H₁₀ClF₃N₂O

【分子量】314.6968

【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 合成路线2 合成路线3

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 was finally isolated by means of chiral HPLC.

参考文献中间体

【1】 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.
【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】 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	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

合成路线2

The condensation of 4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)aniline (I) with (R)-1-phenylethyl isocyanate (II) at low temperature gives a mixture of the urea (III) and tetrahydroquinazolinone (IV). Without isolation the urea (III) is cyclized to the tetrahydroquinazolinone (IV) by heating at 60 C. The dehydration of (IV) by means of SOCl2 and TEA in toluene affords the quinazolinone (V), which, without isolation, is condensed with the cyclopropylacetylide (VI) in THF to provide the alkylated tetrahydroquinazolinone (VII). Finally, this compound is deprotected from the chiral auxiliary by means of TFA or formic acid.

参考文献中间体

【1】 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.
【2】 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)	50015	1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1,1-ethanediol		C₈H₇ClF₃NO₂	详情	详情
(II)	30212	1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate	33375-06-3	C₉H₉NO	详情	详情
(III)	50016	N-[4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)phenyl]-N'-[(1R)-1-phenylethyl]urea		C₁₇H₁₆ClF₃N₂O₃	详情	详情
(IV)	50017	(4S)-6-chloro-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone		C₁₇H₁₄ClF₃N₂O₂	详情	详情
(V)	50018	6-chloro-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-2(3H)-quinazolinone		C₁₇H₁₂ClF₃N₂O	详情	详情
(VI)	50019	bromo(2-cyclopropylethynyl)magnesium		C₅H₅BrMg	详情	详情
(VII)	50020	(4S)-6-chloro-4-(2-cyclopropylethynyl)-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone		C₂₂H₁₈ClF₃N₂O	详情	详情

合成路线3

The condensation of 6-chloro-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. 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) by means of MgBr2 as catalyst.

参考文献中间体

【1】 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)	36610	6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone		C₉H₄ClF₃N₂O	详情	详情
(VI)	36611	(2-cyclopropylethynyl)lithium		C₅H₅Li	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)