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【结 构 式】 
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【分子编号】16572 【品名】1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone 【CA登记号】 |
【 分 子 式 】C8H5ClF3NO 【 分 子 量 】223.5817496 【元素组成】C 42.98% H 2.25% Cl 15.86% F 25.49% N 6.26% O 7.16% |
合成路线1
该中间体在本合成路线中的序号：(IV)Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.
| 【1】 Choudhury, A.; Moore, J.R.; Pierce, M.E.; Fortunak, J.M.; Valvis, I.; Confalone, P.N.; In situ recycling of chiral ligand and surplus nucleophile for a noncatalytic reaction: Amplification of process throughput in the asymmetric addition step of efavirenz (DMP 266). Org Process Res Dev 2003, 7, 3, 324. |
| 【2】 Britcher, S.F.; Tran, L.O.; Young, S.D.; L-743,726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995, 39, 12, 2602-5. |
| 【3】 Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726. Tetrahedron Lett 1995, 36, 49, 8937-40. |
| 【4】 Graul, A.; Rabasseda, X.; Castañer, J.; Efavirenz. Drugs Fut 1998, 23, 2, 133. |
| 【5】 Young, S.D.; Britcher, S.F.; Payne, L.S.; Tran, L.O.; Lumma, W.C. Jr. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. WO 9520389 . |
| 【6】 Young, S.D.; Tran, L.O.; Britcher, S.F.; Lumma, W.C. Jr.; Payne, L.S. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. EP 0582455; JP 1994184124; WO 9403440 . |
| 【7】 Thompson, A.S.; Corley, E.G.; Huntington, M. (Merck & Co., Inc.); Improved synthesis of cyclopropylacetylene. JP 1998512880; WO 9622955 . |
| 【8】 Thompson, A.S.; Corley, E.G.; Grabowski, E.J.J.; Yasuda, N. (Merck & Co., Inc.); Asymmetric synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one. WO 9637457 . |
| 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) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 16571 | 4'-Chloro-2,2-dimethylpropionanilide; N-(4-Chlorophenyl)-2,2-dimethylpropanamide | 65854-91-3 | C11H14ClNO | 详情 | 详情 |
| (IV) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (V) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (VI) | 16574 | 1-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-2,2,2-trifluoro-1-ethanone | C16H13ClF3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 16576 | 5-chloro-1-pentyne | 14267-92-6 | C5H7Cl | 详情 | 详情 |
| (IX) | 16577 | (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol | C13H19NO | 详情 | 详情 | |
| (X) | 16578 | (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C21H19ClF3NO2 | 详情 | 详情 | |
| (XI) | 16579 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C22H17ClF3NO3 | 详情 | 详情 | |
| (XII) | 16580 | 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | 168834-43-3 | C13H11ClF3NO | 详情 | 详情 |
| (XIII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XIV) | 16582 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C14H9ClF3NO2 | 详情 | 详情 | |
| (XV) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (XVI) | 16584 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one | C24H21ClF3NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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.
| 【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 | 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 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(II)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5
该中间体在本合成路线中的序号：(II)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 |