合成路线: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.
参考文献标题:Benzoxazinones as inhibitors of HIV reverse transcriptase
文献作者:Young,S.D.; Britcher,S.F.; Payne,L.S.; Tran,L.O.; Lumma,W.C.Jr.(Merck & Co.,Inc.)
参考来源:WO 9520389
合成路线: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.
参考文献标题:Improved synthesis of cyclopropylacetylene
文献作者:Thompson,A.S.; Corley,E.G.; Huntington,M.(Merck & Co.,Inc.)
参考来源:JP 1998512880; WO 9622955
合成路线: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.
参考文献标题:Asymmetric synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one
文献作者:Thompson,A.S.; Corley,E.G.; Grabowski,E.J.J.; Yasuda,N.(Merck & Co.,Inc.)
参考来源:WO 9637457
合成路线: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.
参考文献标题: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
文献作者:Corley,E.G.; Thompson,A.S.; Huntington,M.F.; Grabowski,E.J.J.
参考来源:Tetrahedron Lett 1995,36(49),8937-40
合成路线: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.
参考文献标题:L-743,726 (DMP-266): A novel,highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase
文献作者:Young,S.D.; Britcher,S.F.; Tran,L.O.; Payne,L.S..; Lumma,W.C.; Lyle,T.A.; Huff,J.R.; Anderson,P.S.; Olsen,D.B.; Carroll,S.S.; et al.
参考来源:Antimicrob Agents Chemother 1995,39(12),2602-5
合成路线: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.
参考文献标题:Efavirenz
文献作者:Graul,A.; Rabasseda,X.; Casta馿r,J.
参考来源:Drugs Fut 1998,23(2),133
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