磷酸奥司他韦奥司他韦Chemical Name: (3R,4R,5S)-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1:1)
CAS No. 204255-11-8, 209965-30-0 (citrate (1:1)), 196618-13-0 (free base), 204255-09-4 (monoHCl)
项目整合开发状态: Launched-1999
项目研究机构: Gilead (Originator), Chugai (Licensee), Roche (Licensee), Shionogi (Comarketer)
合成路线:2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV),which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI).The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII),which is hydrolyzed with HCl,yielding the dihydroxy ester (XVIII).The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX),which is protected with methyl chloromethyl ether to give compound (XX).The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI),which is acylated with mesyl chloride to the mesylate (XXII).The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII),which is treated with sodium azide in hot DMF to give the amino azide (XXIV).The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV),which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI).The cleavage of the aziridine ring of (XXVI) with 3-pentanol,followed by acetylation of the resulting amino group,affords the acetamido aziridine (XXVII),which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII).The esterification of (XXVIII) with ethanol,DCC and DMAP in dichloromethane affords the azido ester (XIII),which is finally reduced with triphenylphosphine in hot THF/water.
📄 详细内容
合成路线:1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III),which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV).The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V),which is dehydrated with SO2Cl2 in dichloromethane,giving the cyclohexenecarboxylate (VI).The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII),which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII).The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX),which is opened with sodium azide and ammonium chloride in ethanol/water,resulting in the the azido alcohol (X).The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI),which is opened by means of sodium azide in hot DMF to the azidoamine (XII).The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII),which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
参考文献标题:Cpds.containing six-membered rings,processes for their preparation,and their use as medicaments
文献作者:Bischofberger,N.W.; Kim,C.U.; Williams,M.A.; Mills,R.G.; Hitchcock,M.J.M.; Dahl,T.C.; Lew,W.; Liu,H.(Gilead Sciences Inc.)
参考来源:EP 1015417; WO 9914185
合成路线:2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV),which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI).The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII),which is hydrolyzed with HCl,yielding the dihydroxy ester (XVIII).The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX),which is protected with methyl chloromethyl ether to give compound (XX).The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI),which is acylated with mesyl chloride to the mesylate (XXII).The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII),which is treated with sodium azide in hot DMF to give the amino azide (XXIV).The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV),which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI).The cleavage of the aziridine ring of (XXVI) with 3-pentanol,followed by acetylation of the resulting amino group,affords the acetamido aziridine (XXVII),which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII).The esterification of (XXVIII) with ethanol,DCC and DMAP in dichloromethane affords the azido ester (XIII),which is finally reduced with triphenylphosphine in hot THF/water.
参考文献标题:Carbocyclic cpds.
文献作者:Bischofberger,N.W.; Kim,C.U.; Williams,M.A.; Lew,W.; Liu,H.(Gilead Sciences Inc.)
参考来源:US 5763483
合成路线:1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III),which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV).The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V),which is dehydrated with SO2Cl2 in dichloromethane,giving the cyclohexenecarboxylate (VI).The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII),which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII).The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX),which is opened with sodium azide and ammonium chloride in ethanol/water,resulting in the the azido alcohol (X).The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI),which is opened by means of sodium azide in hot DMF to the azidoamine (XII).The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII),which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
参考文献标题:Preparation of cyclohexene carboxylate derivs.
文献作者:McGee,L.R.; Kent,K.M.; Portich,M.J.; Kim,C.U.; Williams,M.A.; Zhang,L.; Prisbe,E.J.; Rohloff,J.C.; Munger,J.D.; St.John,D.E.(Gilead Sciences Inc.)
参考来源:WO 9807685
合成路线:1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III),which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV).The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V),which is dehydrated with SO2Cl2 in dichloromethane,giving the cyclohexenecarboxylate (VI).The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII),which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII).The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX),which is opened with sodium azide and ammonium chloride in ethanol/water,resulting in the the azido alcohol (X).The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI),which is opened by means of sodium azide in hot DMF to the azidoamine (XII).The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII),which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
参考文献标题:Preparation of carbocyclic cpds.
文献作者:Postich,M.J.; Williams,M.A.; Rohloff,J.C.; Prisbe,E.J.; McGee,L.R.; Kent,K.M.; Munger,J.D.; Zhang,L.; Kim,C.U.; Kelly,D.E.(Gilead Sciences Inc.)
参考来源:US 5886213
合成路线:1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III),which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV).The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V),which is dehydrated with SO2Cl2 in dichloromethane,giving the cyclohexenecarboxylate (VI).The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII),which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII).The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX),which is opened with sodium azide and ammonium chloride in ethanol/water,resulting in the the azido alcohol (X).The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI),which is opened by means of sodium azide in hot DMF to the azidoamine (XII).The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII),which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
参考文献标题:Practical total synthesis of the anti-influenza drug GS-4104
文献作者:Rohloff,J.C.; Kent,K.M.; Postich,M.J.; et al.
参考来源:J Org Chem 1998,63(13),4545
合成路线:1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III),which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV).The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V),which is dehydrated with SO2Cl2 in dichloromethane,giving the cyclohexenecarboxylate (VI).The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII),which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII).The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX),which is opened with sodium azide and ammonium chloride in ethanol/water,resulting in the the azido alcohol (X).The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI),which is opened by means of sodium azide in hot DMF to the azidoamine (XII).The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII),which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
合成路线:2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV),which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI).The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII),which is hydrolyzed with HCl,yielding the dihydroxy ester (XVIII).The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX),which is protected with methyl chloromethyl ether to give compound (XX).The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI),which is acylated with mesyl chloride to the mesylate (XXII).The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII),which is treated with sodium azide in hot DMF to give the amino azide (XXIV).The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV),which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI).The cleavage of the aziridine ring of (XXVI) with 3-pentanol,followed by acetylation of the resulting amino group,affords the acetamido aziridine (XXVII),which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII).The esterification of (XXVIII) with ethanol,DCC and DMAP in dichloromethane affords the azido ester (XIII),which is finally reduced with triphenylphosphine in hot THF/water.
参考文献标题:Oseltamivir Phosphate
文献作者:Casta馿r,J.; Leeson,P.A.; Graul,A.
参考来源:Drugs Fut 1999,24(11),1189
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