合成路线:Trimegestone has been obtained by several related ways:1) The reaction of 3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one (I) with KCN and acetic acid in methanol,followed by silylation with TMSCl,gives the silylated cyanohydrin (II),which is treated with ethylmagnesium bromide in THF to yield the 17beta-propionyl derivative (III).Acetylation of the 17alpha-hydroxy group of (III) with Ac2O affords acetate (IV),which is methylated with MeI and lithium amide in liquid ammonia,giving the 17alpha-methyl derivative (V).The oxidation of (V) with t-BuOK and oxygen in DMF yields the 17beta-(2-oxopropionyl) derivative (VI),which is isomerized with acetic acid/ hydrochloric acid or acetic acid/perchloric acid,affording 17alpha-methyl-17beta-(2-oxopropionyl)estra-4,9-dien-3-one (VII).Finally,this compound is regio- and enantioselectively reduced with Saccharomyces cerevisiae in a sodium acetate buffer.2) The reaction of the 17alpha-methyl derivative (V) with t-BuOK and iodine in THF gives the 17beta-(2-iodopropionyl) compound (VIII),which by reaction with KOAc in DMF,followed by treatment with acetic acid/perchloric acid as before,is converted into the 17beta-(2-acetoxypropionyl) derivative (IX).Finally,the acetoxy group of (IX) is hydrolyzed with KOH in methanol and the mixture of (R)- and (S)-diastereomers is separated by HPLC over silicagel.3) The 17beta-(2-acetoxypropionyl) derivative (IX) can also be obtained directly by carefully controlled direct oxidation of the 17alpha-methyl-17beta-propionyl intermediate (V) with dry air in DMF in the presence of t-BuOK and triethyl phosphite.4) The diastereoselective hydrolysis of the 17beta-(2-acetoxypropionyl) intermediate (IX) with lipase PS Amano in n-butanol/pH = 5 buffer gives a mixture of unreacted 17beta-[2(S)-acetoxypropinyl] derivative (X) and 17beta-[2(R)-hydroxypropionyl] derivative (XI).This mixture,without separation,is treated with methanesulfonyl chloride and Et3N in dichloromethane to yield a new mixture of the unreacted 17beta-[2(S)-acetoxypropionyl] derivative (X) and 17beta-[2(R)-(methanesulfonyloxy)propionyl] derivative (XII).The reaction of this mixture with potassium acetate in hot bis(2-methoxyethyl)ether affords pure 17beta-[2(S)-acetoxypropionyl] derivative (X),since the acetolysis of the sulfonate (XII) takes place with inversion of the configuration.Finally,this compound is hydrolyzed with KOH in methanol.
参考文献标题:Novel 3,20-dioxo-4,9-diene-21-hydroxy steroid cpds.,process for their preparation,their use in medicines and pharmaceutical compsns.containing them
文献作者:Coussediere,D.(Aventis Pharma SA)
参考来源:EP 0007823; EP 0046001; FR 2430953; JP 1980015475; JP 1988033395; US 4273771
合成路线:Trimegestone has been obtained by several related ways:1) The reaction of 3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one (I) with KCN and acetic acid in methanol,followed by silylation with TMSCl,gives the silylated cyanohydrin (II),which is treated with ethylmagnesium bromide in THF to yield the 17beta-propionyl derivative (III).Acetylation of the 17alpha-hydroxy group of (III) with Ac2O affords acetate (IV),which is methylated with MeI and lithium amide in liquid ammonia,giving the 17alpha-methyl derivative (V).The oxidation of (V) with t-BuOK and oxygen in DMF yields the 17beta-(2-oxopropionyl) derivative (VI),which is isomerized with acetic acid/ hydrochloric acid or acetic acid/perchloric acid,affording 17alpha-methyl-17beta-(2-oxopropionyl)estra-4,9-dien-3-one (VII).Finally,this compound is regio- and enantioselectively reduced with Saccharomyces cerevisiae in a sodium acetate buffer.2) The reaction of the 17alpha-methyl derivative (V) with t-BuOK and iodine in THF gives the 17beta-(2-iodopropionyl) compound (VIII),which by reaction with KOAc in DMF,followed by treatment with acetic acid/perchloric acid as before,is converted into the 17beta-(2-acetoxypropionyl) derivative (IX).Finally,the acetoxy group of (IX) is hydrolyzed with KOH in methanol and the mixture of (R)- and (S)-diastereomers is separated by HPLC over silicagel.3) The 17beta-(2-acetoxypropionyl) derivative (IX) can also be obtained directly by carefully controlled direct oxidation of the 17alpha-methyl-17beta-propionyl intermediate (V) with dry air in DMF in the presence of t-BuOK and triethyl phosphite.4) The diastereoselective hydrolysis of the 17beta-(2-acetoxypropionyl) intermediate (IX) with lipase PS Amano in n-butanol/pH = 5 buffer gives a mixture of unreacted 17beta-[2(S)-acetoxypropinyl] derivative (X) and 17beta-[2(R)-hydroxypropionyl] derivative (XI).This mixture,without separation,is treated with methanesulfonyl chloride and Et3N in dichloromethane to yield a new mixture of the unreacted 17beta-[2(S)-acetoxypropionyl] derivative (X) and 17beta-[2(R)-(methanesulfonyloxy)propionyl] derivative (XII).The reaction of this mixture with potassium acetate in hot bis(2-methoxyethyl)ether affords pure 17beta-[2(S)-acetoxypropionyl] derivative (X),since the acetolysis of the sulfonate (XII) takes place with inversion of the configuration.Finally,this compound is hydrolyzed with KOH in methanol.
参考文献标题:New method of production of 20-keto 21(S)-hydroxy steroid cpds.and intermediates thereof
文献作者:Mackiewicz,P.; Godard,J.-Y.; Buendia,J.; Richard,C.(Aventis Pharma SA)
参考来源:EP 0581649; FR 2694007; JP 1994181796; US 5384419
合成路线:Trimegestone has been obtained by several related ways:1) The reaction of 3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one (I) with KCN and acetic acid in methanol,followed by silylation with TMSCl,gives the silylated cyanohydrin (II),which is treated with ethylmagnesium bromide in THF to yield the 17beta-propionyl derivative (III).Acetylation of the 17alpha-hydroxy group of (III) with Ac2O affords acetate (IV),which is methylated with MeI and lithium amide in liquid ammonia,giving the 17alpha-methyl derivative (V).The oxidation of (V) with t-BuOK and oxygen in DMF yields the 17beta-(2-oxopropionyl) derivative (VI),which is isomerized with acetic acid/ hydrochloric acid or acetic acid/perchloric acid,affording 17alpha-methyl-17beta-(2-oxopropionyl)estra-4,9-dien-3-one (VII).Finally,this compound is regio- and enantioselectively reduced with Saccharomyces cerevisiae in a sodium acetate buffer.2) The reaction of the 17alpha-methyl derivative (V) with t-BuOK and iodine in THF gives the 17beta-(2-iodopropionyl) compound (VIII),which by reaction with KOAc in DMF,followed by treatment with acetic acid/perchloric acid as before,is converted into the 17beta-(2-acetoxypropionyl) derivative (IX).Finally,the acetoxy group of (IX) is hydrolyzed with KOH in methanol and the mixture of (R)- and (S)-diastereomers is separated by HPLC over silicagel.3) The 17beta-(2-acetoxypropionyl) derivative (IX) can also be obtained directly by carefully controlled direct oxidation of the 17alpha-methyl-17beta-propionyl intermediate (V) with dry air in DMF in the presence of t-BuOK and triethyl phosphite.4) The diastereoselective hydrolysis of the 17beta-(2-acetoxypropionyl) intermediate (IX) with lipase PS Amano in n-butanol/pH = 5 buffer gives a mixture of unreacted 17beta-[2(S)-acetoxypropinyl] derivative (X) and 17beta-[2(R)-hydroxypropionyl] derivative (XI).This mixture,without separation,is treated with methanesulfonyl chloride and Et3N in dichloromethane to yield a new mixture of the unreacted 17beta-[2(S)-acetoxypropionyl] derivative (X) and 17beta-[2(R)-(methanesulfonyloxy)propionyl] derivative (XII).The reaction of this mixture with potassium acetate in hot bis(2-methoxyethyl)ether affords pure 17beta-[2(S)-acetoxypropionyl] derivative (X),since the acetolysis of the sulfonate (XII) takes place with inversion of the configuration.Finally,this compound is hydrolyzed with KOH in methanol.
参考文献标题:Synthesis of trimegestone: The first industrial application of Bakers' yeast mediated reduction of a ketone
文献作者:Prat,D.; Richard,C.; Crocq,V.; Vivat,M.; Masson,C.; Lenay,J.; Winter,J.; Buendia,J.; Lemaitre,G.
参考来源:Org Process Res Dev 1997,1(1),2-13
合成路线:Trimegestone has been obtained by several related ways:1) The reaction of 3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one (I) with KCN and acetic acid in methanol,followed by silylation with TMSCl,gives the silylated cyanohydrin (II),which is treated with ethylmagnesium bromide in THF to yield the 17beta-propionyl derivative (III).Acetylation of the 17alpha-hydroxy group of (III) with Ac2O affords acetate (IV),which is methylated with MeI and lithium amide in liquid ammonia,giving the 17alpha-methyl derivative (V).The oxidation of (V) with t-BuOK and oxygen in DMF yields the 17beta-(2-oxopropionyl) derivative (VI),which is isomerized with acetic acid/ hydrochloric acid or acetic acid/perchloric acid,affording 17alpha-methyl-17beta-(2-oxopropionyl)estra-4,9-dien-3-one (VII).Finally,this compound is regio- and enantioselectively reduced with Saccharomyces cerevisiae in a sodium acetate buffer.2) The reaction of the 17alpha-methyl derivative (V) with t-BuOK and iodine in THF gives the 17beta-(2-iodopropionyl) compound (VIII),which by reaction with KOAc in DMF,followed by treatment with acetic acid/perchloric acid as before,is converted into the 17beta-(2-acetoxypropionyl) derivative (IX).Finally,the acetoxy group of (IX) is hydrolyzed with KOH in methanol and the mixture of (R)- and (S)-diastereomers is separated by HPLC over silicagel.3) The 17beta-(2-acetoxypropionyl) derivative (IX) can also be obtained directly by carefully controlled direct oxidation of the 17alpha-methyl-17beta-propionyl intermediate (V) with dry air in DMF in the presence of t-BuOK and triethyl phosphite.4) The diastereoselective hydrolysis of the 17beta-(2-acetoxypropionyl) intermediate (IX) with lipase PS Amano in n-butanol/pH = 5 buffer gives a mixture of unreacted 17beta-[2(S)-acetoxypropinyl] derivative (X) and 17beta-[2(R)-hydroxypropionyl] derivative (XI).This mixture,without separation,is treated with methanesulfonyl chloride and Et3N in dichloromethane to yield a new mixture of the unreacted 17beta-[2(S)-acetoxypropionyl] derivative (X) and 17beta-[2(R)-(methanesulfonyloxy)propionyl] derivative (XII).The reaction of this mixture with potassium acetate in hot bis(2-methoxyethyl)ether affords pure 17beta-[2(S)-acetoxypropionyl] derivative (X),since the acetolysis of the sulfonate (XII) takes place with inversion of the configuration.Finally,this compound is hydrolyzed with KOH in methanol.
参考文献标题:Trimegestone
文献作者:Leeson,P.A.; Casata馿r,J.; Sorbera,L.A.
参考来源:Drugs Fut 2000,25(5),465
产品链接: CAS No. 74513-62-5››