合成路线:There are two options for the synthesis of lamivudine:In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product.This can be effected by an enzyme-mediated enantiospecific reaction.In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained.The first approach is outlined in Scheme 18435601a.The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid.Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization.Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer,notably as a result of the use of SnCl4.Subsequent deprotection affords the racemic nucleoside (VI) (BCH189).The resolution may be effected by a variety of enzymatic processes.Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII).The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX).Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine.Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E.coli.In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X).Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.
参考文献标题:1,3-Oxathiolane nucleoside analogues
文献作者:Coates,J.A.V.; Mutton,I.M.; Penn,C.R.; Storer,R.; Williamson,C.(BioChem Pharma Inc.)
参考来源:EP 0625150; JP 1993501117; JP 1999080153; JP 2000128787; WO 9117159
合成路线:The second general approach to synthesis of lamivudine does not involve intermediacy of the racemic nucleoside.A variety of routes are available for preparing chiral oxathiolane intermediates which may be coupled to the cytosine base under appropriate conditions where the chirality of the oxathiolane is maintained.Various natural carbohydrate precursors have utility in the synthesis of lamivudine; for example,a synthesis from L-gulose has recently been reported.(+)-Thiolactic acid (XI) has served as a starting material for chiral oxathiolane (XII),which is coupled to silylated cytosine in the presence of TMS-iodide to afford (XIII).Separation of the pure beta-anomer and deprotection affords lamivudine.Alternatively,racemic acid (XV) may be prepared from glyoxylic acid (XIV) and resolution using a suitable chiral base such as norephedrine would afford the chiral acid (XVI),which may be esterified prior to coupling with cytosine to give (XVII) followed by final reduction to lamivudine.
参考文献标题:Synthesis of enantiomerically pure (2'R'5'S)-(-)-1-[2-(hydroxymethyl)oxathiolan-5yl]cytosine as a potential antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV)
文献作者:Kim,H.O.; Chu,C.K.; Beach,J.W.; Schinazi,R.F.; Doong,S.-L.; Alves,A.J.; Pohl,D.; Chang,C.-N.; Jeong,L.S.; Cheng,Y.-C.
参考来源:J Org Chem 1992,57(8),2217-9
合成路线:There are two options for the synthesis of lamivudine:In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product.This can be effected by an enzyme-mediated enantiospecific reaction.In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained.The first approach is outlined in Scheme 18435601a.The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid.Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization.Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer,notably as a result of the use of SnCl4.Subsequent deprotection affords the racemic nucleoside (VI) (BCH189).The resolution may be effected by a variety of enzymatic processes.Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII).The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX).Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine.Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E.coli.In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X).Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.
合成路线:The second general approach to synthesis of lamivudine does not involve intermediacy of the racemic nucleoside.A variety of routes are available for preparing chiral oxathiolane intermediates which may be coupled to the cytosine base under appropriate conditions where the chirality of the oxathiolane is maintained.Various natural carbohydrate precursors have utility in the synthesis of lamivudine; for example,a synthesis from L-gulose has recently been reported.(+)-Thiolactic acid (XI) has served as a starting material for chiral oxathiolane (XII),which is coupled to silylated cytosine in the presence of TMS-iodide to afford (XIII).Separation of the pure beta-anomer and deprotection affords lamivudine.Alternatively,racemic acid (XV) may be prepared from glyoxylic acid (XIV) and resolution using a suitable chiral base such as norephedrine would afford the chiral acid (XVI),which may be esterified prior to coupling with cytosine to give (XVII) followed by final reduction to lamivudine.
参考文献标题:Lamivudine
文献作者:Storer,R.; Wilcox,P.; Daniel,M.; Collis,P.; Cameron,J.M.
参考来源:Drugs Fut 1993,18(4),319
合成路线:There are two options for the synthesis of lamivudine:In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product.This can be effected by an enzyme-mediated enantiospecific reaction.In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained.The first approach is outlined in Scheme 18435601a.The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid.Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization.Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer,notably as a result of the use of SnCl4.Subsequent deprotection affords the racemic nucleoside (VI) (BCH189).The resolution may be effected by a variety of enzymatic processes.Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII).The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX).Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine.Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E.coli.In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X).Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.
参考文献标题:The resolution and absolute stereochemistry of the enantiomers of cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (BCH189): Equipotent anti-HIV agents
文献作者:Storer,R.; Belleau,B.; Noble,S.A.; Lamont,B.; Clemens,I.R.; Williamson,C.
参考来源:Nucleosides Nucleotides 1993,12(2),225
合成路线:The second general approach to synthesis of lamivudine does not involve intermediacy of the racemic nucleoside.A variety of routes are available for preparing chiral oxathiolane intermediates which may be coupled to the cytosine base under appropriate conditions where the chirality of the oxathiolane is maintained.Various natural carbohydrate precursors have utility in the synthesis of lamivudine; for example,a synthesis from L-gulose has recently been reported.(+)-Thiolactic acid (XI) has served as a starting material for chiral oxathiolane (XII),which is coupled to silylated cytosine in the presence of TMS-iodide to afford (XIII).Separation of the pure beta-anomer and deprotection affords lamivudine.Alternatively,racemic acid (XV) may be prepared from glyoxylic acid (XIV) and resolution using a suitable chiral base such as norephedrine would afford the chiral acid (XVI),which may be esterified prior to coupling with cytosine to give (XVII) followed by final reduction to lamivudine.
参考文献标题:Expeditious preparation of (-)-2'-deoxy-3'-thiacytidine (3TC)
文献作者:Jones,M.F.; Siddiqui,A.; Payne,J.J.; Tse,H.L.A.; Humber,D.-C.; Ramsey,M.V.J.; Zacharie,B.; Jin,H.; Evans,C.A.
参考来源:Tetrahedron Lett 1992,33(32),4625-8
合成路线:There are two options for the synthesis of lamivudine:In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product.This can be effected by an enzyme-mediated enantiospecific reaction.In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained.The first approach is outlined in Scheme 18435601a.The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid.Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization.Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer,notably as a result of the use of SnCl4.Subsequent deprotection affords the racemic nucleoside (VI) (BCH189).The resolution may be effected by a variety of enzymatic processes.Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII).The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX).Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine.Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E.coli.In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X).Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.
参考文献标题:In situ complexation directs the stereochemistry of N-glycosylation in the synthesis of oxathiolanyl and dioxolanyl nucleoside analogues
文献作者:Choi,W.-B.; Yeola,S.; Liotta,D.C.; Wilson,L.S.; Schinazi,R.F.
参考来源:J Am Chem Soc 1991,1139377-9
产品链接: CAS No. 134678-17-4›› 产品链接: CAS No.131086-21-0››