合成路线:1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III),which by reaction with aqueous HCl in hot ethanol yields monoamine (IV).The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V).The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid,and elimination of the acid with ion exchange resin Amberlite IA-400,by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII).The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX),which is finally treated with cyclopropylamine (X) in refluxing n-butanol.2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII),which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII).Finally,the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
合成路线:3) The condensation of (?-cis-4-acetamido-2-cyclopentenylmethyl acetate (XIV) with 2-amino-4,6-dichloropyrimidine (XV) by means of Ba(OH)2 and triethylamine in refluxing butanol gives the expected condensation product (XVI),which is treated with 4-chlorophenyldiazonium chloride (XVII) in water/acetic acid to yield the corresponding azo-compound (XVIII).The reduction of (XVIII) with Zn/acetic acid in ethanol affords the diamine (XIX),which is cyclized with refluxing diethoxymethyl acetate (XX) to afford the corresponding purine (XXI).The reaction of (XXI) with cyclopropylamine (X) in refluxing ethanol affords racemic abacavir (XXII),which is phosphorylated with POCl3 giving the racemic 4'-O-phosphate (XXIII).Finally,this compound is submitted to stereoselective enzymatic dephosphorylation using snake venom 5'-nucleotidase (EC 3.1.3.5) from Crotalus atrox yielding the (-)-enantiomer,abacavir.
参考文献标题:Therapeutic nucleosides
文献作者:Daluge,S.M.(Glaxo Wellcome plc)
参考来源:EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292
合成路线:1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III),which by reaction with aqueous HCl in hot ethanol yields monoamine (IV).The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V).The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid,and elimination of the acid with ion exchange resin Amberlite IA-400,by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII).The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX),which is finally treated with cyclopropylamine (X) in refluxing n-butanol.2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII),which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII).Finally,the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
参考文献标题:Chloropyrimide intermediates
文献作者:Daluge,S.M.; Martin,M.T.; Fugett,M.J.F.
参考来源:WO 9521161
合成路线:4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI),which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII),using dibutylboron triflate as catalyst,affording the aldol (XXVIII).The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX),which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX).The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI),(XXXII) and (XXXIII),respectively,each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO,affords the purine intermediate (IX) already reported.
参考文献标题:An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89,a potent inhibitor of HIV reverse transcriptase
文献作者:Crimmins,M.T.; King,B.W.
参考来源:J Org Chem 1996,61(13),4192-3
合成路线:The cyclization of glyoxylic acid (I) with cyclopentadiene (II) gives the racemic hydroxylactone (III),which is acylated with Ac2O to yield acetoxy compound (rac)-(IV).The enzymatic optical resolution of (rac)-(IV) by means of Pseudomonas fluorescens affords the chiral hydroxylactone (-)-(V),which is reduced with LiAlH4 in refluxing THF to provide the lactol (VI).The oxidation of (VI) with NaIO4 in ethyl ether/water gives the chiral carbaldehyde (VII),which is reduced with NaBH4 in ethanol to afford the diol (VIII).The reaction of (VIII) with triphosgene by means of TEA in dichloromethane affords the cyclic carbonate (IX),which is condensed with chloropurine (X) by means of Pd(PPh3)4 in DMSO/THF to provide the adduct (XI).Finally,this compound is hydrolyzed with NaOH to afford the target (-)-carbovir.
合成路线:5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII),which is acetylated with acetic anhydride to the acetate (XXXVIII).The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX),which is reduced with LiAlH4 in refluxing THF,affording triol (XL).The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI),which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX).This compound,by reaction with triphosgene and triethylamine in dichloromethane,results in the cyclic carbonate intermediate (XXXII),already reported.
参考文献标题:Practical enantiodivergent syntheses of both enantiomers of carbovir,1592U89 and six-membered ring analogues
文献作者:Yu,J.; Olivo,H.F.
参考来源:J Chem Soc - Perkins Trans I 1998,3(3),391-2
合成路线:1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III),which by reaction with aqueous HCl in hot ethanol yields monoamine (IV).The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V).The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid,and elimination of the acid with ion exchange resin Amberlite IA-400,by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII).The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX),which is finally treated with cyclopropylamine (X) in refluxing n-butanol.2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII),which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII).Finally,the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
合成路线:3) The condensation of (?-cis-4-acetamido-2-cyclopentenylmethyl acetate (XIV) with 2-amino-4,6-dichloropyrimidine (XV) by means of Ba(OH)2 and triethylamine in refluxing butanol gives the expected condensation product (XVI),which is treated with 4-chlorophenyldiazonium chloride (XVII) in water/acetic acid to yield the corresponding azo-compound (XVIII).The reduction of (XVIII) with Zn/acetic acid in ethanol affords the diamine (XIX),which is cyclized with refluxing diethoxymethyl acetate (XX) to afford the corresponding purine (XXI).The reaction of (XXI) with cyclopropylamine (X) in refluxing ethanol affords racemic abacavir (XXII),which is phosphorylated with POCl3 giving the racemic 4'-O-phosphate (XXIII).Finally,this compound is submitted to stereoselective enzymatic dephosphorylation using snake venom 5'-nucleotidase (EC 3.1.3.5) from Crotalus atrox yielding the (-)-enantiomer,abacavir.
合成路线:4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI),which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII),using dibutylboron triflate as catalyst,affording the aldol (XXVIII).The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX),which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX).The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI),(XXXII) and (XXXIII),respectively,each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO,affords the purine intermediate (IX) already reported.
合成路线:5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII),which is acetylated with acetic anhydride to the acetate (XXXVIII).The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX),which is reduced with LiAlH4 in refluxing THF,affording triol (XL).The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI),which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX).This compound,by reaction with triphosgene and triethylamine in dichloromethane,results in the cyclic carbonate intermediate (XXXII),already reported.
参考文献标题:Abacavir Sulfate
文献作者:Graul,A.; Casta馿r,J.; Leeson,P.A.
参考来源:Drugs Fut 1998,23(11),1155-1167
合成路线:A new solid phase synthesis of abacavir has been reported:Condensation of the chiral 4(R)-benzyl-3-(4-pentenoyl)oxazolidin-2-thione (I) with acrolein (II) by means of TiCl4 and DIEA gives the adduct (III),which was transformed into the chiral cyclopentene (IV) by catalytic ring-closing metathesis.The reductive removal of the chiral auxiliary with LiBH4 affords the chiral diol (V),which is selectively silylated with TBDMSCl providing the primary silyl ether (VI).Acylation of the secondary alcohol of (VI) with benzoic anhydride gives the benzoate (VII),which is desilylated with HF in acetonitrile yielding the allylic benzoate (VIII).Benzoate (VIII) is condensed with a p-nitrophenyl Wang carbonate resin (IX) by means of DIEA and DMAP affording the solid phase resin (X) which is condensed with 2-amino-6-chloropurine (XI) by means of a Pd catalyst furnishing the adduct (XII).Thermal condensation of (XII) with cyclopropylamine (XIII) yields the diaminopurine resin (XIV) which,after cleavage from the resin by a treatment with TFA in dichloromethane,gives directly abacavir.
参考文献标题:Solid-phase synthesis of carbocyclic nucleosides
文献作者:Crimmins,M.T.; Zuercher,W.J.
参考来源:Org Lett 2000,2(8),1065
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