合成路线:The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III),which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.
参考文献标题:Synthesis,in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs
文献作者:Oliyai,R.; Dougherty,J.; Bischofberger,N.; Kim,C.U.; Mulato,A.; Shaw,J.P.; Cundy,K.C.; Arimilli,M.N.
参考来源:Antivir Chem Chemother 1997,8(6),557
合成路线:1) The protection of isobutyl D-(+)-lactate (I) with dihydropyran (DHP)/HCl in DMF gives the tetrahydropyranyloxy derivative (II),which is reduced with bis(2-methoxyethoxy)aluminum hydride in refluxing ether/ toluene yielding 2(R)-(tetrahydropyranyloxy)-1-propanol (III).The tosylation of (III) with tosyl chloride as usual affords the expected tosylate (VI),which is condensed with adenine (V) by means of Cs2CO3 in hot DMF,affording 9-[2(R)-(tetrahydropyranyloxy)propyl]adenine (VI).The deprotection of (VI) with sulfuric acid affords 9-[2(R)-hydroxypropyl]adenine (VII),which is N-benzoylated with benzoyl chloride/chlorotrimethylsilane in pyridine to give the benzamide (VIII),which is condensed with tosyl-oxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in DMF to yield 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X).Finally,this compound is hydrolyzed by means of bromotrimethylsilane in acetonotrile.
合成路线:2) The reaction of the previously described (R)-2-(2-tetrahydropyranyloxy)-1-propanol (III) with benzyl bromide (XI) by means of NaH in DMF,followed by a treatment with Dowex 50X,gives 1-benzyloxy-2(R)-propanol (XII),which is condensed with tosyloxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in THF,yielding 2-benzyloxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIII).The hydrogenolysis of (XIII) over Pd/C in methanol affords 2-hydroxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIV),which is tosylated with tosyl chloride/dimethyl-aminopyridine in pyridine to give the expected tosylate (XV).The condensation of (XV) with adenine (VI) by means of Cs2CO3 in hot DMF yields 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X),which is finally hydrolyzed as before.
合成路线:3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII),which is esterified with diethyl carbonate (XVIII)/NaOEt,yielding the cyclic carbonate (XIX).The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII),which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF,giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI).Finally,this compound is hydrolyzed with bromotrimethylsilane as before.Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde,yielding hydroxy- methylphosphonic acid diethyl ester (XXIII),which is finally tosylated as usual.
合成路线:The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III),which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.
参考文献标题:(R)-PMPA and Bis(POC)PMPA
文献作者:Sorbera,L.A.; Castar,J.
参考来源:Drugs Fut 1998,23(12),1279
产品链接: CAS No. 202138-50-9›› 产品链接: CAS No.201341-05-1››