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药物详细合成路线

Name Tenofovir;GS-1278;PMPA-(R);(R)-PMPA
Chemical Name (R)-9-[2-(Phosphonomethoxy)propyl]adenine
      (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid
CAS 147127-20-6
Related CAS 147127-19-3 ((S)-isomer), 206184-49-8 (monohydrate)
Formula C9H14N5O4P
Structure
Formula Weight 287.21683
Stage 上市
Company Gilead (Originator), Nat. Inst. Allergy & Infectious Dis. (Codevelopment)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors
Syn. Route 3
Route 1
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.
List of intermediates No.
1-iodo-4-nitrobenzene (v)
dimethyl 3-(3,5-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-oxo-3-cyclopentene-1,1-dicarboxylate (i)
dimethyl 2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate (ii)
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol (iii)
8-[(7s)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid (iv)
4-(formylamino)-1-methyl-1h-pyrrole-2-carboxylic acid (vi)
n-(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)-4-(formylamino)-1-methyl-1h-pyrrole-2-carboxamide (vii)
n-(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)-4-[[(4-amino-1-methyl-1h-pyrrol-2-yl)carbonyl]amino]-1-methyl-1h-pyrrole-2-carboxamide (viii)
2,2,2-trichloroethyl (11s,11as)-8-[3-[(5-[[(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)oxy]-3-o (ix)
2-amino-5-bromobenzoic acid (x)
Reference 1:
    masojídková, m.; holy, a.; synthesis of enantiomeric n-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. i. the stepwise approach. coll czech chem commun 1995, 60, 7, 1196.
Reference 2:
    sorbera, l.a.; casta?er, j.; (r)-pmpa and bis(poc)pmpa. drugs fut 1998, 23, 12, 1279.
Reference 3:
    holy, a.; dvorakova, h.; declercq, e.d.a.; balzarini, j.m.r. (gilead sciences inc.; stichting rega vzw); antiretroviral enantiomeric nucleotide analogs. ep 0654037; jp 1996503927; us 6057305; wo 9403467 .

Route 2
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.
List of intermediates No.
1-iodo-4-nitrobenzene (v)
2,6-dichloro-3-cyano-1,4-quinoxalinediiumdiolate (xi)
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol (iii)
2,2,2-trichloroethyl (11s,11as)-8-[3-[(5-[[(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)oxy]-3-o (ix)
2-amino-5-bromobenzoic acid (x)
methyl 2-[6-bromo-4-oxo-2-phenethyl-3(4h)-quinazolinyl]acetate (xii)
2-[6-bromo-4-oxo-2-phenethyl-3(4h)-quinazolinyl]acetic acid (xiii)
tert-butyl 6-aminohexylcarbamate (xiv)
tert-butyl 6-([2-[6-bromo-4-oxo-2-phenethyl-3(4h)-quinazolinyl]acetyl]amino)hexylcarbamate (xv)
Reference 1:
    masojídková, m.; holy, a.; synthesis of enantiomeric n-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. i. the stepwise approach. coll czech chem commun 1995, 60, 7, 1196.
Reference 2:
    sorbera, l.a.; casta?er, j.; (r)-pmpa and bis(poc)pmpa. drugs fut 1998, 23, 12, 1279.

Route 3
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.
List of intermediates No.
1-iodo-4-nitrobenzene (v)
6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1h-1-benzothiophen-1-one (xx)
4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2h-1,4-benzothiazine-7-carboxylic acid (xxii)
tert-butyl (1r,2r,4s)-2-(6-methoxy-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (xviii)
n-(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)amino]carbonyl]-1-methyl-1h-pyrrol-3-yl)-4-(formylamino)-1-methyl-1h-pyrrole-2-carboxamide (vii)
tert-butyl 6-([2-[4-oxo-2-phenethyl-6-phenyl-3(4h)-quinazolinyl]acetyl]amino)hexylcarbamate (xvi)
5-methylindoline (xvii)
9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (xix)
3-amino-9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (xxi)
1-methyl-1,3-dihydro-2h-indol-2-one (xxiii)
Reference 1:
    leone-bay, a.; et al.; 4-(4-salicyloylaminophenyl)butyric acid as a novel oral delivery agent for recombinant human growth hormone. 211th acs natl meet (march 24-28, new orleans) 1996, abst medi 006.
Reference 2:
    schultze, l.m.; chapman, h.h.; dubree, n.j.p.; et al.; practical synthesis of the anti-hiv drug, pmpa. tetrahedron lett 1998, 39, 14, 1853.
Reference 3:
    sorbera, l.a.; casta?er, j.; (r)-pmpa and bis(poc)pmpa. drugs fut 1998, 23, 12, 1279.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名泰诺福韦;英文名Tenofovir;GS-1278;PMPA-(R);(R)-PMPA;CAS[147127-20-6]

 
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