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Name Befloxatone;MD-370503
Chemical Name 5(R)-(Methoxymethyl)-3-[4-[4,4,4-trifluoro-3(R)-hydroxybutoxy]phenyl]oxazolidin-2-one
CAS 134564-82-2
Related CAS
Formula C15H18F3NO5
Structure
Formula Weight 349.30961
Stage II 期临床
Company Sanofi-synthélabo (Originator)
Activity/Mechanism Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Smoking Cessation, Aid to, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, MAO-A Inhibitors
Syn. Route 3
Route 1
befloxatone is obtained by condensation of 1,1,1-trifluoro-4-(tosyloxy)-2(r)-butanol (i) with 3-(4-hydroxyphenyl)-5(r)-(methoxymethyl)oxazolidin-2-one (ii) by means of k2co3 in hot dmf.
List of intermediates No.
n-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4-(trifluoromethyl)[1,1-biphenyl]-2-carboxamide (i)
2-[[(methylsulfonyl)oxy]methyl]-5-([[4-(trifluoromethyl)[1,1-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate (ii)
Reference 1:
    castaner, j.; sorbera, l.a.; rabasseda, x.; befloxatone. drugs fut 1999, 24, 10, 1057.
Reference 2:
    koenig, j.-j.; schoofs, a.; jarreau, f.-x.; rovei, v. (laboratoires delalande); 3-aryl oxazolidinones, process for their preparation and their therapeutical use. ep 0424243; ep 0424244; ep 0428421; jp 1992502333; jp 1992502334; jp 1992502335; us 5036090; us 5036091; us 5171747; us 5196543; wo 9105775 .
Reference 3:
    jarreau, f.-x.; koenig, j.-j.; rovei, v. (laboratoires delalande); 3-aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. ep 0511031; fr 2675504; jp 1993112542; us 5264443 .

Route 2
1) synthesis of butanol (i):1a) the reduction of 4,4,4-trifluoro-2-oxobutyric acid ethyl ester (iii) with nabh4 in dichloromethane gives 4,4,4-trifluoro-2-hydroxybutyric acid ethyl ester (iv), which is hydrolyzed with naoh in ethanol, yielding the corresponding acid (v). the optical resolution of (v) with 1(s)-phenylethylamine in hot ethanol affords the 3(r)-hydroxy enantiomer (vi) (1,3), which is reduced with nabh4 and bf3 ethearate in thf to provide 4,4,4-trifluorobutane-1,3(r)-diol (vii). finally, this compound is monotosylated by means of tosyl chloride and dmap in pyridine to afford intermediate (i).1b) the digestion of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester (iv) with novozym in a phosphate buffer gives the corresponding (r)-enantiomer (viii), which is reduced with nabh4 in ethanol, yielding 4,4,4-trifluorobutane-1,3(r)-diol (vii) (4). finally, this compound is monotosylated by means of tosyl chloride as before to give butanol (i).
List of intermediates No.
(2s,3s,4s,5r,6s)-4-azido-5-[((2s,3r,4r,5s,6r)-4,5-dihydroxy-6-(hydroxymethyl)-3-[[3-(trifluoromethyl)benzoyl]amino]tetrahydro-2h-pyran-2-yl)oxy]-3-methoxy-6-(phenylsulfanyl)tetrahydro-2h-pyran-2-carboxamide (iii)
n-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4-(trifluoromethyl)[1,1-biphenyl]-2-carboxamide (i)
n-(2-aminoethyl)acetamide (iv)
n-[2-[2-(acetamido)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinyl]-4-(trifluoromethyl)[1,1-biphenyl]-2-carboxamide (v)
n-[2-(2-aminoethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-4-(trifluoromethyl)[1,1-biphenyl]-2-carboxamide (vi)
4-bromophenethylamine; 2-(4-bromophenyl)-1-ethanamine (vii)
4-bromophenethylformamide (viii)
Reference 1:
    castaner, j.; sorbera, l.a.; rabasseda, x.; befloxatone. drugs fut 1999, 24, 10, 1057.
Reference 2:
    koenig, j.-j.; schoofs, a.; jarreau, f.-x.; rovei, v. (laboratoires delalande); 3-aryl oxazolidinones, process for their preparation and their therapeutical use. ep 0424243; ep 0424244; ep 0428421; jp 1992502333; jp 1992502334; jp 1992502335; us 5036090; us 5036091; us 5171747; us 5196543; wo 9105775 .
Reference 3:
    jarreau, f.-x.; koenig, j.-j.; rovei, v. (laboratoires delalande); 3-aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. ep 0511031; fr 2675504; jp 1993112542; us 5264443 .

Route 3
2) synthesis of oxazolidinone (ii):2a) the reaction of 4-benzyloxyaniline (ix) with 1,4-dioxaspiro[4.5]decan-2(s)-ylmethyl methanesulfonate (x) by means of tea at 140 c gives 3-(4-benzyloxyphenylamino)propane-1,2(r)-diol (xi), which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene, yielding 3-(4-benzyloxyphenyl)-5(r)-(hydroxymethyl)oxazolidin-2-one (xii). the methylation of (xii) with dimethyl sulfate, naoh and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (xiii). finally, this compound is debenzylated by hydrogenation with h2 over pd/c in ethanol/dichloromethane to give oxazolidinone (ii).2b) the methylation of 4(s)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (xiv) with dimethyl sulfate and naoh gives 4(s)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (xv), which is hydrolyzed with hot aqueous hcl to 3-methoxypropane-1,2(r)-diol (xvi). the cyclization of (xvi) with diethyl carbonate by means of nah affords 4(s)-(methoxymethyl)-1,3-dioxolan-2-one (xvii) (2, 5). the condensation of (xvii) with n-(4-benzyloxyphenyl)carbamic acid methyl ester (xviii) (obtained by reaction of 4-benzyloxyaniline (ix) with methyl chloroformate) by means of k2co3 at 160 c provides the protected oxazolidinone (xiii), which is finally debenzylated as before to give oxazolidinone (ii).
List of intermediates No.
diethyl n-(4-aminobenzoyl)glutamate; diethyl 2-[(4-aminobenzoyl)amino]pentanedioate (xiv)
6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine; 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine (ix)
2-[[(methylsulfonyl)oxy]methyl]-5-([[4-(trifluoromethyl)[1,1-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate (ii)
7-bromo-3,4-dihydroisoquinoline (x)
7-bromo-1,2,3,4-tetrahydroisoquinoline (xi)
7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline (xiii)
tert-butyl 7-bromo-6-nitro-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xv)
tert-butyl 6-amino-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xvi)
tert-butyl 6-([[4-(trifluoromethyl)[1,1-biphenyl]-2-yl]carbonyl]amino)-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xvii)
n-(1,2,3,4-tetrahydro-6-isoquinolinyl)-4-(trifluoromethyl)[1,1-biphenyl]-2-carboxamide (xviii)
1h-imidazole-2-carbaldehyde (xii)
Reference 1:
    castaner, j.; sorbera, l.a.; rabasseda, x.; befloxatone. drugs fut 1999, 24, 10, 1057.
Reference 2:
    koenig, j.-j.; schoofs, a.; jarreau, f.-x.; rovei, v. (laboratoires delalande); 3-aryl oxazolidinones, process for their preparation and their therapeutical use. ep 0424243; ep 0424244; ep 0428421; jp 1992502333; jp 1992502334; jp 1992502335; us 5036090; us 5036091; us 5171747; us 5196543; wo 9105775 .
Reference 3:
    jarreau, f.-x.; koenig, j.-j.; rovei, v. (laboratoires delalande); 3-aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. ep 0511031; fr 2675504; jp 1993112542; us 5264443 .

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贝氟沙通;英文名Befloxatone;MD-370503;CAS[134564-82-2]

 
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