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药物详细合成路线

Name Brodimoprim;Ro-10-5970;Unitrim;Hyprim
Chemical Name 2,4-Diamino-5-(4-bromo-3,5-dimethoxybenzyl)pyrimidine;5-(4-Bromo-3,5-dimethoxybenzyl)-2,4-pyrimidinediamine
CAS 56518-41-3
Related CAS 56518-40-2 (HCl)
Formula C13H15BrN4O2
Structure
Formula Weight 339.1941
Stage 上市-1993
Company Helsinn (Originator), AstraZeneca (Licensee)
Activity/Mechanism Antibacterial Drugs, ANTIINFECTIVE THERAPY, Dihydrofolate Reductase (DHFR) Inhibitors, Trimethoprim Analogs
Syn. Route 2
Route 1
the reaction of dimethyl 2,6-dimethoxyterphthalate (i) with hydroxylamine by means of polyphosphoric acid at 70 c gives methyl 4-(n-hydroxycarbamoyl)-3,5-dimethoxybenzoate (ii), which by further reaction with ppa is converted into methyl 4-amino-3,5-dimethoxybenzoate (iii). the reaction of (iii) with nano2 and hbr affords the corresponding diazonium salt, which without isolation is treated with cubr yielding methyl-4-bromo-3,5-dimethoxybenzoate (iv). the reduction of (iv) with diisobutylaluminum hydride in thf gives 4-bromo-3,5-dimethoxybenzaldehyde (v), which is condensed with 3-methoxypropionitrile (vi) by means of sodium methoxide in refluxing methanol to yield 4-bromo-3,5-dimethoxy-alpha-(methoxymethyl)cinnamic acid nitrile (vii). finally, this compound is cyclized with guanidine (a) by means of sodium methoxide in hot methanol dmso.2) the hydrolysis of (iv) with koh in ethanol gives 4-bromo-3,5-dimethoxybenzoic acid (viii), which is treated with socl2 in refluxing benzene - dmf to afford 4-bromo-3,5-dimethoxybenzoylchloride (ix). then the reduction of (ix) with h2 over pd/baso4 in xylene yields (v), already obtained.
List of intermediates No.
allyl 4,4-dimethyl-3-oxopentanoate (a)
tert-butyl (2s)-1-[[(2s)-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-yl]carbonyl]-2-pyrrolidinecarboxylate (i)
tert-butyl (2s)-1-[[(2r)-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-yl]carbonyl]-2-pyrrolidinecarboxylate (ii)
(2r)-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-carboxylic acid (iii)
(2r)-n-methyl-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-carbothioamide (iv)
methyl (2r)-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-carbodithioate (v)
methyl (2r)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate (vi)
methyl (2r)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate (vii)
3-([[amino(imino)methyl]sulfanyl]methyl)pyridine (viii)
4-chlorobutyl 3-pyridinylmethyl sulfide; 3-[[(4-chlorobutyl)sulfanyl]methyl]pyridine (ix)
Reference 1:
    kompis, i. (f. hoffmann-la roche ag); benzylpyirimidine derivates. ca 1017743; de 2452889; fr 2250533; gb 1449387; jp 50077378; nl 7414528 .
Reference 2:
    sweetman, a.j.; serradell, m.n.; castaner, j.; blancafort, p.; brodimoprim. drugs fut 1982, 7, 2, 93.
Reference 3:
    kompis, i.; wick, a.; synthesis of 4-halo-substituted analogs of trimethropin. helv chim acta 1977, 60, 8, 3025-34.

Route 2
the reaction of (v) with 3-morpholinopropionitrile (x) by means of sodium methoxide in methanol - dmso gives 4-bromo-3,5-dimethoxy-alpha-(morpholinomethyliden)hydrocinnamic acid nitrile (xi), which by reaction with aniline (b) and hcl in refluxing isopropanol is converted into 4-bromo-3,5-dimethoxy-alpha-(anilinomethyliden)hydrocinnamic acid nitrile (xii). finally, this compound is condensed with guanidine (a) as before.
List of intermediates No.
1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (b)
allyl 4,4-dimethyl-3-oxopentanoate (a)
methyl (2r)-2-(3-pyridinyl)tetrahydro-2h-thiopyran-2-carbodithioate (v)
3-[[(4-chlorobutyl)sulfinyl]methyl]pyridine; 4-chlorobutyl 3-pyridinylmethyl sulfoxide (x)
(2r)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2h)-one (xi)
(2r)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2h)-one (xii)
Reference 1:
    sweetman, a.j.; serradell, m.n.; castaner, j.; blancafort, p.; brodimoprim. drugs fut 1982, 7, 2, 93.
Reference 2:
    kompis, i.; wick, a.; synthesis of 4-halo-substituted analogs of trimethropin. helv chim acta 1977, 60, 8, 3025-34.

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溴莫普林;英文名Brodimoprim;Ro-10-5970;Unitrim;Hyprim;CAS[56518-41-3]

 
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