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药物详细合成路线

Name Doramapimod;BIBR-796;BIRB-796 BS;BIRB-0796;BIRB-796
Chemical Name N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N-[4-[2-(4-morpholinyl)ethoxy]naphthalen-1-yl]urea
CAS 285983-48-4
Related CAS
Formula C31H37N5O3
Structure
Formula Weight 527.67224
Stage II 期临床
Company Boehringer Ingelheim (Originator)
Activity/Mechanism Antiarthritic Drugs, Antipsoriatics, DERMATOLOGIC DRUGS, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, p38 Protein Kinase Inhibitors, TNF-alpha Production Inhibitors
Syn. Route 3
Route 1
the cyclization of 4-methylphenylhydrazine (i) with pivaloylacetonitrile (ii) in refluxing methanol gives the aminopyrazole (iii), which is treated with troc-cl and naoh in water/ethyl acetate to yield the carbamate (iv). finally, this compound is condensed with 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (v) by means of diea in hot dmso to afford the target urea.the intermediate 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (v) is obtained by condensation of 2-(4-morpholinyl)ethanol (vi) with 4-nitro-1-naphthol (vii) by means of naoh and k2co3 in hot 1-methyl-2-pyrrolidone to yield the corresponding ether (viii), which is finally reduced with h2 over pd/c in methanol.
List of intermediates No.
isonicotinamide (vi)
6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5h-pyrrolo[3,4-b]pyrazin-5-one (i)
ethyl beta-hydroxyhydrocinnamate (ii)
Reference 1:
    zhang, l.-h.; zhu, l. (boehringer ingelheim pharmaceuticals inc.); novel process for synthesis of heteroaryl-substd. urea cpds.. wo 0104115 .

Route 2
the n-protection of 4-amino-1-naphthol (i) with boc2o by means of buli in thf gives the carbamate (ii), which is condensed with 4-(2-chloroethyl)morpholine (iii) by means of k2co3 in hot acetonitrile, yielding the corresponding aryl ether (iv). the deprotection of the amino group of (iv) with hcl in dioxane affords the naphthylamine (v), which is finally condensed with 3-(tert-butyl)-1-(4-methylphenyl)-1h-pyrazole-5-amine (vi) by means of cocl2 in toluene/dichloromethane and aq. nahco3 to provide the target urea.the intermediate 3-(tert-butyl)-1-(4-methylphenyl)-1h-pyrazole-5-amine (vi) is obtained by cyclization of 4-methylphenylhydrazine (vii) with 4,4-dimethyl-3-oxopentanenitrile (viii) by means of hcl in refluxing ethanol.
List of intermediates No.
6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5h-pyrrolo[3,4-b]pyrazin-5-one (vii)
ethyl 2-(4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy)-2-methylpropanoate (iii)
ethyl beta-hydroxyhydrocinnamate (viii)
Reference 1:
    regan, j.r.; zhang, l.-h.; cirillo, p.f.; hickey, e.r.; gilmore, t.a. (boehringer ingelheim pharmaceuticals inc.); aromatic heterocyclic cpds. as antiinflammatory agents. ep 1147104; us 6319921; wo 0043384 .

Route 3
the reaction of 4-amino-1-naphthol (i) with boc2o in thf gives the carbamate (ii), which is condensed with 4-(2-chloroethyl)morpholine (iii) by means of k2co3 in hot acetonitrile to yield ether (iv). the hydrolysis of the carbamate group of (iv) by means of hcl in dioxane affords the naphthylamine (v), which is finally condensed with 3-tert-butyl-1-(4-methylphenyl)-1h-pyrazol-5-amine (vi) and phosgene (vii) in thf to provide the target urea. the intermediates 3-tert-butyl-1-(4-methylphenyl)-1h-pyrazol-5-amine (vi) and phosgene (vii) are obtained by cyclization of 4-methylphenylhydrazine (viii) with 4,4-dimethyl-3-oxopentanenitrile (ix) in refluxing toluene or by means of hcl in refluxing ethanol.
List of intermediates No.
6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5h-pyrrolo[3,4-b]pyrazin-5-one (viii)
ethyl 2-(4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy)-2-methylpropanoate (iii)
ethyl beta-hydroxyhydrocinnamate (ix)
Reference 1:
    regan, j.; et al.; pyrazole urea-based inhibtitors of p38 map kinase: from lead compound to clinical candidate. j med chem 2002, 45, 14, 2994.

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1-[2-(4-甲基苯基)-5-叔丁基吡唑-3-基]-3-[4-(2-吗啉-4-基乙氧基)萘-1-基;英文名Doramapimod;BIBR-796;BIRB-796 BS;BIRB-0796;BIRB-796;CAS[285983-48-4]

 
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