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药物详细合成路线

Name Nabumetone;BRL-14777;Nabuser;Listran;Relafen;Relifen;Arthaxan;Relifex
Chemical Name 4-(6-Methoxy-2-naphthalenyl)-2-butanone
CAS 42924-53-8
Related CAS
Formula C15H16O2
Structure
Formula Weight 228.29357
Stage 上市-1985
Company GlaxoSmithKline (Originator), Procter & Gamble (Not Determined), Meda (Licensee), Uriach (Licensee)
Activity/Mechanism Antiarthritic Drugs, Osteoarthritis, Treatment of, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs
Syn. Route 7
Route 1
the condensation of 6-methoxy-2-naphthaldehyde (i) with ethyl aceto-acetate (ii) gives ethyl 2-(6-methoxy-2-naphthylmethylene)acetoacetate (iii), which is reduced to ethyl 2-(6-methoxy-2-naphthylmethyl)acetoacetate (iv). finally, this compound is hydrolyzed and decarboxylated in acidic medium.
List of intermediates No.
5-[4-hydroxy-2-(3-hydroxypentyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid (ii)
[[(5r,6r)-5-(benzyloxy)-6-methyl-7-octenyl]oxy](triisopropyl)silane; benzyl (1r,2r)-2-methyl-1-[4-[(triisopropylsilyl)oxy]butyl]-3-butenyl ether (i)
(2s,3r)-3-(benzyloxy)-2-methyl-7-[(triisopropylsilyl)oxy]heptanal (iii)
(4s,5r,6r)-6-(benzyloxy)-5-methyl-10-[(triisopropylsilyl)oxy]-1-decen-4-ol (iv)
Reference 1:
    rose, c.j.; miller, d. (smithkline beecham plc); a1 14777 by hydrogenation. ca 1134384 .

Route 2
the condensation of 6-methoxy-2-naphthaldehyde (i) with acetone by means of naoh in water gives 4-(6-methoxy-2-naphtyl)-3-buten-2-one (ii), which is reduced with h2 over pd/c in ethyl acetate.
List of intermediates No.
2-[[([(2s,3s,5r)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(oxo)phosphoranyl]oxy]-1-[(palmitoyloxy)methyl]ethyl palmitate (a)
[[(5r,6r)-5-(benzyloxy)-6-methyl-7-octenyl]oxy](triisopropyl)silane; benzyl (1r,2r)-2-methyl-1-[4-[(triisopropylsilyl)oxy]butyl]-3-butenyl ether (i)
(3r,4s)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone (ii)
Reference 1:
    goudie, a.c. ert al.; 4-(6-methoxy-2-naphtyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds. j med chem 1978, 21, 12, 1260.
Reference 2:
    kyburz, e.; aschwanden, w. (f. hoffmann-la roche ag); 1-(p-methoxy-p-hydroxy, and p-benzyloxybenzoyl)-2-pyrrolidinones. dd 141828; ep 0005143; ep 0044088; es 477587; es 483756; jp 54117468 .
Reference 3:
    neuman, m.; blancafort, p.; castaner, j.; serradell, m.n.; nabumetone. drugs fut 1981, 6, 1, 35.

Route 3
the reduction of methyl 6-methoxy-2-naphtyl acetate (iii) with lialh4 in refluxing ether gives 2-(6-methoxy-2-naphthyl)ethanol (iv), which by treatment with pbr3 in refluxing benzene is converted into 2-(6-methoxy-2-naphthyl)ethyl bromide (v). the reaction of (v) with kcn in refluxing ethanol - water affords 3-(6-methoxy-2-naphthyl)propionitrile (vi), which is finally treated with methylmagnesium iodide in refluxing ethanol.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4,12-bis(acetoxy)-15-[[(2r,3s)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (iii)
(3r,4s)-3-hydroxy-4-phenyl-2-azetidinone (iv)
sodium butyrate (v)
butanoyl chloride (vi)
Reference 1:
    goudie, a.c. ert al.; 4-(6-methoxy-2-naphtyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds. j med chem 1978, 21, 12, 1260.
Reference 2:
    neuman, m.; blancafort, p.; castaner, j.; serradell, m.n.; nabumetone. drugs fut 1981, 6, 1, 35.

Route 4
a short, simple and economical process for large-scale preparation of nabumetone has been reported:condensation of commercially available 2-acetyl-6-methoxynaphthalene (2-acetylnaroline) (i) with ethyl acetate (ii) by means of potassium sec-butoxide (sec-buok) in dmso gives the ketoenol (iii), which is reduced with h2 over pd/c in ethyl acetate with a catalytic amount of sulfuric acid.
List of intermediates No.
(2r,3r,4s,5r,6r)-3-(acetyloxy)-6-[(acetyloxy)methyl]-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-5-{[(2r,3r,4s,5r,6r)-3,4-bis(acetyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]oxy}tetrahydro-2h-pyran-4-yl acetate (i)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-6-[(acetyloxy)methyl]-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-5-[((2s,3r,4r,5r,6r)-3,4-bis(acetyloxy)-5-[(methylsulfonyl)oxy]-6-{[(methylsulfonyl)oxy]methyl}tetrahydro-2h-pyran-2-yl)oxy]tetrahydro-2h-pyran-4-yl acetate (iii)
Reference 1:
    nageshwar, d.; devi, a.s.; reddy, g.o.; sarma, m.r.; reddy, g.b.; vyas, k.; prabhakar, c.; reddy, c.m.; babu, j.m.; process research and structural studies on nabumetone. org process res dev 1999, 3, 2, 121.

Route 5
the bromination of beta-naphthol (i) gives the 1,6-dibromo-beta-naphthol (ii), which is partially debrominated with sn and brh, yielding 1-bromo-beta-naphthol (iii). the methylation of (iii) with methanol/sulfuric acid affords the corresponding methyl ether (iv), which is treated with mg and dmf to provide 6-methoxynaphthalene-2-carbaldehyde (v). the condensation of (v) with ethyl acetoacetate (vi) gives the expected adduct (vii), which is reduced with h2 over pd/c to provide 2-acetyl-3-(6-methoxy-2-naphthyl)propionic acid ethyl ester (viii). finally, this compound is decarboxylated with aqueous hcl.
List of intermediates No.
5-[4-hydroxy-2-(3-hydroxypentyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid (vi)
[[(5r,6r)-5-(benzyloxy)-6-methyl-7-octenyl]oxy](triisopropyl)silane; benzyl (1r,2r)-2-methyl-1-[4-[(triisopropylsilyl)oxy]butyl]-3-butenyl ether (v)
(2s,3r)-3-(benzyloxy)-2-methyl-7-[(triisopropylsilyl)oxy]heptanal (vii)
(4s,5r,6r)-6-(benzyloxy)-5-methyl-10-[(triisopropylsilyl)oxy]-1-decen-4-ol (viii)
methyl (2r)-2-amino-3-(4-nitrophenyl)propanoate (i)
1-amino-1-cyclopropanecarboxylic acid; 1-aminocyclopropane-1-carboxylic acid; 1-aminocyclopropane carboxylic acid; carboxycyclopropylamine (ii)
boc-1-aminocyclopropane-1-carboxylic acid; boc-aminocyclopropanecarboxylic acid; boc-l-alpha-aminocyclopropanecarboxylic acid (iii)
tert-butyl 1-{[(butylsulfonyl)amino]carbonyl}cyclopropylcarbamate (iv)
Reference 1:
    zhang, g.; et al.; a study on the synthesis of a new anti-inflammatory agent - nabumetone. j shenyang coll pharm 1988, 5, 4, 259.

Route 6
the condensation of 2-bromo-6-methoxynaphthalene (i) with 3-buten-2-one (ii) by means of pdcl2, pph3 and k2co3 in dmf at 132 c gives 4-(6-methoxy-2-naphthyl)-3-buten-2-one (iii), which is then hydrogenated with h2 over pd/c in dmf. the same condensation can be performed with pdcl2 , pph3 and nahco3 in 1-methyl-2-pyrrolidone at 130 c.the reaction of 4-hydroxy-2-butanone (iv) with acetic anhydride or acetyl chloride gives 4-acetyl-2-butanone (v), which is condensed with 2-bromo-6-methoxynaphthalene (i) by means of pdcl2, pph3 and k2co3 in dmf at 132 c to yield the previously reported 4-(6-methoxy-2-naphthyl)-3-buten-2-one (iii).
List of intermediates No.
(2s,3e)-3-penten-2-ol (ii)
(3r,4s)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone (iii)
tert-butyl 1-{[(butylsulfonyl)amino]carbonyl}cyclopropylcarbamate (i)
{(1s,2s,3r,6s)-9-[(z)-(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]dec-2-yl}methyl benzoate (iv)
((1s,2s,3r,6s)-9-{(z)-[3-chloro-4-(tributylstannyl)phenyl]methylidene}-7-azatricyclo[4.3.1.0~3,7~]dec-2-yl)methyl benzoate (v)
Reference 1:
    aslam, m.; et al.; convenient synthesis of nabumetone. synthesis 1989, 869.
Reference 2:
    fritch, j.r.; rios, d.e.; smith, j.c.; aslam, m. (celanese ag); use of 4-substd. 2-butanones to prepare nabumetone. wo 9640608 .

Route 7
by condensation of 2-bromo-6-methoxynaphthalene (i) with 3-buten-2-ol (vi) catalyzed by pd(oac)2 or pdcl2, along with pph3 and nahco3 in 1-methyl-2-pyrrolidone at 140 c.the reaction of 2-bromo-6-methoxynaphthalene (i) with mg in thf gives the expected grignard reagent (vii), which is then condensed with 3-buten-2-one (ii) by means of zncl2-amine complex in the same solvent.
List of intermediates No.
(2s,3e)-3-penten-2-ol (ii)
tert-butyl 1-{[(butylsulfonyl)amino]carbonyl}cyclopropylcarbamate (i)
2-(trifluoromethyl)benzylamine; [2-(trifluoromethyl)phenyl]methanamine (vi)
1,4-oxathiane-2,6-dione (vii)
Reference 1:
    aslam, m.; et al.; convenient synthesis of nabumetone. synthesis 1989, 869.
Reference 2:
    wang, s.-m.; chen, z.-x.; novel synthesis of nabumetone. chin j pharm 1989, 20, 4, 146.
Reference 3:
    davenport, k.g.; aslam, m. (celanese ag); method of preparation of nabumetone. ep 0376516 .

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萘丁美酮;英文名Nabumetone;BRL-14777;Nabuser;Listran;Relafen;Relifen;Arthaxan;Relifex;CAS[42924-53-8]

 
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