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Name Febuxostat;TMX-67;TEI-6720
Chemical Name 2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid
CAS 144060-53-7
Related CAS
Formula C16H16N2O3S
Structure
Formula Weight 316.38152
Stage 上市-2009
Company Teijin (Originator), Ipsen (Licensee), TAP (Licensee)
Activity/Mechanism METABOLIC DRUGS, Treatment of Disorders of Purine and Pyrimidine Metabolism, Treatment of Gout, Uricosurics, Xanthine Oxidase Inhibitors
Syn. Route 3
Route 1
reaction of 4-hydroxy-3-nitrobenzaldehyde (i) with hydroxylamine and sodium formate in refluxing formic acid gives 4-hydroxy-3-nitrobenzonitrile (ii), which is treated with thioacetamide in hot dmf to yield the corresponding thiobenzamide (iii). the cyclization of (iii) with 2-chloroacetoacetic acid ethyl ester (iv) in refluxing ethanol affords 2-(4-hydroxy-3-nitrophenyl)-5-methylthiazole-4-carboxylic acid ethyl ester (v), which is alkylated at the phenolic group by means of isobutyl bromide (vi) and k2co3 in hot dmf, providing the isobutyl ether (vii). the reduction of the no2 group of (vii) with h2 over pd/c in ethanol/ethyl acetate gives the expected amino derivative (viii), which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (ix) by diazotation with nano2/hcl and treatment with cucn and kcn. finally, this compound is hydrolyzed with naoh in hot thf.
List of intermediates No.
methyl 1-(2-iodoethyl)-2-(2-methoxy-2-oxoethyl)-1h-pyrrole-3-carboxylate (i)
(8s)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-[(5,6,7-trimethoxy-1h-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylic acid (iv)
n-[(1s,2r)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide (vi)
11-bromoundecanoic acid (ii)
ethyl 11-[3-imino-5,6-dihydrobenzo[h]cinnolin-2(3h)-yl]undecanoate (iii)
11-[3-imino-5,6-dihydrobenzo[h]cinnolin-2(3h)-yl]undecanoic acid (v)
(3s)-3-[((2s)-4-amino-2-{[(2s)-2-(decanoylamino)-3-(1h-indol-3-yl)propanoyl]amino}-4-oxobutanoyl)amino]-4-{[(3s,6s,9r,15s,18r,21s,24s,30s,31s)-3-[2-(2-aminophenyl)-2-oxoethyl]-24-(3-aminopropyl)-15,21-bis(carboxymethyl)-6-[(1r)-2-carboxy-1-methylethyl]-9-(hydroxymethyl)-18,31-dimethyl-2,5,8,11,14,17,20,23,26,29-decaoxo-1-oxa-4,7,10,13,16,19,22,25,28-nonaazacyclohentriacontan-30-yl]amino}-4-oxobutanoic acid (vii)
4-nitrophenyl 2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)propanoate (viii)
2,3,4,5,6-pentafluorophenyl 2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)propanoate (ix)
Reference 1:
    sorbera, l.a.; castaner, j.; rabasseda, x.; revel, l.; tmx-67. drugs fut 2001, 26, 1, 32.
Reference 2:
    kondo, s.; fukushima, h.; hasegawa, m.; tsuchimoto, m.; nagata, i.; osada, y.; komoriya, k.; yamaguchi, h. (teijin ltd.); 2-arylthiazole deriv. and pharmaceutical compsn. containing the same. ep 0513379; jp 1993500083; us 5614520; wo 9209279 .

Route 2
the reaction of 4-nitrobenzonitrile (x) with kcn in hot dmso, followed by treatment with isobutyl bromide (vi) and k2co3, gives 4-isobutoxybenzene-1,3-dicarbonitrile (xi), which is treated with thioacetamide in hot dmf to yield 3-cyano-4-isobutoxythiobenzamide (xii). cyclization of (xii) with 2-chloroacetoacetic acid ethyl ester (iv) in refluxing ethanol affords 2-(3-cyano-4-isoutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (ix), which is hydrolyzed with naoh in hot thf/water.
List of intermediates No.
(8s)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-[(5,6,7-trimethoxy-1h-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylic acid (iv)
n-[(1s,2r)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide (vi)
2,3,4,5,6-pentafluorophenyl 2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)propanoate (ix)
(x)
(8r,9s,13s,14s,17r)-17-ethynyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-diol (xi)
(8r,9s,13s,14s,17r)-17-ethynyl-13-methyl-3-[(triethylsilyl)oxy]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-17-ol (xii)
Reference 1:
    sorbera, l.a.; castaner, j.; rabasseda, x.; revel, l.; tmx-67. drugs fut 2001, 26, 1, 32.
Reference 2:
    hasegawa, m.; a facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. heterocycles 1998, 47, 2, 857.
Reference 3:
    hasegawa, m.; komoriya, k. (teijin ltd.); cyano cpds. and their preparation method. jp 1994345724 .

Route 3
cyclization of 4-hydroxythiobenzamide (xiii) with 2-bromoacetoacetic acid ethyl ester (xiv) in refluxing ethanol provides 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (xv), which is formylated by reaction with hexamethylenetetramine (hmta) and polyphosphoric acid (ppa) in hot hoac/water to afford 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (xvi). alkylation af (xvi) with isobutyl bromide (vi), k2co3 and ki in dmf gives 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (xvii), which is treated with formic acid, sodium formate and hydroxylamine hydrochloride to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-catboxylic acid ethyl ester (ix). finally, this compound is hydrolyzed with naoh in thf/etoh.alternatively, 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (xvi) can also be treated first with formic acid, sodium formate and hydroxylamine hydrochloride to provide 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (xviii), which is then alkylated with isobutyl bromide (vi), k2co3 and ki in dmf to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (ix).
List of intermediates No.
n-[(1s,2r)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide (vi)
2,3,4,5,6-pentafluorophenyl 2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)propanoate (ix)
3-{(8r,9s,13s,14s,17s)-17-hydroxy-13-methyl-3-[(triethylsilyl)oxy]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-17-yl}-2-propynoic acid (xiii)
5-cyclodecene-3,7-diyn-1-ylmethanol (xiv)
5-cyclodecene-3,7-diyn-1-ylmethyl 3-{(8r,9s,13s,14s,17s)-17-hydroxy-13-methyl-3-[(triethylsilyl)oxy]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-17-yl}-2-propynoate (xv)
(xvi)
(3r,4s,5s,6r)-6-[(acetyloxy)methyl]-3,4,5-tris(benzyloxy)tetrahydro-2h-pyran-2-yl acetate (xvii)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-6-[(benzyloxy)methyl]-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-5-hydroxytetrahydro-2h-pyran-4-yl acetate (xviii)
Reference 1:
    sorbera, l.a.; castaner, j.; rabasseda, x.; revel, l.; tmx-67. drugs fut 2001, 26, 1, 32.
Reference 2:
    miller, b. (american cyanamid co.); thiazolylphenyl phosphates. us 3518279 .
Reference 3:
    watanabe, k.; fujii, t.; tanaka, t.; kondo, s. (teijin ltd.); preparation method of 2-(4-alkoxy-3-cyanophenyl)thiazol derivs., and novel intermediates for the synthesis of them. jp 1994329647 .
Reference 4:
    watanabe, k.; yarino, t.; hiramatsu, t. (teijin ltd.); preparation method of 2-(4-alkoxy-3-cyanophenyl)thiazole derivs.. jp 1998045733 .

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名非布索坦;英文名Febuxostat;TMX-67;TEI-6720;CAS[144060-53-7]

 
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