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藥物詳細合成路線

Name Ketorolac;RS-37619
Chemical Name (±)-5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid;(±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
CAS 74103-06-3
Related CAS 74103-07-4 (tromethamine salt)
Formula C15H13NO3
Structure
Formula Weight 255.27576
Stage 上市-1991
Company Roche (Originator), Allergan (Licensee), Recordati (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Non-Steroidal Antiinflammatory Drugs
Syn. Route 2
Route 1
the benzoylation of 2-methylthiopyrrole (i) with n,n-dimethylbenzamide (ii) by means of pocl3 in refluxing ch2cl2 gives 5-benzoyl-2-methylthiopyrrole (iii), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (iv) by means of nah in dmf yielding compound (v). the oxidation of (v) with m-chloroperbenzoic acid in ch2cl2 affords the sulfone (vi), which is submitted to methanolysis with methanol and hcl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (vii). the cyclization of (vii) with nah in dmf yields dimethyl 5-benzoyl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (viii), which is finally hydrolyzed and decarboxylated with koh in refluxing methanol.compound (iii) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (ix), which is then condensed with spiro compound (iv) as before to afford compound (vi), already obtained.
List of intermediates No.
4-(4-pyridinyl)heptanedioic acid (iv)
2-pyrazinecarboxylic acid; pyrazinoic acid (i)
tert-butyl (4s)-3-oxopyrazolidinylcarbamate (ii)
diethyl 1-cyanovinylphosphonate (iii)
diethyl 2-[(4s)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-cyanoethylphosphonate (v)
allyl (6s)-6-[(tert-butoxycarbonyl)amino]-2-cyano-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (vi)
diethyl 1-(methylsulfonyl)vinylphosphonate (vii)
diethyl 2-[(4s)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-(methylsulfonyl)ethylphosphonate (viii)
allyl (6s)-6-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyl)-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (ix)
Reference 1:
    muchowski, j.m.; franco, f.; greenhouse, r.; novel syntheses of 5-aryl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylic acids. j org chem 1982, 47, 9, 1682-88.
Reference 2:
    arrigoni-martelli, e.; castaner, j.; blancafort, p.; serradell, m.n.; rs-37,619. drugs fut 1983, 8, 10, 871.

Route 2
the condensation of dimethylacetone-1,3-dicarboxylate (x) with ethanolamine (xi) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (xii), which is cyclized with bromoacetaldehyde diethylacetal (xiii) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (xiv). acylation of (xiv) with methanesulfonyl chloride (xv) and triethylamine in ch2cl2 yields the corresponding mesylate (xvi), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (xvii). the cyclization of (xvii) with nah in dmf yields dimethyl 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (xviii), which is hydrolyzed with koh in refluxing methanol - water to the corresponding diacid (xix). partial esterification of (xix) with isopropanol and hcl gives isopropyl 1,2-dihydro-3h-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (xx), which is decarboxylated by heating at 270 c affording isopropyl 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylate (xxi). benzoylation of (xxi) with n,n-dimethylbenzamide (xxii) and pocl3 in refluxing ch2cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylate (xxiii), which is finally hydrolyzed with k2co3 or naoh in methanol - water.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (xi)
2,2,3-trimethyloxirane (xiii)
(2s,5r)-2-[[(benzyloxy)carbonyl]amino]-5-[(2r,4r)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid (x)
tert-butyl (4s)-3-oxopyrazolidinylcarbamate (xxii)
methyl 2-[(tert-butoxycarbonyl)amino]-3-[[(4-methylphenyl)sulfonyl]oxy]propanoate (xii)
(xiv)
allyl (e)-4-oxo-3-(phenylsulfonyl)-2-pentenoate (xvi)
allyl 2-acetyl-6-[(tert-butoxycarbonyl)amino]-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (xvii)
tert-butyl 3-oxo-4-pyrazolidinylcarbamate (xviii)
2-(2-methylphenyl)-4,5-dihydro-1h-imidazole (xix)
(xx)
methyl 4-(3,4,5-trimethoxyphenethyl)benzoate (xxi)
5-[4-(3,4,5-trimethoxyphenethyl)phenyl]-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinolin-5-ol (xxiii)
Reference 1:
    blancafort, p.; serradell, m.n.; hillier, k.; castaner, j.; bppc. drugs fut 1981, 6, 11, 669.
Reference 2:
    muchowski, j.m.; kluge, a.f. (roche bioscience); 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylic acids derivatives and process for the production thereof. de 2731678; es 460706; es 470214; fr 2358406; fr 2375234; gb 1554075 .
Reference 3:
    arrigoni-martelli, e.; castaner, j.; blancafort, p.; serradell, m.n.; rs-37,619. drugs fut 1983, 8, 10, 871.

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酮咯酸;英文名Ketorolac;RS-37619;CAS[74103-06-3]

 
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