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药物详细合成路线

Name Etiracetam;UCB-6474
Chemical Name (±)-2-(2-Oxopyrrolidin-1-yl)butyramide
CAS 33996-58-6
Related CAS
Formula C8H14N2O2
Structure
Formula Weight 170.21298
Stage II 期临床
Company UCB (Originator)
Activity/Mechanism Cognition Disorders, Treatment of, NEUROLOGIC DRUGS
Syn. Route 2
Route 1
reaction of (s)-2-aminobutyramide (i) with ethyl 4-bromobutyrate (ii) in the presence of triethylamine in toluene gives ethyl (s)-4-[1-(carbamoyl)propylamino]butyrate (iii), which is cyclized in toluene by means of 2-hydroxypyridine.compound (i) can also be condensed with 4-chlorobutyryl chloride (iv) either directly in the presence of tetrabutylammonium bromide (tbab) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (s)-n-[1-(carbamoyl)propyl]-4-chlorobutyramide (v).an alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (vi) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (vii), which is resolved by fractional crystallization with (r)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (s)-2-(2-oxopyrrolidin-1-yl)butyric acid (viii). compound (viii) is finally treated with ethyl chloroformiate and ammonia in dichloromethane.a third procedure involves ni-raney desulfurization of (s)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (xi), prepared from (s)-2-amino-4-(methylthio)butyramide (ix) by reaction with 4-chlorobutyryl chloride (iv).compound (xi) can also be obtained by treatment of (ix) with ethyl 4-bromobutyrate (ii) to give ethyl (s)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (x), which is cyclized in toluene by means of 2-hydroxypyridine.
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran
((3r)-2-[[(2r,3r,4s,11r,12s)-5-ethyl-3,4-dihydroxy-9-[[(2r,4r,5s)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2h-pyran-2-yl]oxy]-2,4,8,10,12,14-hexamethyl-7-oxo-6,15-dioxabicyclo[10.2.1]pentadec-1(14)-en-11-yl]oxy]-3-hydroxy-6-methyltetrahydro-2h-pyr (i)
(6r,7s,9s,11r,12r,13s)-14-ethyl-9-fluoro-4,6,7,12,13-pentahydroxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione (ii)
1-[4-(2,4-difluorobenzoyl)-1-piperidinyl]-1-ethanone (iii)
(2,4-difluorophenyl)(4-piperidinyl)methanone (iv)
(2,4-difluorophenyl)(4-piperidinyl)methanone oxime (v)
3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4h-pyrido[1,2-a]pyrimidin-4-one (vi)
methyl (2s)-3-(1h-imidazol-4-yl)-2-[[(2r)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate (vii-rac)
methyl (2s)-2-amino-3-(1h-imidazol-4-yl)propanoate (viii)
(2s)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid (ix)
tert-butyl (1s)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate (x)
3-cyclohexylpropanoyl chloride (xi)
Reference 1:
    gobert, j.; geerts, j.-p.; bodson, g. (ucb sa); (s)-alpha-ethyl-2-oxopyrrolidineacetamide. au 8542530; ep 0162036; es 8608485; es 8704893; us 4696943; us 4837223 .
Reference 2:
    cossement, e.; motte, g.; geerts, j.-p.; gobert, j. (ucb sa); the preparation of s-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. gb 2225322 .
Reference 3:
    castaner, j.; prous, j.; mealy, n.; levetiracetam. drugs fut 1994, 19, 2, 111.

Route 2
the condensation of pyrrolidin-2-one (i) with ethyl 2-bromobutyrate (ii) by means of nah or sodium ethoxide gives ethyl 2-(2-oxopyrrolidino)butyrate (iii), which is then treated with nh3 in methanol.
List of intermediates No.
3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4h-pyrido[1,2-a]pyrimidin-4-one (iii)
benzhydryl (6r,7s)-3-[[(aminocarbonyl)oxy]methyl]-7-hydroxy-7-[[(z)-1-methoxy-2-(2-thienyl)ethylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
dimethyl 4-(acetamido)-6-chloroisophthalate (ii)
Reference 1:
    de angelis, l.; blancafort, p.; castaner, j.; serradell, m.n.; etiracetam. drugs fut 1981, 6, 9, 552.
Reference 2:
    strubbe, j.h.l.; linz, r.a. (ucb sa); new n-substd. lactams. de 2106418 .

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乙拉西坦;英文名Etiracetam;UCB-6474;CAS[33996-58-6]

 
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