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藥物詳細合成路線

Name Etiracetam levo-isomer;Levetiracetam;L-059;SIB-S1;UCB-L059;Keppra
Chemical Name (-)-(S)-alpha-Ethyl-2-oxo-1-pyrrolidineacetamide
      (-)-2(S)-(2-Oxopyrrolidin-1-yl)butyramide
CAS 102767-28-2
Related CAS
Formula C8H14N2O2
Structure
Formula Weight 170.21298
Stage 上市-2000
Company UCB (Originator), Lundbeck (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, Antimigraine Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, N-Type Calcium Channel Blockers
Syn. Route 8
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]butirate (iii), which is cyclized in toluene by means of 2-hydroxypyridine.
List of intermediates No.
((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)
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:
    castaner, j.; prous, j.; mealy, n.; levetiracetam. drugs fut 1994, 19, 2, 111.

Route 2
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-(carbamol)propyl]-4-chlorobutyramide (v).
List of intermediates No.
((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)
(2,4-difluorophenyl)(4-piperidinyl)methanone (iv)
(2,4-difluorophenyl)(4-piperidinyl)methanone oxime (v)
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:
    castaner, j.; prous, j.; mealy, n.; levetiracetam. drugs fut 1994, 19, 2, 111.

Route 3
an alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)burytate (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.
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (a)
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)
methyl (2s)-2-amino-3-(1h-imidazol-4-yl)propanoate (viii)
Reference 1:
    cossement, e.; motte, g.; geerts, j.-p.; gobert, j. (ucb sa); the preparation of s-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. gb 2225322 .
Reference 2:
    castaner, j.; prous, j.; mealy, n.; levetiracetam. drugs fut 1994, 19, 2, 111.

Route 4
a third procedure involves ni-raney desulfurization of (s)-4-(methylthio)-2-(2-oxopirrolidin-1-yl)butyramide (xi), prepared from (s)-2-amino-4-(methylthio)butyramide (ix) by reacttion 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-(methythio)propylamino]butyrate (x), which is cyclized in toluene by means of 2-hydroxypyridine.
List of intermediates No.
(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)
(2,4-difluorophenyl)(4-piperidinyl)methanone
(2s)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid (ix)
tert-butyl (1s)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate (x)
3-cyclohexylpropanoyl chloride (xi)
Reference 1:
    cossement, e.; motte, g.; geerts, j.-p.; gobert, j. (ucb sa); the preparation of s-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. gb 2225322 .
Reference 2:
    castaner, j.; prous, j.; mealy, n.; levetiracetam. drugs fut 1994, 19, 2, 111.

Route 5
the condensation of 2-pyrrolidone (i) with 2-oxobutyric acid (ii) in refluxing toluene gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid (iii), which is treated with pcl5 in thf to yield the acyl chloride (iv). the reaction of (iv) with dry ammonia affords the corresponding amide (v), which is finally submitted to an asymmetric hydrogenation with h2 over a chiral rh catalyst to provide the desired chiral butyramide.
List of intermediates No.
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)
(3ar,5s,6r,6ar)-6-azido-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (ii)
Reference 1:
    michel, p.; differding, e.; pasau, p.; kenda, b.; lallemand, b.; matagne, a.; talaga, p. (ucb sa); 2-oxo-1-pyrrolidine derivs., processes for preparing them and their uses. wo 0162726; wo 0164637 .

Route 6
the condensation of 2-pyrrolidone (i) with ethyl 2-bromobutyrate (ii) by means of naoet in ethanol gives 2-(2-oxopyrrolidin-1-yl)butyric acid ethyl ester (iii), which is hydrolyzed with naoh to the corresponding acid (iv). the reaction of (iv) with socl2 affords the acyl chloride (v), which is treated with ammonia to provide the expected amide (vi). alternatively, the reaction of acid (iv) with ammonia and thermolysis of the resulting ammonium salt also gives the butyramide (vi). finally, the optical resolution of the racemic amide (vi) is performed by chiral hplc.
List of intermediates No.
methyl (2s)-3-(1h-imidazol-4-yl)-2-[[(2r)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate (iv)
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)
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:
    strubbe, j.h.l.; linz, r.a. (ucb sa); new n-substd. lactams. de 2106418 .
Reference 3:
    cavoy, e.; hamende, m.; deleers, m.; canvat, j.-p.; zimmermann, v.; futagawa, t. (daicel chemical industries, ltd.; ucb sa); process for the preparation of levetiracetam. us 6107492 .
Reference 4:
    cavoy, e.; hamende, m.; deleers, m.; canvat, j.-p.; zimmermann, v. (ucb sa); process for preparing (s)- and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. us 6124473 .

Route 7
the condensation of 2-pyrrolidinone (i) with 2-oxoacetic acid (ii) in ethyl ether gives 2-hydroxy-2-(2-oxopyrrolidin-1-yl)acetic acid (iii), which is fully methylated with methanol and conc. sulfuric acid to yield 2-methoxy-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (iv). the reaction of (iv) with pcl3 in hot toluene affords 2-chloro-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (v), which is condensed with triethyl phosphite (vi), also in hot toluene, to provide the dimethyl phosphonate (vii). the condensation of (vii) with acetaldehyde (viii) in thf by means of tetramethylguanidine gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid methyl ester (ix), which is reduced with h2 and a chiral rhodium catalyst in thf to yield 2(s)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (x). finally, this ester is treated with ammonia in methanol to afford the target chiral amide.
List of intermediates No.
n-[(3as,5s,6r,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]-n-(2-chloroethyl)urea (viii)
(2s)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoic acid (vi)
tert-butyl(diphenyl)silyl (z)-7-((1r,2r,3r)-2-[(e,3s)-3-[(2-bromoacetyl)oxy]-1-octenyl]-3-hydroxy-5-oxocyclopentyl)-5-heptenoate (ii)
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)
Reference 1:
    boaz, n.w.; debenham, s.d.; highly enantiomerically pure lactam-substd. propanoic acid derivs. and methods of making and using same. wo 0226705 .

Route 8
the reaction of 2(s)-aminobutyric acid (i) with socl2 gives the acyl chloride (ii), which is treated with methanol to yield the methyl ester (iii). the condensation of (iii) with ethyl 4-bromobutyrate (iv) by means of na2co3 in refluxing water affords 2(s)-[3-(ethoxycarbonyl)propylamino)butyric acid methyl ester (v), which is cyclized by means of 2-pyridinol in refluxing toluene to provide 2(s)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (vi). finally this compound is treated with ammonia in water to furnish the target lavetiracetam.
List of intermediates No.
2-methyl-2-[(4r,5s,6s)-2,2,5-trimethyl-6-[(1s)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal (i)
Reference 1:
    cavoy, e.; ates, c.; surtees, j.; burteau, a.-c.; marmon, v. (ucb sa); oxopyrrolidine cpds., preparation of said cpds. and their use in the manufacturing of levetiracetam and analogues. wo 0314080 .

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左乙拉西坦;英文名Etiracetam levo-isomer;Levetiracetam;L-059;SIB-S1;UCB-L059;Keppra;CAS[102767-28-2]

 
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