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药物详细合成路线

Name Vigabatrin;M071754;RMI-71890((+)-enantiomer);GVG;MDL-71754;RMI-71754;Sabrilex;Sabril
Chemical Name 4-Amino-5-hexenoic acid;gamma-VinylGABA
CAS 60643-86-9
Related CAS
Formula C6H11NO2
Structure
Formula Weight 129.16007
Stage 上市-1989
Company Aventis Pharma (Originator), Novartis (Licensee), Ovation Pharmaceuticals (Licensee)
Activity/Mechanism Antiepileptic Drugs, NEUROLOGIC DRUGS, Treatment of Alcohol Dependency, Treatment of Cocaine Dependency, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, GABA Aminotransferase Inhibitors
Syn. Route 6
Route 1
the synthesis of [14c]-labeled vigabatrin has been described:the reduction by known methods of pyroglutamic acid (i) to the alcohol (ii) and its acylation with p-toluenesulfonyl chloride gives 5-(tosyloxymethyl)pyrrolidin-2-one (iii), which by reaction with [14c]-labeled sodium cyanide in hot dmf yields 5-([14c]-cyanomethyl)pyrrolidin-2-one (iv). the reduction of (vi) with h2 over pd/al2o3 and treatment with dimethylamine affords 5-[2-(dimethylamino)ethyl]pyrrolidin-2-one (vi), which is oxidized with h2o2 in water to the n-oxide (vi). the treatment of (vi) with k2co3 in refluxing xylene affords 5-([14c]-vinyl)pyrrolidin-2-one (vii), which is finally submitted to ring opening with hot 5 m aqueous hcl, followed by neutralization with triethylamine.
List of intermediates No.
6-(2,4-difluorophenoxy)-2,3-dihydro-1h-inden-5-ylamine (i)
n-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydro-1h-inden-5-yl]acetamide (ii)
n-[6-(2,4-difluorophenoxy)-3-oxo-2,3-dihydro-1h-inden-5-yl]acetamide (iii)
2,4-difluorophenol (iv)
n-[tert-butoxy(dimethylamino)methyl]-n,n-dimethylamine (v)
n,n-dimethylurea (vi)
2-[(e)-benzylidene]-3,4-dihydro-1(2h)-naphthalenone (vii)
methyl (2s)-1-amino-2-pyrrolidinecarboxylate (iv)
methyl (2s)-1-{[(2s)-2-({(2r)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoyl}amino)-3-methylbutanoyl]amino}-2-pyrrolidinecarboxylate (v)
(3r)-3-({[(1s)-1-({[(2s)-2-(methoxycarbonyl)pyrrolidinyl]amino}carbonyl)-2-methylpropyl]amino}carbonyl)octanoic acid (vi)
1-((2r,4s,5r)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxytetrahydro-2-furanyl)-5-iodo-2,4(1h,3h)-pyrimidinedione (vii)
Reference 1:
    wagner, e.r.; schuster, a.j.; synthesis of carbon-14 labeled vigabatrin. j label compd radiopharm 1993, 33, 3, 213.

Route 2
an efficient new synthesis for [14c]-labeled vigabatrin has been described:the reaction of triphenylphosphine (i) with [14c]-labeled methyl iodide (ii) in benzene gives the corresponding phosphonium salt (iii), which is submitted to a wittig condensation with 1-(1-butenyl)-5-oxopiperidin-2-carbaldehyde (iv) to afford the vinylpyrrolidone (v). finally, this compound is hydrolyzed with 6n hcl at 95 c.
List of intermediates No.
n,n-dibutyl-1-butanaminium ([3,4-bis(acetoxy)-5-[4-(methoxyamino)-2-oxo-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(octadecyloxy)oxophosphoranolate (iv)
n-(2-bromoethyl)-2-nitrobenzamide (v)
4-({(2r,3s,5r)-2-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-3-furanyl}oxy)-4-oxobutanoic acid (v)
Reference 1:
    gill, h.s.; an efficient synthesis of carbon-14 labelled vigabatrin. j label compd radiopharm 1995, 36, 5, 425.

Route 3
this compound can be prepared in two different ways:1) the reaction of 1,4-dichloro-2-butene (i) with diethyl malonate (ii) by means of sodium ethoxide in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (iii), which by reaction with ammonia gas in dmf at 120 c is converted into 3-carboxamido-5-vinyl-2-pyrrolidone (iv). finally, this compound is treated with concentrated hcl in refluxing acetic acid.2) the treatment of (iv) with sodium ethoxide in refluxing ethanol gives 3-carboxy-5-vinyl-2-pyrrolidone (v), which is decarboxylated by treatment with refluxing acetic acid to afford 5-vinyl-2-pyrrolidone (vi). the bromination of (vi) with br2 in ccl4 yields 5-(1,2-dibromoethyl)-2-pyrrolidone (vii), which by treatment with na in liquid nh3 in a pressure vessel at 25 c is converted into 4-aminohex-5-inoic acid (viii). finally, this compound is partially reduced with h2 over a suitable catalyst.
List of intermediates No.
2-(1-benzothiophen-3-yl)-1-[4-(dimethylamino)-1-piperidinyl]-1-ethanone (ii)
benzaldehyde (i)
methyl (2s,3r)-3-methoxy-2-[[(e)-benzylidene]amino]butanoate (iii)
methyl (2s,3r)-2-[(3r,4s)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate (iv)
methyl (2s,3r)-2-[(3r,4s)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate (v)
methyl (z)-2-[(3r,4s)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate (vi)
methyl 2-[(3r,4s)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate (vii)
(3r,4s)-2-oxo-4-phenylazetidinyl acetate (viii)
Reference 1:
    gittos, m.w.; leterre, g.j.; process for making 4-aminohex-5-enoic acid. fr 2415630; gb 2013205; jp 54112860; us 4178463 .
Reference 2:
    metcalf, b.w.; jung, m.; olefinic derivatives of amino acids. us 4039549 .
Reference 3:
    metcalf, b.w.; jung, m.; olefinic derivatives of amino acids. ca 1077487; fr 2304329; gb 1472525; jp 76125320; us 3960927 .
Reference 4:
    blancafort, p.; paton, d.m.; serradell, m.n.; castaner, j.; rmi-71,754. drugs fut 1981, 6, 6, 363.

Route 4
the enantiocontrolled addition of phthalimide (i) to 1,3-butadiene monoepoxide (ii) with a chiral palladium catalyst and na2co3 in dichloromethane gives n-(2-hydroxy-1(s)-vinylethyl)phthalimide (iii), which is treated with triflic anhydride and tea in dichloromethane to yield the triflate (iv). the condensation of (iv) with dimethyl malonate (v) by means of nah in thf affords the alkylated malonate (vi), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing hcl.note that the synthesis of the biologically active (s)-enantiomer simply requires a change in the chirality of the pd catalyst used in the first step of the synthesis.
List of intermediates No.
1-[(2-aminoethyl)amino]-3-(2-chlorophenoxy)-2-propanol (i)
[(1r,2r)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepin-2-yl]methanol (v)
tert-butyl(dimethyl)silyl (2s,4r,6s)-2-[(e)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-6-methoxytetrahydro-2h-pyran-4-yl ether; 3-[(e)-2-((2s,4r,6s)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxytetrahydro-2h-pyran-2-yl)ethenyl]-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine (ii)
12-[[tert-butyl(dimethyl)silyl]oxy]dodecyl 3-((3-aminopropyl)[4-[bis(3-aminopropyl)amino]butyl]amino)propylcarbamate (iii)
(2r,3r,4s,5s,6r)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-([13-[4-(bis[3-[([[6-([(2r,3r,4s,5s,6r)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2h-pyran-2-yl]oxy)hexyl]oxy]carbonyl)amino]propyl]amino)butyl]-33,33,34,34-tetramethyl-8,18-dioxo-7,19,32-trioxa-9,13,17-triaza-33-silapentatriacont-1-yl]oxy)tetrahydro-2h-pyran-3-yl acetate (iv)
14,29-dioxo-36-([(2r,3r,4s,5s,6r)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2h-pyran-2-yl]oxy)-19,24-bis[3-[([[6-([(2r,3r,4s,5s,6r)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2h-pyran-2-yl]oxy)hexyl]oxy]carbonyl)amino]propyl]-13,30-dioxa-15,19,24,28-tetraazahexatriacont-1-yl 1h-imidazole-1-carboxylate (vi)
Reference 1:
    trost, b.m.; et al.; dynamic kinetic asymetric transformation of diene monoepoxides: a practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol. j am chem soc 2000, 122, 25, 5968.

Route 5
the reaction of 3-aminotetrahydrofuran-2-one (i) with benzyloxycarbonyl chloride (ii) and tea in chloroform gives the carbamate (iii), which is reduced to the lactol (iv) by means of dibal in toluene. it has been observed that lactol (iv) is in equilibrium with its tautomeric open chain aldehydic form.(v). the reaction of (iv)??(v) with phosphonium bromide (vi) by means of bu-li in thf yields 3-amino-4-penten-1-ol (vii), which is reprotected with benzyloxycarbonyl chloride (ii) and tea to afford the carbamate (viii). the reaction of (viii) with cbr4 and pph3 in dichloromethane provides the pentenyl bromide (ix), which is treated with licn in thf to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (x). finally this compound is hydrolyzed with conc. hcl to yield the target 4-amino-5-hexenoic acid.
List of intermediates No.
[5-[3-benzoyl-2,4-dioxo-5-vinyl-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate (ii)
Reference 1:
    zhang, z.; ding, y.s.; studenov, a.r.; gerasimov, m.r.; ferrieri, r.a.; novel synthesis of [1-11c]gamma-vinyl-gamma-aminobutyric acid ([1-11c]gvg) for pharmacokinetic studies of addiction treatment. j label compd radiopharm 2002, 45, 3, 199.

Route 6
the reaction of 3-aminotetrahydrofuran-2-one (i) with benzyloxycarbonyl chloride (ii) and tea in chloroform gives the carbamate (iii), which is reduced to the lactol (iv) by means of dibal in toluene. it has been observed that lactol (iv) is in equilibrium with its tautomeric open chain aldehydic form (v). the reaction of (iv)??(v) with phosphonium bromide (vi) by means of bu-li in thf yields 3-amino-4-penten-1-ol (vii), which is reprotected with benzyloxycarbonyl chloride (ii) and tea to afford the carbamate (viii). the reaction of (viii) with cbr4 and pph3 in dichloromethane provides the pentenyl bromide (ix), which is treated with 11c labeled licn in thf to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (x). finally this compound is hydrolyzed with conc. hcl to yield the target 11c labeled 4-amino-5-hexenoic acid.
List of intermediates No.
[5-[3-benzoyl-2,4-dioxo-5-vinyl-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate (ii)
Reference 1:
    zhang, z.; ding, y.s.; studenov, a.r.; gerasimov, m.r.; ferrieri, r.a.; novel synthesis of [1-11c]gamma-vinyl-gamma-aminobutyric acid ([1-11c]gvg) for pharmacokinetic studies of addiction treatment. j label compd radiopharm 2002, 45, 3, 199.

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氨己烯酸;英文名Vigabatrin;M071754;RMI-71890((+)-enantiomer);GVG;MDL-71754;RMI-71754;Sabrilex;Sabril;CAS[60643-86-9]

 
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