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Name Tiagabine hydrochloride;NN-301;A-70569;ABT-569;Abbott-70569;NO-328;NNC-05-0328;NO-05-0328;Tiabex;Gabitril
Chemical Name (-)-(R)-1-[4,4-Bis(3-methyl-2-thienyl)-3-butenyl]piperidine-3-carboxylic acid hydrochloride
CAS 145821-59-6
Related CAS 115103-54-3 (free base)
Formula C20H26ClNO2S2
Structure
Formula Weight 412.01672
Stage 上市-1996
Company Novo Nordisk (Originator), Cephalon (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, GABA Reuptake Inhibitors
Syn. Route 2
Route 1
the synthesis of 5-hydroxytiagabine, a metabolite of tiagabine in humans, has been undertaken to confirm that it is present entirely as (e)- and (z)-isomers of the tautomeric 5-oxo form: the bromination of 3-methylthiophene (i) with n-bromosuccinimide gives 2-bromo-3-methylthiophene (ii), which is chlorinated with n-chlorosuccinimide to yield 2-bromo-5-chloro-3-methylthiophene (iii). the reaction of (iii) with mg affords 5-chloro-3-methylthien-2-ylmagnesium bromide (iv), which is condensed with 3-methylthiophene-2-carboxaldehyde (v) (obtained from (ii) by reaction with magnesium and dimethylformamide) to give the bisthienylmethanol (vi). the oxidation of (vi) with pyridinium chlorochromate (pcc) yields the bisthienyl ketone (vii), which is treated with sodium methoxide to afford the bis(2-thienyl)ketone (viii). the grignard reaction of (viii) with cyclopropylmagnesium bromide (ix) gives the trisubstituted methanol (x), which is submitted to ring opening with trimethylsilyl bromide to afford the thiophenone (xi) as a mixture of the (e)- and (z)-isomers. the condensation of (xi) with piperidine-3(r)-carboxylic acid ethyl ester (xii) by means of k2co3 gives 1-[4-(3-methyl-5-oxo-2,5-dihydrothien-2-ylidene)-4-(3-methyl-2-thienyl) butyl]piperidine-3(r)-carboxylic acid ethyl ester (xiii) (also as a mixture of (e)- and (z)-isomers). finally, this compound is hydrolyzed to the free acid in hcl medium.
List of intermediates No.
2,3,4,5,6-pentamethylbenzyl 4-fluorocyclohexanecarboxylate (i)
4-fluorocyclohexanecarbonyl chloride (ii)
phenethyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate (iii)
glutamine (iv)
n(2)-(2-[[(phenethyloxy)carbonyl]amino]propanoyl)glutamine (v)
butyl 5-amino-5-oxo-2-[(2-[[(phenethyloxy)carbonyl]amino]propanoyl)amino]pentanoate (vi)
butyl 5-amino-2-[(2-aminopropanoyl)amino]-5-oxopentanoate (vii)
2-[[(8r)-7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propionic acid (viii)
butyl 2-([2-[(2-[[(8r)-7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoate (ix)
tabersonine; methyl 3a-ethyl-3a,4,6,11,12,13a-hexahydro-1h-indolizino[8,1-cd]carbazole-5-carboxylate (x)
methyl (13ar,13bs)-13a-ethyl-12-hydroxy-5,6,12,13,13a,13b-hexahydro-3h-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylate (xi)
methyl (13ar,13bs)-13a-ethyl-5,6,12,13,13a,13b-hexahydro-3h-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylate (xii)
[(13ar,13bs)-13a-ethyl-5,6,12,13,13a,13b-hexahydro-3h-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl]methanol (xiii)
Reference 1:
    thogersen, h.; chorghade, m.s.; lee, e.c.; andersen, k.e.; sorensen, p.o.; lundt, b.f.; begtrup, m.; lau, j.; petersen, h.; the synthesis of novel gaba uptake inhibitors. 2. synthesis of 5-hdroxytiagabine, a human metabolite of the gaba reuptake inhibitor tiagabine. tetrahedron 1994, 50, 29, 8699.

Route 2
this compound has been obtained by two different ways:1) the grignard condensation of 3-methylthiophene-2-carbaldehyde (i) with 3-methylthiophen-2-ylmagnesium bromide (ii) in ethyl ether gives the carbinol (iii), which is oxidized with mno2 in dichloromethane yielding the corresponding ketone (iv). a new grignard condensation of (iv) with cyclopropylmagnesium bromide (v) in thf affords the carbinol (vi), which is dehydrated with simultaneous cyclopropane ring opening by means of hbr or tms-br in acetic acid giving 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (vii).the condensation of (vii) with piperidine-2(r)-carboxylic acid ethyl ester (viii) by means of k2co3 and ki in acetone yields the ethyl ester (ix) of the target compound, which is finally hydrolyzed with naoh in ethanol.2) the reaction of 2-bromo-3-methylthiophene (x) with buli in ethyl ether gives the corresponding lithium derivative (xi), which is condensed with ethyl 4-bromobutyrate (xii) in the same solvent to afford the previously reported 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (vii).
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 (xii)
4-fluorocyclohexanecarbonyl chloride (x)
n(2)-(2-[[(phenethyloxy)carbonyl]amino]propanoyl)glutamine (i)
butyl 2-([2-[(2-[[(8r)-7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoate (v)
methyl (13ar,13bs)-13a-ethyl-5,6,12,13,13a,13b-hexahydro-3h-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylate (viii)
(e)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid (ii)
(z)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid (iii)
methyl (z)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate (iv)
methyl (e)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate (vi)
(e)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid (vii)
benzyl 2-[[(2s)-2-benzyl-3-hydroxypropanoyl]amino]acetate (ix)
benzyl 2-([(2s)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate (xi)
Reference 1:
    braestrup, c.; gronvald, f.c. (novo nordisk a/s); amino acid derivs.. au 8661336; ep 0236342; es 8800927; jp 1987503172; us 5010090; wo 8700171 .
Reference 2:
    andersen, k.e.; et al.; the synthesis of novel gaba uptake inhibitors. 1. elucidation of the structure-activity studies leading to the choice of (r)-1-[4, 4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. j med chem 1993, 36, 12, 1716.

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鹽酸噻加賓;英文名Tiagabine hydrochloride;NN-301;A-70569;ABT-569;Abbott-70569;NO-328;NNC-05-0328;NO-05-0328;Tiabex;Gabitril;CAS[145821-59-6]

 
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