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药物详细合成路线

Name Lamotrigine;BW-430C;Labileno;Lamictal
Chemical Name 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
CAS 84057-84-1
Related CAS
Formula C9H7Cl2N5
Structure
Formula Weight 256.09564
Stage 上市-1990
Company GlaxoSmithKline (Originator), FAES (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Glutamate Release Inhibitors, Sodium Channel Blockers
Syn. Route 4
Route 1
the grignard condensation of 2,3-dichloroiodobenzene (i) with co2 by means of mg / ether gives 2,3-dichlorobenzoic acid (ii), which is converted to the corresponding acyl chloride (iii) by refluxing with socl2.the reaction of (iii) with cuprous cyanide and ki in refluxing xylene yields 2,3-dichlorobenzoyl cyanide (iv). finally, this compound is cyclized with aminoguanidine (v) in dmso.
List of intermediates No.
(2r)-4-(3-chloro-4-methoxyphenyl)-2-[(methoxycarbonyl)amino]-4-oxobutyric acid (v)
2-[4-(benzyloxy)phenyl]oxirane; benzyl 4-(2-oxiranyl)phenyl ether (i)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]amino]-1-ethanol (ii)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]imino]-1-ethanone (iii)
ethyl 7-bromoheptanoate (iv)
Reference 1:
    baxter, m.g.; elphick, a.r.; miller, a.a.; sawyer, d.a. (glaxo wellcome plc); 1,2,4-triazine derivs., process for preparing such cpds., pharmaceutical compsns. and intermediates utilized for this process. ca 1133938; ep 0021121 .
Reference 2:
    castaner, j.; prous, j.; lamotrigine. drugs fut 1986, 11, 6, 456.

Route 2
condensation of 2,3-dichlorobenzoyl cyanide (i) with aminoguanidine (ii) by means of ppa in hot acetonitrile yields 2,3-dichlorobenzoyl cyanide amidinohydrazone (iii), which is cyclized to the target 1,2,4-triazine by heating in refluxing propanol with or without dmso.
List of intermediates No.
(2r)-4-(3-chloro-4-methoxyphenyl)-2-[(methoxycarbonyl)amino]-4-oxobutyric acid (ii)
ethyl 7-bromoheptanoate (i)
Reference 1:
    nadaka, v.; lexner, j.; kaspi, j. (chemagis ltd.); process for preparing substd. benzoyl cyanide amidinohydrazones. ep 1127873 .

Route 3
hydrogenation of 2,3-dichloronitrobenzene (i) with h2 over ra-ni in methanol gives 2,3-dichloroaniline (ii), which is diazotized with nano2 and hcl and treated with cucn to yield 2,3-dichlorobenzonitrile (iii). hydrolysis of the nitrile (iii) with naoh in refluxing methanol/water affords 2,3-dichlorobenzoic acid (iv), which is treated with hot socl2 to provide the corresponding acyl chloride (v). reaction of (v) with cucn and ki in refluxing chlorobenzene gives 2,3-dichlorobenzoyl cyanide (vi), which is condensed with aminoguanidine (vii) by means of h2so4/tsoh in hot toluene to yield 2,3-dichlorobenzoyl cyanide amidinohydrazone (viii). finally, this compound is cyclized by treatment with naome in refluxing methanol.
List of intermediates No.
(2r)-4-(3-chloro-4-methoxyphenyl)-2-[(methoxycarbonyl)amino]-4-oxobutyric acid (vii)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]amino]-1-ethanol (iv)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]imino]-1-ethanone (v)
ethyl 7-bromoheptanoate (vi)
(18s)-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione (ii)
(2r,3s,4s)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal (iii)
Reference 1:
    srivastava, a.r.; sasikumar, t.m.; radhakrishnan, t.v. (rpg life sciences ltd); a process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine. wo 0149669 .

Route 4
the reaction of 2,3-dichlorobenzoic acid (i) with oxalyl chloride in dichloromethane gives the acyl chloride (ii), which is condensed with labeled copper cyanide (iii) by means of ki in refluxing xylene to yield the 2,3-dichlorobenzoyl cyanide (iv). the condensation of (iv) with labeled aminoguanidine (v) by means of sulfuric acid in acetonitrile/water affords adduct (vi), which is finally cyclized by refluxing under the conditions of the preceding reaction to provide the target labeled diaminotriazine.the intermediate labeled copper cyanide (iii) has been obtained by reaction of cuso4 with labeled potassium cyanide (vii) and na2s2o5 in hot water.the intermediate labeled aminoguanidine (v) has been obtained by methylation of thiourea (viii) with dimethyl sulfate in boiling water to give s-methylisothiourea (ix), which is finally treated with hydrazine (x) and naoh in water.
List of intermediates No.
methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (viii)
ethyl 2-[(z)-(6-amino-9h-purin-9-yl)methylidene]cyclopropanecarboxylate (ix)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]amino]-1-ethanol (i)
1-[4-(benzyloxy)phenyl]-2-[[3-(2-methoxyphenyl)-1,1-dimethylpropyl]imino]-1-ethanone (ii)
ethyl 7-bromoheptanoate (iv)
1-methoxy-4-([[(methylimino)(methylsulfanyl)methyl]amino]methyl)benzene (x)
Reference 1:
    manning, c.o.; et al.; synthesis of stable isotopically labelled versions of lamotrigine and its methylated metabolite. j label compd radiopharm 2002, 45, 7, 611.

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拉莫三嗪;英文名Lamotrigine;BW-430C;Labileno;Lamictal;CAS[84057-84-1]

 
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