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药物详细合成路线

Name Levamisole hydrochloride;KW-2299;R-12;564;Ergamisol
Chemical Name 6(S)-Phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole hydrochloride
CAS 16595-80-5
Related CAS 14769-73-4 (free base)
Formula C11H13ClN2S
Structure
Formula Weight 240.75666
Stage 上市
Company Janssen (Originator), Kyowa Hakko (Licensee)
Activity/Mechanism Oncolytic Drugs
Syn. Route 4
Route 1
the cyclization of (s)-(+)-phenylethylenediamine (i) with cs2 in alkaline water gives (s)-(+)-4-phenyl-2-mercaptoimidazolidine (ii), which is then cyclized again with 1,2-dibromoethane (a) in alkaline isopropanol-water.
List of intermediates No.
ethyl 2-[2-([[(4-chlorophenyl)sulfonyl]amino]methyl)-2,3-dihydro-1h-inden-5-yl]-2-(methylsulfanyl)acetate (a)
4-[(z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol (i)
(z)-4-[4-[2-(benzyloxy)ethoxy]phenyl]-3,4-diphenyl-3-buten-1-ol (ii)
Reference 1:
    casta?er, j.; hopkins, s.j.; blancafort, p.; serradell, m.n.; levamisole hydrochloride. drugs fut 1979, 4, 6, 420.
Reference 2:
    raeymaekers, a.h.m.; et al.; absolute configurations of the optical isomers of the broad spectrum anthelmintic tetramisole. tetrahedron lett 1967, 16, 1467-70.

Route 2
the reaction of beta-chloroethylamine (iii) with ammonium thiocyanate (b) gives beta-aminoethylthiocyanate (iv), which is alkylated with alpha,beta-dichloroethylbenzene (v) in hot benzene yielding the secondary amine (vi). the cyclization of (vi) in hot aqueous naoh affords racemic levamisole, which is finally resolved in its optical isomers through the d-10-camphorsulfonate or n-benzene (or p-toluene)sulfonyl-l-(+)-glutamic salt.
List of intermediates No.
n-[3-acetyl-4-(cyclopropylmethoxy)phenyl]-n,n-diethylurea (iii)
1-[2-(benzyloxy)ethoxy]-4-[(z)-4-chloro-1,2-diphenyl-1-butenyl]benzene; benzyl 2-[4-[(z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]ethyl ether (b)
2,3-dichloro-4-hydroxybenzaldehyde (iv)
2,3-dichloro-4-formylphenyl trifluoromethanesulfonate (v)
2-bromobenzenethiol; 2-bromothiophenol (vi)
4-[(2-bromophenyl)sulfanyl]-2,3-dichlorobenzaldehyde (rac-xii)
Reference 1:
    bullock, m.w.; de 1645975 .
Reference 2:
    dick, p.r.; rombi, m.; fr 2183313 .
Reference 3:
    casta?er, j.; hopkins, s.j.; blancafort, p.; serradell, m.n.; levamisole hydrochloride. drugs fut 1979, 4, 6, 420.
Reference 4:
    us 3579530 .

Route 3
the reaction of phenacyl bromide (vii) with 2-aminothiazoline (viii) in mecn at 100 c gives 2-imino-3-phenacylthiazolidine (ix), which is reduced to the corresponding alcohol (x) with nabh4 in methanol. finally, this compound is cyclized with socl2 and refluxing acetic anhydride giving the racemic levamisole which is resolved resolved in its optical isomers through the d-10-camphorsulfonate, n-benzene (or p-toluene)sulfonyl-l-(+)-glutamic salt.compound (x) can be acetylated under milder conditions than before giving the n-acetyl compound (xi), which is cyclized socl2 and refluxing acetic anhydride.
List of intermediates No.
3,4-dimethoxy-5-propylbenzoic acid (vii)
4-[(2-bromophenyl)sulfanyl]-2,3-dichlorobenzaldehyde (rac-xii)
(2-ethoxy-2-oxoethyl)(triphenyl)phosphonium chloride (viii)
ethyl (e)-3-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]-2-propenoate (ix)
ethyl (1s,2r)-2-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]cyclopropanecarboxylate (x)
(1s,2r)-2-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]cyclopropanecarboxylic acid (xi)
Reference 1:
    janssen pharm. n.v.; us 3274209 .
Reference 2:
    us 3579530 .
Reference 3:
    casta?er, j.; hopkins, s.j.; blancafort, p.; serradell, m.n.; levamisole hydrochloride. drugs fut 1979, 4, 6, 420.
Reference 4:
    bullock, m.w.; de 1645975 .

Route 4
the inactive d-(+)-levamisole can be isomerized by reaction with a strong nonaqueous base such as potassium tert-butylate, sodium amide or sodium hydride with or without solvent (dmf, dmso). the racemic mixture obtained is resolved in its optical isomers through the d-10-camphorsulfonate, n-benzene (or p-toluene)sulfonyl-l-(+)-glutamic salt.
List of intermediates No.
4-[(2-bromophenyl)sulfanyl]-2,3-dichlorobenzaldehyde (rac-xii)
n-(3-aminopropyl)-2-pyrrolidinone; n-(3-aminopropyl)-2-pyrrolidinone (+-xii)
Reference 1:
    us 3579530 .
Reference 2:
    bullock, m.w.; de 1645975 .
Reference 3:
    casta?er, j.; hopkins, s.j.; blancafort, p.; serradell, m.n.; levamisole hydrochloride. drugs fut 1979, 4, 6, 420.
Reference 4:
    bullock, m.w.; hand, j.j.; us 3673206 .

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盐酸左旋咪唑;英文名Levamisole hydrochloride;KW-2299;R-12;564;Ergamisol;CAS[16595-80-5]

 
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