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药物详细合成路线

Name beta-Elemene;Elemene
Chemical Name (1alpha,2beta,4beta)-2,4-Diisopropenyl-1-methyl-1-vinylcyclohexane
      (1alpha,2beta,4beta)-1-Ethenyl-1-methyl-2,4-bis(1-methylethenyl)cyclohexane
CAS 33880-83-0
Related CAS 192460-89-2 ((-)-alpha-isomer), 515-13-9 ((-)-beta-isomer), 29873-99-2 ((-)-gamma-isomer), 5951-67-
Formula C15H24
Structure
Formula Weight 204.35853
Stage III 期临床
Company Dalian Jin Gang (Originator)
Activity/Mechanism ONCOLYTIC DRUGS
Syn. Route 1
Route 1
a stereoselective synthesis of beta-elemene has been reported: reaction of 2-allylpropane-1,3-diol (i) with tosyl chloride and pyridine gives the ditosylate (ii), which is treated with nacn in refluxing dmf to yield the dinitrile (iii). the methanolysis of (iii) with tsoh and refluxing methanol affords the dicarboxylic acid (iv), which is reduced with lialh4 in thf providing 3-allyl-1,5-pentanediol (v). the reaction of (v) with cbr4 and pph3 in dichloromethane gives the dibromide (vi), which is ozonolyzed with ozone and pph3 in dichloromethane to yield the aldehyde (vii). condensation of (vii) with the phosphorane (viii) in dichloromethane affords the unsaturated ester (ix), which is reduced with dibal in toluene to afford alcohol (x). condensation of (x) with triethyl orthopropionate (xi) in refluxing phenol/toluene gives the anti-dibromoester (xii), along with some syn-isomer that is easily separated. cyclization of (xii) with lda in thf yields the cyclohexanecarboxylate (xiii), which is treated with t-buok in thf to afford the divinylcylohexanecarboxylate (xiv). reduction of (xv) with dibal in toluene provides the carbinol (xv), which is treated with cucl, pdcl2 and o2 in dmf/water giving the acetyl derivative (xvi). oxidation of (xvi) with pcc and acona in dichloromethane gives keto-aldehyde (xvii), which is finally submitted to a double wittig methylenation with methylenetriphenylphosphorane (xviii) in thf.
List of intermediates No.
4-phenylnicotinic acid (xi)
benzyl ethyl[1-(4-[methyl(phenylsulfonyl)amino]-3-phenyl-3-[[2-(trimethylsilyl)ethoxy]methyl]butyl)-4-piperidinyl]carbamate (xviii)
ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate (viii)
(1s,5s,6r,7s)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one (i)
(1s,5s,6r,7r)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one (ii)
(1s,5s,6r,7r)-7-chloro-3-ethoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1s,5s,6r,7r)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl ethyl ether (iii)
n-[4-fluoro-2-nitro-5-(trifluoromethyl)phenyl]acetamide (iv)
n-[4-[4-(hydroxymethyl)-1h-imidazol-1-yl]-2-nitro-5-(trifluoromethyl)phenyl]acetamide (v)
{1-[4-amino-5-nitro-2-(trifluoromethyl)phenyl]-1h-imidazol-4-yl}methanol (vi)
{1-[4,5-diamino-2-(trifluoromethyl)phenyl]-1h-imidazol-4-yl}methanol (vii)
diethyl ketomalonate; diethyl mesoxalate; diethyl oxomalonate; mesoxalic acid diethyl ester (ix)
ethyl 7-[4-(hydroxymethyl)-1h-imidazol-1-yl]-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2-quinoxalinecarboxylate (x)
ethyl 7-{4-[({[4-(ethoxycarbonyl)anilino]carbonyl}oxy)methyl]-1h-imidazol-1-yl}-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2-quinoxalinecarboxylate (xii)
sodium 5-amino-4-hydroxy-7-sulfo-2-naphthalenesulfonate (xiii)
disodium 4-[(2,3-dichlorobenzoyl)amino]-5-hydroxy-2,7-naphthalenedisulfonate (xiv)
2,5-dimethoxy-4-nitroaniline (xv)
2,5-dimethoxy-4-nitrobenzenediazonium chloride (xvi)
disodium 5-[(2,3-dichlorobenzoyl)amino]-3-[(e)-2-(2,5-dimethoxy-4-nitrophenyl)hydrazono]-4-oxo-3,4-dihydro-2,7-naphthalenedisulfonate (xvii)
Reference 1:
    lee, j.; kim, s.; kim, d.; chang, j.; stereoselective synthesis of (±)-beta-elemene by a doubly diastereodifferentiating internal alkylation: a remarkable difference in the rate of enolization between syn and anti esters. tetrahedron 2001, 57, 7, 1247.

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榄香烯;英文名beta-Elemene;Elemene;CAS[33880-83-0]

 
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