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药物详细合成路线

Name Atipamezole;MPV-1248;Antisedan
Chemical Name 4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)imidazole
      4-(2-Ethylindan-2-yl)-1H-imidazole
      4(5)-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)imidazole
CAS 104054-27-5
Related CAS
Formula C14H16N2
Structure
Formula Weight 212.29702
Stage I 期临床
Company Orion Pharma (Originator), US Department of Health & Human Services (Originator)
Activity/Mechanism RENAL-UROLOGIC DRUGS, Treatment of Male Sexual Dysfunction, alpha2-Adrenoceptor Antagonists
Syn. Route 3
Route 1
this compound can be obtained in two different ways:1) the bromination of 1-(2-ethylindan-2-yl)-1-ethanone (i) with br2 in ether gives 2-bromo-1-(2-ethylindan-2-yl)-1-ethanone (ii), which is then cyclized with formamide by heating at 170-80 c.2) the cyclization of alpha,alpha-dibromo-o-xylene (iii) with 4-penten-2-one (iv) by means of tetrabutylammonium hydroxide in toluene at 100 c gives 1-(2-vinylindan-2-yl)-1-ethanone (v), which is brominated with br2 in dichloromethane to yield 2-bromo-1-(2-vinylindan-2-yl)-1-ethanone (vi). the cyclization of (vi) with formamide at 160 c as before affords 4-(2-vinylindan-2-yl)-1h-imidazole (vii), which is finally hydrogenated with h2 over pd/c in ethanol.
List of intermediates No.
tert-butyl (2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-(phenethylamino)propyl]-1-pyrrolidinecarboxylate (i)
methyl 3-phenylpropanoate (ii)
methyl 2-(3-hydroxy-2-oxo-2,3-dihydro-1h-indol-3-yl)-3-phenylpropanoate (iii)
2-(1h-indol-3-yl)-3-phenyl-1-propanol (iv)
methyl 2-(4-benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate (v)
2-(1h-indol-3-yl)acetic acid methyl ester (vi)
methyl 2-(1h-indol-3-yl)-3-phenylpropanoate (vii)
Reference 1:
    graziano, m.p.; maxham, c.p.; malbon, c.c.; purified rat hepatic beta2-adrenergic receptor: structural similarities in the rat fat cell beta1-adrenergic receptor. j biol chem 1985, 260, 7665-74.
Reference 2:
    karjalainen, a.l.; karjalainen, a.j. (orion pharma); 4(5)-substd. imidazole derivs., and intermediates and processes for their preparation. ep 0247764; us 4933359 .
Reference 3:
    karjalainen, a.j.; virtanen, r.e.; kurkela, k.o.a.; karjalainen, a. (orion pharma); substd. imidazole derivs. and their preparation and use. au 8550083; ep 0183492; ep 0310745; es 8704462; es 8801248; gb 2167408; jp 1986143366 .
Reference 4:
    prous, j.; castaner, j.; atipamezole. drugs fut 1990, 15, 5, 448.

Route 2
a new synthesis of atipamezole has been described:the cyclization of alpha,alpha-dibromo-o-xylene (i) with acetylacetone (ii) by means of naoh and tetrabutylammonium bromide in toluene/water at 80 c under phase-transfer conditions gives the unstable diacetyl derivative (iii), which presumably undergoes cleavage to afford 2-acetylindane (iv). the alkylation of (iv) with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindane (v), which is brominated with br2 to give 2-(bromoacetyl)-2-ethylindane (vi). finally, this compound is cyclized with formamide at 160 c [some 2-ethyl-2-(4-oxazolyl)indane is also formed but is easily eliminated]; the cyclization can also be carried out with formamidine in liquid ammonia.
List of intermediates No.
tert-butyl (2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-(phenethylamino)propyl]-1-pyrrolidinecarboxylate (v)
methyl 3-phenylpropanoate (vi)
benzoyl isothiocyanate (i)
n-benzoyl-n-(2-hydroxy-4-methylphenyl)thiourea (ii)
n-(2-hydroxy-4-methylphenyl)thiourea (iii)
2-amino-5-methylphenol (iv)
Reference 1:
    wong, w.c.; gluchowski, c.; a concise synthesis of atipamezole. synthesis 1995, 2, 2, 139.

Route 3
the alkylation of indane-2-carboxylic acid methyl ester (i) with ethyl iodide by means of lithium isopropylcyclohexylamide (liica) in thf/dmso gives the 2-ethyl substituted compound (ii), which is hydrolyzed with tbu-ok in dmso, yielding 2-ethylindane-2-carboxylic acid (iii). the reaction of (iii) with methanesulfonyl chloride and diazomethane affords the alpha-diazoketone (iv), which is treated with dimethyldioxirane (dmdo) in acetone to provide the ketoaldehyde (v). finally, this compound is cyclized with 11c-formaldehyde and nh4oh by means of zno in thf/water to yield the target labeled imidazole derivative.the intermediate ketoaldehyde (v) has also been obtained in two other ways: a) the alkylation of 2-(diethoxyacetyl)indane (vi) with ethyl iodide by means of tbu-ok in thf gives the corresponding 2-ethyl-substituted compound (vii), which is finally hydrolyzed to the desired ketoaldehyde (v) with hcl in thf/water. b) the oxidation of 2-acetyl-2-ethylindane (viii) with seo2 in hot acetic acid/water gives also the desired ketoaldehyde (v).
List of intermediates No.
tert-butyl (2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-(phenethylamino)propyl]-1-pyrrolidinecarboxylate (viii)
Reference 1:
    roeda, d.; et al.; synthesis of [11c]atipamezole, a potential pet ligand for the alpha2-adrenergic receptor in the brain. j label compd radiopharm 2002, 45, 1, 37.

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阿替美唑;英文名Atipamezole;MPV-1248;Antisedan;CAS[104054-27-5]

 
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