酮康唑 [CAS:65277-42-1]详细合成路线—武汉东康源原料药研发中心
Name Ketoconazole;R-41400;Sebazole;Extina;Panfungol;Ketoderm;Nizoral
Chemical Name
cis-1-Acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]ph
enyl]piperazine
CAS 65277-42-1
Related CAS
Formula C 26H 28Cl 2N 4O 4
Structure
Formula Weight 531.44346
Stage 上市-1981
Company 武汉东康源科技有限公司
Activity/Mec hanism price Antifungal Agents, ANTIINFECTIVE THERAPY, DERMATOLOGIC DRUGS, Antiestrogens, Aromatase Inhibitors
1000rmb/kg,
tel 027-******** 180******** email chem@https://www.doczj.com/doc/dd986185.html, Syn. Route 1 Route 1
the cyclization of 2,4-dichlorophenacyl bromide (i) with glycerol (ii) gives
cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (iii), which is then benzoylated with benzoyl chloride (a) yielding
cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (iv). the condensation of (iv) with 1h-imidazole (v) affords
cis-2-(2,4-dichlorophenyl)-2-(1h-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (vi), which is then debenzoylated in basic medium giving
cis-2-(2,4-dichlorophenyl)-2-(1h-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (vii). the
reaction of (vii) with methanesulfonyl chloride (b) yields
cis-2-(2,4-dichlorophenyl)-2-(1h-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate
(viii). finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (ix) by
means of nah in benzene - dmso. compound (ix) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (x) with acetic anhydride by means of k2co3 in refluxing acetic acid.
List of intermediates No. (3r,4s)-1-(4-methoxyphenyl)-4-[(e)-1-propenyl]-3-[(triisopropylsilyl)oxy]-2-azetidinone (v) (3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (a)
4,6-dichloro-2-[(4-methoxybenzyl)sulfanyl]pyrimidine (ii) (1r,3r,4r,5s,6r)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl
sulfide;
(b) (1s,2r,3r,5r,7r)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfanyl]-2-phenyl-8-azabicyclo[3
.2.1]octane
4-(2-chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8h-thieno[3,2-b]azepin-8-one (ix) 1,4-bis(benzyloxy)-5-hydroxy-8-nitroanthra-9,10-quinone (iv) 2-nitro-6(5h)-phenanthridinone (i) 4-hydroxy-1-naphthaldehyde (iii) 4-fluorobenzotrifluoride; alpha,alpha-4-tetrafluorotoluene (vi) tert-butyl 4-[4-(trifluoromethyl)phenoxy]-1-piperidinecarboxylate (vii) 4-[4-(trifluoromethyl)phenoxy]piperidine; 4-piperidinyl 4-(trifluoromethyl)phenyl ether (viii) 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-piperidinyl 4-(trifluoromethyl)phenyl ether;
(x) 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-[4-(trifluoromethyl)phenoxy]piperidine
Reference 1:
heeres, j.; et al.; de 2804096 .
Reference 2:
blancafort, p.; sweetman, a.j.; castaner, j.; serradell, m.n.; ketoconazole. drugs fut 1979, 4, 7, 496. Reference 3:
backx, l.j.j.; mostmans, j.h.; heeres, j. (janssen pharmaceutica nv);
1-(1,3-dioxolan-2-ylmethyl)-1h-imidazoles. us 4335125 .