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Name Venlafaxine hydrochloride;Wy-45030;Effexor LP;Efexor XL;Efexor XR;Efectin;Trevilor;Vandral;Dobupal;Efexor;Effexor
Chemical Name (±)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride;(±)-1-[alpha-(Dimethylaminomethyl)-4-methoxybenzyl]cyclohexanol hydrochloride
CAS 99300-78-4
Related CAS 93413-78-6 (deleted CAS), 93413-69-5 (free base)
Formula C17H28ClNO2
Structure
Formula Weight 313.87121
Stage 上市-1994
Company Wyeth Pharmaceuticals (Originator), Solvay (Marketer), Almirall Prodesfarma (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antidepressants, Anxiolytics, Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Generalized Anxiety Disorder (GAD), Treatment of, Mood Disorders, Treatment of, Neuropathic Pain, Treatment of, Posttraumatic Stress Disorder (PTSD), Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Social Phobia, Treatment for, Treatment of Diabetic Complications, 5-HT Reuptake Inhibitors, Norepinephrine Reuptake Inhibitors
Syn. Route 3
Route 1
the condensation of cyclohexanone (i) with 4 methoxyphenylacetonitrile (ii) by means of n-butyllithium in thf gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl) acetonitrile (iii), which is reduced with h2 over rh/a12o3 in ethanol-ammonia yielding 1-[2-amino-1-(4 methoxyphenyl)ethyl]cyclohexanol (iv). finally, this compound is methylated with formaldehyde and formic acid in refluxing water.
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (i)
(ii)
(iii)
2-fluorophenyl isocyanate; 1-fluoro-2-isocyanatobenzene (iv)
Reference 1:
    husbands, g.e.; et al.; novel phenethylamine antidepressants. 190th acs natl meet (chicago) 1985, 20, 29-30, abst medi 80.
Reference 2:
    morris, g.e.; muth, e.a.; yardley, j.p. (american home products corp.); phenethylamine derivs.. ep 0112669; es 8702336; gb 2133788; jp 1991135948; jp 1991178953; us 4535186 .
Reference 3:
    prous, j.; castaner, j.; wy-45030. drugs fut 1988, 13, 9, 839.
Reference 4:
    yardley, j.p.; husbands, g.e.m.; stack, g.; et al.; 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity. j med chem 1990, 33, 10, 2899-905.

Route 2
the condensation of 2-(4-methoxyphenyl)-n,n-dimethylthioacetamide (i) with cyclohexanone (ii) by means of isopropylmagnesium bromide in toluene/methyl tert-butyl ether gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-n,n-dimethylthioacetamide (iii), which is finally desulfurized by means of raney-nickel in dioxane/acetic acid.
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (ii)
2-adamantanethione (i)
tert-butyl 2-(2-sulfanyl-2-adamantyl)acetate (iii)
Reference 1:
    shepard, r.g. (john wyeth & brother ltd.); preparation of cyclohexanol derivs. and novel thioamide intermediates. us 5043466 .

Route 3
a new process for the production of venlafaxine has been reported: esterification of 2-(4-methoxyphenyl)-acetic acid (i) with ethanol and sulfuric acid gives the corresponding ethyl ester (ii), which is condensed with ethyl formate by means of nah to yield 2-formyl-3-(4-methoxyphenyl)acetic acid ethyl ester (iii). reaction of (iii) with dimethylamine and k2co3 in etoh affords 3-(dimethylamino)-2-(4-methoxyphenyl)acrylic acid ethyl ester (iv), which is reduced with either nabh4, lialh4 or h2 over pd/c or pt/c in ethanol to provide the corresponding propionic ester (v). finally, this compound is cyclized with the bismagnesiane (vi) in thf.alternatively, acrylic ester (iv) can be obtained directly by condensation of acetate (ii) with dimethylformamide diethylacetal (vii) at 135 c.alternatively, propionic ester (v) can be obtained by condensation of acetate (ii) with n,n-dimethylmethylene-iminium iodide (viii) by means of lda in thf/heptane/ ethylbenzene.
List of intermediates No.
4,8-dimethyl-1,2,4,4a,5,6-hexahydro-3h-pyrido[1,2-a]quinolin-3-one (vii)
(5s)-5-(acetamido)-9,10,11-trimethoxy-6,7-dihydro-5h-dibenzo[a,c]cyclohepten-3-yl di(tert-butyl) phosphite (i)
4-methoxy-3-(3-methoxypropoxy)benzaldehyde (ii)
propyl 3-methylbutanoate (iii)
propyl 2-{hydroxy[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate (iv)
propyl 2-{(acetyloxy)[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate (v)
propyl (e)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoate (vi)
(e)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propen-1-ol (viii)
Reference 1:
    camps garcia, p.; bosch i llado, j.; onrubia miguel, m.c.; arnalot i aguilar, c.; soldevila madrid, n. (medichem sa); venlafaxine production process. wo 0107397 .

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名鹽酸文拉法辛;英文名Venlafaxine hydrochloride;Wy-45030;Effexor LP;Efexor XL;Efexor XR;Efectin;Trevilor;Vandral;Dobupal;Efexor;Effexor;CAS[99300-78-4]

 
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