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Name Keoxifene hydrochloride;Raloxifene hydrochloride;LY-139481(free base);LY-156758;Optruma;Loxifen;Evista
Chemical Name 1-[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-1-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]benzo[b]thiophene hydrochloride
CAS 82640-04-8
Related CAS 84449-90-1 (free base)
Formula C28H28ClNO4S
Structure
Formula Weight 510.05666
Stage 上市-1998
Company Lilly (Originator), Chugai (Licensee), Esteve (Licensee), Gador (Licensee)
Activity/Mechanism Bone Diseases, Treatment of, Breast Cancer Therapy, CARDIOVASCULAR DRUGS, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , METABOLIC DRUGS, Oncolytic Drugs, Prevention of Osteoporosis, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Treatment of Osteoporosis, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM)
Syn. Route 4
Route 1
the synthesis of radiolabeled raloxifene has been reported:the esterification of 3,5-dibromo-4-hydroxybenzoic acid (i) with methanol/hcl gives the corresponding methyl ester (ii), which is condensed with 1-(2-chloroethyl)piperidine (iii) by means of k2co3 in dmf yielding 3,5-dibromo-4-[2-(1-piperidyl)ethoxy]benzoic acid methyl ester (iv). the hydrolysis of (iv) with naoh in methanol affords the corresponding free acid (v), which by treatment of socl2 in toluene is converted to the acyl chloride (vi). the friedel-crafts condensation of (vi) with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (vii) by means of alcl3 in dichloromethane gives [3,5-dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl]-[6-methoxy-2-(4-methoxy phenyl)benzo[b]thien-3-yl]methanone (viii), which is demethylated with alcl3 and ethylmercaptane to dibromoraloxifene (ix). finally, this compound is submitted to hydrogenolysis with tritium over pd/c in methanol.
List of intermediates No.
(2r,3r)-3-(bromomethyl)-2-oxiranecarboxamide (i)
[(2s,3r)-3-(aminocarbonyl)oxiranyl]methyl acetate (ii)
methyl (2r,3s)-3-[(acetoxy)methyl]-2-oxiranecarboxylate (iii)
(2s,3r)-2-amino-3,4-dihydroxybutanamide (iv)
(1r,2r,3e)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether (v)
methyl 7-oxoheptanoate (vi)
methyl 7-[(2r,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((e,3r,4r)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-7-hydroxyheptanoate (vii)
methyl 7-[(2r,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((e,3r,4r)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentylidene]heptanoate (viii)
4-cyclopentene-1,3-diol (ix)
Reference 1:
    dodge, j.a.; stocksdale, m.g.; jones, c.d.; a chemical probe for the estrogen receptor: synthesis of the h-3 isotopomer of raloxifene. j label compd radiopharm 1995, 36, 1, 43.

Route 2
the two major metabolites of raloxifene, the glucuronide conjugates (vi) and (viii) are synthesized as follows:the partial silylation of raloxifene (i) with tert-butyldimethylsilyl chloride (tbdms-cl) by means of dimethylaminopyridine (dmap) in thf/dmf gives a mixture of the monosilylated compounds (ii) and (iii), which are separated by chromatography. compounds (ii) and (iii) are independently condensed with methyl 1,2,3,4-tetra-o-acetyl-d-glucuronate (iv) by means of bf3.oet2 in dichloromethane yielding protected glucuronides (v) and (vii), respectively. finally, both compounds are deprotected by a treatment first with lioh in dioxane to hydrolyzed the ester groups, and then with tetrabutylammonium fluoride in thf to eliminate the silyl groups, thus obtaining the desired metabolites (vi) and (viii), respectively.
List of intermediates No.
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[2-o-acetyl-3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o-propionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-4-methoxy-8-methyl-3,9-bis(trimethylsilyloxy)hexadeca-10,12-dieno-15-lctone (i)
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[2-o-acetyl-3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o,4-o-dipropionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-4-methoxy-8-methyl-6-(4-propionyloxy-2-butenyl)-3,9-bis(trimethylsilyloxy)hexadeca-10,12-dieno-15-lctone (ii)
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[2-o-acetyl-3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o,4-o-dipropionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-3,9-dihydroxy-4-methoxy-8-methylhexadeca-10,12-dieno-15-lctone (iii)
2-[(8r,13s,14s,17r)-17-hydroxy-13-methyl-3-oxo-2,3,4,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]acetonitrile (iv)
2-[(8s,13s,14s,17r)-5,10-dibromo-17-hydroxy-13-methyl-3-oxohexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]acetonitrile (v)
6-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3ah)-one (vi)
[(dimethoxyphosphoryl)methyl]lithium (vii)
dimethyl [6-(benzyloxy)-4-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylphosphonate (viii)
Reference 1:
    glasebrook, a.l.; frolik, c.a.; dodge, j.a.; cho, s.; phillips, d.l.; lugar, c.w.; osborne, j.j.; synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (ly139481). bioorg med chem lett 1997, 7, 8, 993.
Reference 2:
    dodge, j.a.; stocksdale, m.g.; jones, c.d.; a chemical probe for the estrogen receptor: synthesis of the h-3 isotopomer of raloxifene. j label compd radiopharm 1995, 36, 1, 43.

Route 3
keoxifene has been synthesized using the following process:a portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-pipendinoethoxy)benzoyl]benzo[b]thiophene hydrochloride (i) was combined with denatured alcohol and 5n sodium hydroxide, and stirred under a nitrogen atmosphere. the reaction mixture was evaporated to dryness under vacuum, and the residue dissolved in water and washed with diethyl ether. the water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. the mixture was then acidified with 1n hydrochloric acid, and then made basic with excess sodium bicarbonate the precipitate was collected by filtration and washed with cold water to obtain crude product, which was purified on a column of silica gel. the column was eluted first with 700 ml of 5% methanol in chloroform, followed by 1l of 10% methanol in chloroform. the impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain a yellow oil. the oil was dissolved in acetone seeded and chilled in a freezer to obtain the purified product.
List of intermediates No.
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[2-o-acetyl-3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o-propionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-4-methoxy-8-methyl-3,9-bis(trimethylsilyloxy)hexadeca-10,12-dieno-15-lctone (ii)
1-[[(benzyloxy)carbonyl]amino]ethylphosphinic acid (i)
Reference 1:
    peters, m.k.; jones, c.d.; benzothiophene compounds and process for preparing them. ep 0062053; gb 2097788 .
Reference 2:
    pento, j.t.; keoxifene. drugs fut 1984, 9, 7, 516.

Route 4
two related new syntheses of raloxifene have been described:1) the acylation of n-(6-methoxy-1-benzothiophen-2-yl)-n,n-dimethylamine (i) with 4-fluorobenzoyl chloride (ii) by heating at 100 c in chlorobenzene gives the 3-acyl derivative (iii), which is condensed with 4-methoxyphenylmagnesium bromide (iv) in thf yielding 3-(4-fluorobenzoyl)-6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene (v). the condensation of (v) with 1-(2-hydroxyethyl)piperidine (vi) by means of nah in dmf affords the ether (vii), which is finally demethylated with alcl3 and ethanethiol.2) the intermediate (iii) can also be condensed first with 1-(2-hydroxyethyl)piperidine (vi) by means of nah as before giving the piperidinoethyl ether (viii), which is then condensed with the grignard reagent (iv) affording the previously reported ether (vii).
List of intermediates No.
1-(1h-imidazol-1-ylsulfinyl)-1h-imidazole (ii)
ethyl (3ar,7as)-2-[1-(acetoxy)-5-methoxy-5-oxopentyl]-2,3,3a,4,7,7a-hexahydro-1h-indene-2-carboxylate (v)
3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide (i)
benzyl (3s,4s)-4-(6-fluoro-2-phenyl-1h-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate (iii)
benzyl (3r,4r)-4-fluoro-3-(6-fluoro-2-phenyl-1h-indol-3-yl)-1-piperidinecarboxylate (iv)
4-bromo-2-(1h-1,2,3,4-tetraazol-5-yl)phenylamine; 4-bromo-2-(1h-1,2,3,4-tetraazol-5-yl)aniline (vi)
ethyl 2-oxo-3-(3-pyridinyl)propanoate (viii)
ethyl 2-(dimethoxyphosphoryl)-2-hydroxy-3-(3-pyridinyl)propanoate (vii)
Reference 1:
    bradley, d.a.; et al.; synergistic methodologies for the synthesis of 3-aroyl-2-arylbenzo[b]thiophene-based selective estrogen receptor modulators. two concise syntheses of raloxifene. tetrahedron lett 1999, 40, 28, 5155.

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雷洛昔芬;英文名Keoxifene hydrochloride;Raloxifene hydrochloride;LY-139481(free base);LY-156758;Optruma;Loxifen;Evista;CAS[82640-04-8]

 
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