Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481(free base), LY-156758, Optruma, Loxifen, Evista, -Drug Synthesis Database

【结构式】

【药物名称】Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481(free base), LY-156758, Optruma, Loxifen, Evista

【化学名称】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

【CA登记号】82640-04-8, 84449-90-1 (free base)

【分子式】C₂₈H₂₈ClNO₄S

【分子量】510.05666

【开发单位】Lilly (Originator), Chugai (Licensee), Esteve (Licensee), Gador (Licensee)

【药理作用】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)

合成路线1 合成路线2 合成路线3 合成路线4

合成路线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.

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10115	3,5-Dibromo-4-hydroxybenzoic acid	3337-62-0	C₇H₄Br₂O₃	详情	详情
(II)	10116	methyl 3,5-dibromo-4-hydroxybenzoate	41727-47-3	C₈H₆Br₂O₃	详情	详情
(III)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(IV)	10118	methyl 3,5-dibromo-4-(2-piperidinoethoxy)benzoate		C₁₅H₁₉Br₂NO₃	详情	详情
(V)	10119	3,5-Dibromo-4-(2-piperidinoethoxy)benzoic acid		C₁₄H₁₇Br₂NO₃	详情	详情
(VI)	10120	3,5-Dibromo-4-(2-piperidinoethoxy)benzoyl chloride		C₁₄H₁₆Br₂ClNO₂	详情	详情
(VII)	10121	4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene	63675-74-1	C₁₆H₁₄O₂S	详情	详情
(VIII)	10122	[3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone		C₃₀H₂₉Br₂NO₄S	详情	详情
(IX)	10123	[3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone		C₂₈H₂₅Br₂NO₄S	详情	详情

合成路线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.

参考文献中间体

【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.
【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17321	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone		C₂₈H₂₇NO₄S	详情	详情
(II)	17322	[6-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(III)	17323	[2-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-6-hydroxy-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(IV)	17324	methyl (2S,3R,4S,5R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate	7355-18-2	C₁₅H₂₀O₁₁	详情	详情
(V)	17325	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VI)	17326	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VII)	17327	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情
(VIII)	17328	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情

合成路线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.

参考文献中间体

【1】 Peters, M.K.; Jones, C.D.; Benzothiophene compounds and process for preparing them. EP 0062053; GB 2097788 .
【2】 Pento, J.T.; Keoxifene. Drugs Fut 1984, 9, 7, 516.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	30520	[6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-(4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]phenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₃₉NO₄S₃	详情	详情
(II)	17321	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone		C₂₈H₂₇NO₄S	详情	详情

合成路线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).

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	30906	N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine; 6-methoxy-N,N-dimethyl-1-benzothiophen-2-amine		C₁₁H₁₃NOS	详情	详情
(II)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(III)	37673	[2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl](4-fluorophenyl)methanone		C₁₈H₁₆FNO₂S	详情	详情
(IV)	37674	Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide	352-13-6	C₇H₇BrMgO	详情	详情
(V)	21916	(4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone		C₂₃H₁₇FO₃S	详情	详情
(VI)	37675	2-(1-piperidinyl)-1-ethanol	3040-44-6	C₇H₁₅NO	详情	详情
(VII)	37677	[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₀H₃₁NO₄S	详情	详情
(VIII)	37676	[2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₂₅H₃₀N₂O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)