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【结 构 式】 
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【分子编号】17263 【品名】4-fluorobenzoyl chloride 【CA登记号】403-43-0 |
【 分 子 式 】C7H4ClFO 【 分 子 量 】158.5592632 【元素组成】C 53.03% H 2.54% Cl 22.36% F 11.98% O 10.09% |
合成路线1
该中间体在本合成路线中的序号：(II)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).
| 【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 |
合成路线2
该中间体在本合成路线中的序号：(A)The acidic hydrolysis of 3-nitro-4-hydroxyphenyl-alpha-methylacetonitrile (I) gives 3-nitro-4-hydroxyphenyl-alpha-methylacetic acid (II), which is converted to 3-amino 4-hydroxyphenyl-alpha-methylacetic acid (III) by catalytic hydrogenation. The condensation of (III) with 4-fluorobenzoyl chloride yields 3-(4-fluoro benzamido)-4-hydroxyphenyl-alpha-methylacetic acid (IV), which is cyclized in acidic medium to give 2-(4-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid (V). The racemic (V) was optically resolved by N-methyl-D-glucamine, yielding S-(+)-2-(4-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid.
| 【1】 Forgione, A.; Flunoxaprofen. Drugs Fut 1986, 11, 3, 187. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (I) | 24054 | 2-(4-hydroxy-3-nitrophenyl)propanenitrile | C9H8N2O3 | 详情 | 详情 | |
| (II) | 24055 | 2-(4-hydroxy-3-nitrophenyl)propionic acid | C9H9NO5 | 详情 | 详情 | |
| (III) | 24056 | 2-(3-amino-4-hydroxyphenyl)propionic acid | C9H11NO3 | 详情 | 详情 | |
| (IV) | 24057 | 2-[3-[(4-fluorobenzoyl)amino]-4-hydroxyphenyl]propionic acid | C16H14FNO4 | 详情 | 详情 | |
| (V) | 24058 | 2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propionic acid | C16H12FNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)In a related procedure, 4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine. Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI). This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII), which was finally oxidized as above.
| 【1】 Gallagher, T.F.; et al.; Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem 1997, 5, 1, 49. |
| 【2】 Gallagher, T.F.; et al.; 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg Med Chem Lett 1995, 5, 11, 1171. |
| 【3】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 . |
| 【4】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazoles for treating cytokine mediated disease. WO 9503297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22829 | 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether | C12H21NOSi | 详情 | 详情 | |
| (VII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (VIII) | 55083 | 4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide | C21H16FN3S | 详情 | 详情 | |
| (IX) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (X) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (XI) | 22831 | 2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C19H24FNO2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Protected piperidone (I) is condensed with methoxybromobenzene (II) via Grignard reaction by means of Mg and catalytic iodine in refluxing THF, and the resulting alcohol is then dehydrated with refluxing HCl in dioxane to afford compound (III). Hydrogenation of tetrahydropyridine (III) over Pd/C in EtOH yields piperidine derivative (IV), which is then demethylated with aqueous HBr to provide phenol (V). Condensation of (V) with 4-fluorobenzoyl chloride (VI) by means of NaOH in iPrOH/MeOH/H2O furnishes N-benzoylpiperidine derivative (VII), which is converted into the desired product by reaction with ethyl 2-bromo-2-methylpropanoate (VIII) by means of K2CO3 followed by hydrolysis with NaOH in H2O/MeOH/dioxane.
| 【1】 Komoto, T.; et al.; Preparation of new fibrates with piperidine ring and the pharmacological activity. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-06. |
| 【2】 Komoto, T.; et al.; New strong fibrates with piperidine moiety. Chem Pharm Bull 2000, 48, 12, 1978. |
| 【3】 Komoto, T.; Hirota, H.; Sato, S.; Othsuka, M.; Koya, H.; Mizuno, H.; Kuraishi, T. (SSP Co., Ltd.); Arylamide derivs.. EP 0607536; JP 1995053517; US 5411972 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (III) | 47137 | 1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine; 3-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether | C19H21NO | 详情 | 详情 | |
| (IV) | 47138 | 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 | |
| (V) | 47139 | 3-(4-piperidinyl)phenol | C11H15NO | 详情 | 详情 | |
| (VI) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (VII) | 47140 | (4-fluorophenyl)[4-(3-hydroxyphenyl)-1-piperidinyl]methanone | C18H18FNO2 | 详情 | 详情 | |
| (VIII) | 39799 | ethyl 2-bromo-2-methylpropanoate | 600-00-0 | C6H11BrO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 5-acetyl-2,2-dimethyl-2H-1-benzopyran (III), which is enantioselectively epoxidized catalyzed by chiral salen Mn(III) catalysts to yield the (3R,4R)-epoxide (IV). The reaction of (IV) with ammonia in ethanol affords the (3R,4S)-aminoalcohol (V), which is finally acylated with 4-fluorobenzoyl chloride (VI) and TEA in dichloromethane to provide the target amide. Alternatively, the target amide can also be obtained by direct cleavage of the epoxide ring of (IV) with 4-fluorobenzamide (VII) by means of tBu-OK in tert-butanol.
| 【1】 Chan, W.N.; et al.; Synthesis of novel trans-4-(substituted-benzamido)-3, 4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile. J Med Chem 1996, 39, 23, 4537. |
| 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) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (III) | 28706 | 1-(2,2-dimethyl-2H-chromen-6-yl)-1-ethanone | C13H14O2 | 详情 | 详情 | |
| (IV) | 28707 | 1-[(1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-1-ethanone | C13H14O3 | 详情 | 详情 | |
| (V) | 28708 | 1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone | C13H17NO3 | 详情 | 详情 | |
| (VI) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (VII) | 37090 | 4-fluorobenzamide | 824-75-9 | C7H6FNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)This compound can be obtained by two different ways: 1) The acetylation of 1-nitrosopiperazine (I) with acetyl chloride and pyridine in dioxane gives 1-acetyl-4-nitrosopiperazine (II), which is reduced with Zn and acetic acid/water to 1-acetyl-4-aminopiperazine (III). Finally, this compound is acylated with 4-fluorobenzoyl chloride (IV) by means of triethylamine in dichloromethane. 2) The nitrosation of piperazine (V) with NaNO2/HCl in water, followed by condensation with benzyloxycarbonyl chloride (VI) by means of NaOH yields 1-(benzyloxycarbonyl)-4-nitrosopiperazine (VII), which is reduced with Zn and acetic acid/water as before to the corresponding amino derivative (VIII). The acylation of (VIII) with 4-fluorobenzoyl chloride and triethylamine in dichloromethane affords N-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-fluorobenzamide (IX), which is deprotected with HBr in acetic acid to yield N-(1-piperazinyl)-4-fluorobenzamide (X). Finally, this compound is acetylated with acetic anhydride/NaOH in water.
| 【1】 Graul, A.; Tracy, M.; Castañer, J.; FK-960. Drugs Fut 1997, 22, 8, 830. |
| 【2】 Oku, T.; Todo, E.; Yokota, Y.; Kayakiri, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New aminopiperazine derivs. EP 0436734; JP 1991510050; US 5250528; WO 9101979 . |
| 【3】 Oku, T.; Kayakiri, H.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Novel intermediate for synthetic use and process for producing aminopiperazine derivs. WO 9500502 . |
| 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) | 17260 | 1-nitrosopiperazine | C4H9N3O | 详情 | 详情 | |
| (II) | 17261 | 1-(4-nitrosopiperazino)-1-ethanone | C6H11N3O2 | 详情 | 详情 | |
| (III) | 17262 | 1-(4-aminopiperazino)-1-ethanone | C6H13N3O | 详情 | 详情 | |
| (IV) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 17266 | benzyl 4-nitrosotetrahydro-1(2H)-pyrazinecarboxylate | C12H15N3O3 | 详情 | 详情 | |
| (VIII) | 17267 | benzyl 4-aminotetrahydro-1(2H)-pyrazinecarboxylate | C12H17N3O2 | 详情 | 详情 | |
| (IX) | 17268 | benzyl 4-[(4-fluorobenzoyl)amino]tetrahydro-1(2H)-pyrazinecarboxylate | C19H20FN3O3 | 详情 | 详情 | |
| (X) | 17269 | 4-fluoro-N-piperazinobenzamide | C11H14FN3O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Friedel Crafts condensation of benzothiophene (I) with p-fluorobenzoyl chloride (II) yielded the benzoyl benzothiophene (III). Then, substitution of the fluorine atom of (III) with 2-(1-piperidinyl)ethanethiol (VI) (obtained from b-chloroethylpiperidine (IV) and thiourea (V)), afforded sulfide (VII). Finally, deprotection of the methyl ethers of (VII) with BBr3 in cold 1,2-dichloroethane furnished the target compound.
| 【1】 Glasebrook, A.W.; Schmid, C.R.; Duke, K.M.; Sluka, J.P.; Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene. Bioorg Med Chem Lett 1999, 9, 4, 523. |
| 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) | 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 |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 21916 | (4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone | C23H17FO3S | 详情 | 详情 | |
| (IV) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 21919 | 2-(1-piperidinyl)ethylhydrosulfide; 2-(1-piperidinyl)-1-ethanethiol | C7H15NS | 详情 | 详情 | |
| (VII) | 21920 | [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl](4-[[2-(1-piperidinyl)ethyl]sulfanyl]phenyl)methanone | C30H31NO3S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Condensation of 5-nitroindole (I) with 1-methyl-4-piperidone (II) in the presence of KOH produced tetrahydropyridinyl indole (III). Subsequent catalytic hydrogenation of (III) over Pd/C gave the 5-amino-3-piperidinylindole (VI). In a related procedure, 5-aminoindole (IV) was condensed with piperidone (II), and the resulting tetrahydropyridine (V) was hydrogenated to yield (VI). Aminoindole (VI) was finally condensed with 4-fluorobenzoyl chloride (VII) to produce the corresponding amide, which was isolated as the fumarate salt.
| 【1】 Audia, J.E.; Dressman, B.A.; Droste, J.J.; Fritz, J.E.; Kaldor, S.W.; Koch, D.J.; Krushinski, J.H. Jr.; Nissen, J.S.; Rocco, V.P.; Schaus, J.M.; Thompson, D.C. (Eli Lilly and Company); 5-Substd.-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1H-indoles: New 5-HT1F agonists. EP 0733628; JP 1999502816; US 5708008; WO 9629075 . |
| 【2】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); Use of a serotonin 5-HT1F agonist in the manufacture of a medicament for treating or ameliorating the symptoms of common cold or allergic rhinitis. EP 0824917; US 5962473; WO 9806402 . |
| 【3】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); A method for the prevention of migraine. WO 9811895 . |
| 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) | 26916 | 5-Nitroindole; 5-nitro-1H-indole | 6146-52-7 | C8H6N2O2 | 详情 | 详情 |
| (II) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (III) | 26917 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole | C14H15N3O2 | 详情 | 详情 | |
| (IV) | 26918 | Indole-5-amine; 1H-indol-5-ylamine; 5-Aminoindole | 5192-03-0 | C8H8N2 | 详情 | 详情 |
| (V) | 26919 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine | C14H17N3 | 详情 | 详情 | |
| (VI) | 26920 | 3-(1-methyl-4-piperidinyl)-1H-indol-5-amine | C14H19N3 | 详情 | 详情 | |
| (VII) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The reaction of 4-fluorobenzoyl chloride (I) with N,O-dimethylhydroxylamine (II) in pyridine gives the N-methylhydroxamate (III), which is condensed with 5-bromo-1H-indole (IV) by means of KH and t-BuLi yielding the ketone (V). The alkylation of (V) with ethyl iodide and NaH in DMF affords (1-ethylindol-5-yl)(4-fluorophenyl)methanone (VI), which is reduced with NaBH4 in methanol to the corresponding carbinol (VII). Finally, this compound is treated with carbonyl diimidazole in THF.
| 【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333. |
| 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) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (IV) | 13309 | 5-Bromo-1H-indole; 5-Bromoindole | 10075-50-0 | C8H6BrN | 详情 | 详情 |
| (V) | 29515 | (4-fluorophenyl)(1H-indol-5-yl)methanone | C15H10FNO | 详情 | 详情 | |
| (VI) | 29516 | (1-ethyl-1H-indol-5-yl)(4-fluorophenyl)methanone | C17H14FNO | 详情 | 详情 | |
| (VII) | 29517 | (1-ethyl-1H-indol-5-yl)(4-fluorophenyl)methanol | C17H16FNO | 详情 | 详情 | |
| (VIII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The acylation of indole (I) with 4-fluorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(4-fluorobenzoyl)indole (III), which is N-alkylated with ethyl iodide and K2CO3 in acetone yielding 1-ethyl-3-(4-fluorobenzoyl)indole (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.
| 【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333. |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 29518 | (4-fluorophenyl)(1H-indol-3-yl)methanone | C15H10FNO | 详情 | 详情 | |
| (IV) | 29519 | (1-ethyl-1H-indol-3-yl)(4-fluorophenyl)methanone | C17H14FNO | 详情 | 详情 | |
| (V) | 29520 | (1-ethyl-1H-indol-3-yl)(4-fluorophenyl)methanol | C17H16FNO | 详情 | 详情 | |
| (VI) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)The methylation of 5-bromo-1H-indole (I) with methyl iodide and NaH in DMSO gives the 1-methyl derivative (II), which is acylated with 4-fluorobenzoyl chloride (III) and AlCl3 in dichloromethane yielding the 3-acyl derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.
| 【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333. |
| 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) | 13309 | 5-Bromo-1H-indole; 5-Bromoindole | 10075-50-0 | C8H6BrN | 详情 | 详情 |
| (II) | 29521 | 5-bromo-1-methyl-1H-indole | C9H8BrN | 详情 | 详情 | |
| (III) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (IV) | 29522 | (5-bromo-1-methyl-1H-indol-3-yl)(4-fluorophenyl)methanone | C16H11BrFNO | 详情 | 详情 | |
| (V) | 29523 | (5-bromo-1-methyl-1H-indol-3-yl)(4-fluorophenyl)methanol | C16H13BrFNO | 详情 | 详情 | |
| (VI) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Acylation of 4-nitroaniline (I) with 4-fluorobenzoyl chloride (II) affords benzanilide (III). Catalytic hydrogenation of the nitro group of (III) employing Pt/C then gives amine (IV). Diazotization of (IV), followed by reduction with SnCl2 leads to hydrazine (V). Reaction of 5-chloro-2-pentanone (VI) with dimethylamine yields the amino ketone (VII). Finally, the title compound is obtained by Fisher indole synthesis from aryl hydrazine (V) and ketone (VII) under acidic conditions.
| 【1】 Xu, Y.-C.; Johnson, K.W.; Phebus, L.A.; et al.; N-[3-(2-Dimethylaminoethyl)-2-methyl-1-H-indol-5-yl]-4-fluorobenzamide: A potent, selective, and orally active 5-HT1F receptor agonist potentially useful for migraine therapy. J Med Chem 2001, 44, 24, 4031. |
| 【2】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); Use of a serotonin 5-HT1F agonist in the manufacture of a medicament for treating or ameliorating the symptoms of common cold or allergic rhinitis. EP 0824917; US 5962473; WO 9806402 . |
| 【3】 Fritz, J.E.; Hahn, P.J.; Kaldor, S.W.; Siegel, M.G.; Xu, Y.-C. (Eli Lilly and Company); N-[2-Substd.-3-(2-aminoethyl)-1H-indol-5-yl]-amides: New 5-HT1F agonists. EP 0768301; JP 1999513666; WO 9713512 . |
| 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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 60456 | 4-fluoro-N-(4-nitrophenyl)benzamide | C13H9FN2O3 | 详情 | 详情 | |
| (IV) | 60457 | N-(4-aminophenyl)-4-fluorobenzamide | C13H11FN2O | 详情 | 详情 | |
| (V) | 60458 | 4-fluoro-N-(4-hydrazinophenyl)benzamide | C13H12FN3O | 详情 | 详情 | |
| (VI) | 60460 | 5-chloro-2-pentanone | C5H9ClO | 详情 | 详情 | |
| (VII) | 60459 | 5-(dimethylamino)-2-pentanone | C7H15NO | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XI)2-Bromo-4-methylaniline (I) is converted to quinoline (II) upon condensation with glycerol under Skraup synthesis conditions. Radical bromination of (II) with N-bromosuccinimide affords the benzylic bromide (III), which is subsequently displaced with sodium methanesulfinate to yield sulfone (IV). Alkylation of sulfone (IV) with iodomethane in the presence of potassium tert-butoxide affords the dimethylated sulfone (V). This is then subjected to Suzuki coupling with the boronic acid (VI) to produce the 8-aryl quinoline (VII). Condensation of aldehyde (VII) with 4-(methylthio)aniline (VIII) generates imine (IX), to which methyllithium is added to furnish the alpha methylated amine (X). Acylation of amine (X) by 4-fluorobenzoyl chloride (XI) gives amide (XII). The methylsulfanyl group of (XII) is finally oxidized with oxone to the target bis-sulfone derivative.
| 【1】 Lacombe, P.; Dubé, D.; Deschenes, D.; et al.; Heteroatom-bridged substituted 8-arylquinolines as potent PDE IV inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 328. |
| 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) | 57056 | 2-Bromo-4-methylaniline; 2-Bromo-p-toluidine; 3-Bromo-4-aminotoluene; 4-Amino-3-bromotoluene | 583-68-6 | C7H8BrN | 详情 | 详情 |
| (II) | 57057 | 8-bromo-6-methylquinoline | C10H8BrN | 详情 | 详情 | |
| (III) | 57058 | 8-bromo-6-(bromomethyl)quinoline | C10H7Br2N | 详情 | 详情 | |
| (IV) | 57059 | 8-bromo-6-[(methylsulfonyl)methyl]quinoline; (8-bromo-6-quinolinyl)methyl methyl sulfone | C11H10BrNO2S | 详情 | 详情 | |
| (V) | 57060 | 1-(8-bromo-6-quinolinyl)-1-methylethyl methyl sulfone; 8-bromo-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline | C13H14BrNO2S | 详情 | 详情 | |
| (VI) | 57061 | 3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid | 87199-16-4 | C7H7BO3 | 详情 | 详情 |
| (VII) | 57062 | 3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}benzaldehyde | C20H19NO3S | 详情 | 详情 | |
| (VIII) | 57066 | 4-(Methylmercapto)aniline; 4-(Meylthio)aniline; 4-(Meylthio)benzenamine; 4-Aminothioanisole; p-(Methylmercapto)aniline; p-(Meylthio)aniline; p-(Meylthio)benzenamine; p-Aminothioanisole | 104-96-1 | C7H9NS | 详情 | 详情 |
| (IX) | 57063 | N-[(E)-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)methylidene]-N-[4-(methylsulfanyl)phenyl]amine; N-[(E)-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)methylidene]-4-(methylsulfanyl)aniline | C27H26N2O2S2 | 详情 | 详情 | |
| (X) | 57064 | N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-4-(methylsulfanyl)aniline; N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-N-[4-(methylsulfanyl)phenyl]amine | C28H30N2O2S2 | 详情 | 详情 | |
| (XI) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (XII) | 57065 | 4-fluoro-N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-N-[4-(methylsulfanyl)phenyl]benzamide | C35H33FN2O3S2 | 详情 | 详情 |