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【结 构 式】 
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【分子编号】12028 【品名】Bromo[3-(trifluoromethyl)phenyl]magnesium 【CA登记号】402-26-6 |
【 分 子 式 】C7H4BrF3Mg 【 分 子 量 】249.3129696 【元素组成】C 33.72% H 1.62% Br 32.05% F 22.86% Mg 9.75% |
合成路线1
该中间体在本合成路线中的序号：(I)By a Grignard reaction between 3-trifluoromethylphenylmagnesium bromide (I) and propiophenone (II) in ethyl ether.
| 【1】 Edit, T.; et al. (Gedeon Richter Ltd.); alpha-Substituted benzhydrol derivatives and a process for the preparation thereof. BE 0818801; DE 2438399; FR 2240725; GB 1478185; JP 50062959; US 4039589 . |
| 【2】 Castaner, J.; Hillier, H.; Flumecinol. Drugs Fut 1978, 3, 10, 742. |
合成路线2
该中间体在本合成路线中的序号：(II)Grignard reaction of 3-trifluoromethylbenzene-magnesium bromide (II) with 3-pyridinecarboxaldehyde (I) in THF at 15 C gives alpha-[3-(trifluoromethyl)phenyl]-3-pyridinemethanol (III). Oxidation of this compound with MnO2 in refluxing CH2Cl2 yields the corresponding ketone (IV). The oximation reaction carried out with NH2OH.HCl in isopropanol-HCl at 70 C affords (3-pyridinyl)-[3-(trifluoromethyl)phenyl]methanone oxime (V) (more than 90% of the E-isomer). The alkylation of (V) with ethyl bromovalerate in the presence of NaOH in DMF produces ethyl 5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy] pentanoate (VI). Hydrolysis of the ester with aqueous NaOH followed by HCl treatment gives, after recrystallization from diisopropylether, ridogrel.
| 【1】 Freyne, E.J.E.; Raeymaekers, A.H.; Sipido, V.; Venet, M.G. (Janssen Pharmaceutica NV); Pharmaceutical use of [[[(3-pyridinyl)methylen]amino]oxy]alkanoic acid and esters. EP 0221601; JP 1987161759; JP 1991068556; US 4746671 . |
| 【2】 Freyne, E.J.; Raeymaekers, A.H.M.; Venet, M.G.; Sipido, V.K.; De Clerck, F.; RIDOGREL. Drugs Fut 1990, 15, 5, 463. |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 12028 | Bromo[3-(trifluoromethyl)phenyl]magnesium | 402-26-6 | C7H4BrF3Mg | 详情 | 详情 |
| (III) | 12029 | 3-Pyridinyl[3-(trifluoromethyl)phenyl]methanol | C13H10F3NO | 详情 | 详情 | |
| (IV) | 12030 | 3-Pyridinyl[3-(trifluoromethyl)phenyl]methanone | C13H8F3NO | 详情 | 详情 | |
| (V) | 12031 | 3-Pyridinyl[3-(trifluoromethyl)phenyl]methanone oxime | C13H9F3N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)A synthesis of [14C]-labeled SR-57746A has been described: The iodination of [14C6]-benzene (I) with nitric acid/I2 gives iodobenzene (II), which is treated with sodium trifluoroacetate and CuI yielding trifluoromethylbenzene (III). The nitration of (III) with sodium nitrate affords 3-(trifluoromethyl)nitrobenzene (IV), which is reduced with Fe/HCl to the corresponding aniline (V). The reaction of (V) with tert-butyl nitrite and CuBr2 provides 3-(trifluoromethyl)bromobenzene (VI), which is treated with Mg in THF affording the corresponding Grignard reagent (VII). The condensation of (VII) with piperidone (VIII) gives the piperidol (IX), which is finally dehydrated in acidic medium. In order to aviod radioactive contamination during the purification of compounds iodobenzene (II) and trifluoromethylbenzene (III) by liquid chromatography, a safer route using less volatile compounds has been developed: The nitration of [14C6]-benzene (I) with nitric acid gives nitrobenzene (X), which is iodinated with IPy2BF4/CF3SO3H yielding 3-iodonitrobenzene (XI). Finally, this compound is trifluoromethylated with CF3SiMe3, CuI and KF to provide 3-(trifluoromethyl)nitrobenzene (IV) already reported.
| 【1】 Robic, N.; Noel, J.P.; Synthesis of [trifluoromethyl-[C-14(6)]-phenyl] SR 57746A. J Label Compd Radiopharm 1999, 42, 2, 109. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 45201 | benzene | C6H6 | 详情 | 详情 | |
| (II) | 26344 | 1-Iodobenzene | 591-50-4 | C6H5I | 详情 | 详情 |
| (II) | 45202 | 1-iodobenzene | C6H5I | 详情 | 详情 | |
| (III) | 26345 | 1-(Trifluoromethyl)benzene | 98-08-8 | C7H5F3 | 详情 | 详情 |
| (III) | 45203 | 1-(trifluoromethyl)benzene | C7H5F3 | 详情 | 详情 | |
| (IV) | 26346 | 1-nitro-3-(trifluoromethyl)benzene | 98-46-4 | C7H4F3NO2 | 详情 | 详情 |
| (IV) | 45204 | 1-nitro-3-(trifluoromethyl)benzene | C7H4F3NO2 | 详情 | 详情 | |
| (V) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (V) | 45205 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline | C7H6F3N | 详情 | 详情 | |
| (VI) | 26348 | 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride | 401-78-5 | C7H4BrF3 | 详情 | 详情 |
| (VI) | 45206 | 1-bromo-3-(trifluoromethyl)benzene | C7H4BrF3 | 详情 | 详情 | |
| (VII) | 12028 | Bromo[3-(trifluoromethyl)phenyl]magnesium | 402-26-6 | C7H4BrF3Mg | 详情 | 详情 |
| (VII) | 45207 | bromo[3-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 26349 | 1-[2-(2-naphthyl)ethyl]-4-piperidinone | C17H19NO | 详情 | 详情 | |
| (IX) | 26350 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (IX) | 45208 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (X) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (X) | 45209 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (XI) | 26352 | 3-Iodonitrobenzene; 1-iodo-3-nitrobenzene | 645-00-1 | C6H4INO2 | 详情 | 详情 |
| (XI) | 45210 | 1-iodo-3-nitrobenzene | C6H4INO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)3-Bromobenzotrifluoride (I) is converted into the corresponding Grignard reagent (II), which is then condensed with 1,2-dibromo-1-methoxyethane (III) producing the phenethyl bromide (IV). Reaction of bromide (IV) with (S)-alpha-methylbenzylamine (V) yields amine (VI) as a diastereomeric mixture. Recrystallization of (VI) from isopropanol leads to a pure diastereoisomer, which is subsequently treated with ethyl bromoacetate to furnish amino ester (VII). Reduction of (VII) using LiAlH4 provides alcohol (VIII), and further chlorination with SOCl2 leads to chloro amine (IX). Acid (X) is then alkylated with chloride (IX) producing ester (XI). The chiral auxiliary alpha-methylbenzyl group is finally removed by hydrogenolysis to afford the title compound.
| 【1】 Wierzbicki, M.; Hugon, P.; Duhault, J.; Lacour, F.; Boulanger, M. (ADIR et Cie.); Ethanolaminebenzoate deriv., process for their preparation and pharmaceutical compsns. containing them. EP 0518769; FR 2677647; JP 1993238997; US 5266718 . |
| 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) | 26348 | 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride | 401-78-5 | C7H4BrF3 | 详情 | 详情 |
| (II) | 12028 | Bromo[3-(trifluoromethyl)phenyl]magnesium | 402-26-6 | C7H4BrF3Mg | 详情 | 详情 |
| (III) | 58091 | 1,2-dibromo-1-methoxyethane; 1,2-dibromoethyl methyl ether | C3H6Br2O | 详情 | 详情 | |
| (IV) | 58092 | 1-(2-bromo-1-methoxyethyl)-3-(trifluoromethyl)benzene; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethyl methyl ether | C10H10BrF3O | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 58093 | 2-methoxy-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine; N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1S)-1-phenylethyl]amine | C18H20F3NO | 详情 | 详情 | |
| (VII) | 58094 | ethyl 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}acetate | C22H26F3NO3 | 详情 | 详情 | |
| (VIII) | 58095 | 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}-1-ethanol | C20H24F3NO2 | 详情 | 详情 | |
| (IX) | 58096 | N-(2-chloroethyl)-N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1R)-1-phenylethyl]amine; N-(2-chloroethyl)-2-methoxy-N-[(1R)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine | C20H23ClF3NO | 详情 | 详情 | |
| (X) | 58097 | 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoic acid | C24H21NO3 | 详情 | 详情 | |
| (XI) | 58098 | 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}ethyl 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoate | C44H43F3N2O4 | 详情 | 详情 |