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【结 构 式】

【分子编号】28002

【品名】1-bromo-3-fluorobenzene; 3-Bromofluorobenzene

【CA登记号】1073-06-9

【 分 子 式 】C6H4BrF

【 分 子 量 】175.0001632

【元素组成】C 41.18% H 2.3% Br 45.66% F 10.86%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

The starting 3-fluorothiophenol (I) is obtained either from 3-fluoro-1-bromobenzene (II) by reaction with Mg and a following treatment with S, or from 3-fluoroaniline (III) by the Leuckart method via 3-fluorobenzenediazonium xanthate and 3-fluorophenyl xanthate. Two different ways were described for obtaining the acid (VI): 1) Reaction of (I) with 5-chloro-2-iodobenzoic acid (A) in a boiling aqueous KOH solution in the presence of Cu, which leads to the acid (IV). This is transformed in three steps (reduction with sodium dihydrodibis(2-methoxyethoxy)aluminate, followed by reaction with SOCl2 in pyridine, and final reaction with NaCN in boiling aqueous ethanol) to the nitrile (V), which is hydrolyzed with a boiling solution of KOH in aqueous ethanol. 2) Reaction of (I) with 2,5-dichloro acetophenone (B) in dimethylformamide at 150 C in the presence of Cu. The resulting ketone (VII) is proceased by the Kindler's modification of the Willgerodt reaction: treatment with S in boiling morpholine (C) gives the thiomorpholide (VIII), which is hydrolyzed either with a boiling ethanolic KOH solution or with a refluxing mixture of dilute H2SO4 and acetic acid. The acid (VI), obtained by both routes, is cyclized with polyphosphoric acid at 150 C to the ketone (IX), which is reduced with sodium borohydride in aqueous ethanol to the alcohol (X). Treatment with HCl in benzene in the presence of CaCl2 affords the reactive chloride (XI), which can be converted to the final product (XIV) by two methods: (b) substitution reaction of (XI) with 1-(ethoxycarbonyl)piperazine (D), followed by alkaline hydrolysis of the carbamate (XII) and addition of the secondary amine (XIII) to acrylamide in tert-butyl alcohol in the presence of benzyltriethylammonium hydroxide. (a) substitution reaction with 3-(1-piperazinyl)propionamide (E) in boiling chloroform gives directly (XIV);

1 Rand, K.H.; Houck, H.; Coll Czech Chem Commun 1975, 40, 2887.
2 Nagaoka, M.R.; et al.; Coll Czech Chem Commun 1968, 33, 1852.
3 Coll Czech Chem Commun 1978, 43, 1276.
4 Parola, M.; Robino, G.; Pastacaldi, S.; Gentilini, P.; Pinzani, M.; Marra, F.; Coll Czech Chem Commun 1986, 51, 2598.
5 Yu, D.; Mortin, L.I.; Zhang, X.; Alder, J.; Li, T.; Coll Czech Chem Commun 1967, 32, 2021.
6 Ghiro, L.; et al.; Z Physik Chem (Leipzig) 1931, 156 A, 3, 397.
7 Pomykácek, J.; Diabac, A.; Protiva, M.; Valchár, M.; Jilek, J.; Cervena, I. (SPOFA - United Pharmaceutical Works); N-Substd.-2-chloro-7-fluoro-10-piperazino-10, 11-dihydrobenzo[b,f]thiepins and acid addition salts thereof. EP 0189310; JP 1986204181; US 4678788 .
8 Protiva, M.; VUFB-15496. Drugs Fut 1987, 12, 7, 636.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(F) 10851 Acrylamide 79-06-1 C3H5NO 详情 详情
(D) 24694 N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine 120-43-4 C7H14N2O2 详情 详情
(A) 28004 5-chloro-2-iodobenzoic acid 13421-00-6 C7H4ClIO2 详情 详情
(B) 28005 1-(2,5-dichlorophenyl)-1-ethanone 2476-37-1 C8H6Cl2O 详情 详情
(E) 28016 3-(1-piperazinyl)propanamide C7H15N3O 详情 详情
(I) 28003 3-fluorobenzenethiol 2557-77-9 C6H5FS 详情 详情
(II) 28002 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene 1073-06-9 C6H4BrF 详情 详情
(III) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(IV) 28006 5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid C13H8ClFO2S 详情 详情
(V) 28007 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetonitrile C14H9ClFNS 详情 详情
(VI) 28008 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetic acid C14H10ClFO2S 详情 详情
(VII) 28009 1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone C14H10ClFOS 详情 详情
(VIII) 28010 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-(4-morpholinyl)-1-ethanethione C18H17ClFNOS2 详情 详情
(IX) 28011 2-chloro-7-fluorodibenzo[b,f]thiepin-10(11H)-one C14H8ClFOS 详情 详情
(X) 28012 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-ol C14H10ClFOS 详情 详情
(XI) 28013 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine C14H9Cl2FS 详情 详情
(XII) 28014 ethyl 4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylate C21H22ClFN2O2S 详情 详情
(XIII) 28015 1-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine C18H18ClFN2S 详情 详情
(C) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

Treatment of ethyl acrylate (I) with N-benzylmethylamine (II) affords aminopropionate derivative (III), which is then subjected to Grignard reaction with 3-bromoflurobenzene (IV) by means of Mg and catalytic iodine in refluxing THF and crystallized as a hydrochloride salt by treatment with HCl to provide propylamino derivative (V). Alcohol (V) is converted into allylamine (VI) by elimination induced by heating with HCl/HOAc, and finally the target product is obtained by hydrogenation of (VI) catalyzed by Pd(OH)2/C in EtOH.

1 Moe, S.; Mueller, A.; Balandrin, M. (NPS Pharmaceuticals, Inc.); Methods and cpds. for treating depression and other disorders. EP 1096926; WO 0002551 .
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) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(II) 11969 N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine 103-67-3 C8H11N 详情 详情
(III) 48848 ethyl 3-[benzyl(methyl)amino]propanoate C13H19NO2 详情 详情
(IV) 28002 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene 1073-06-9 C6H4BrF 详情 详情
(V) 48849 3-[benzyl(methyl)amino]-1,1-bis(3-fluorophenyl)-1-propanol C23H23F2NO 详情 详情
(VI) 48850 N-benzyl-N-[3,3-bis(3-fluorophenyl)-2-propenyl]-N-methylamine; N-benzyl-3,3-bis(3-fluorophenyl)-N-methyl-2-propen-1-amine C23H21F2N 详情 详情
Extended Information