1-bromo-3-fluorobenzene; 3-Bromofluorobenzene -Drug Synthesis Database

【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 合成路线2

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);

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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