bromo(3-fluorophenyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】35384

【品名】bromo(3-fluorophenyl)magnesium

【CA登记号】

【分子式】C₆H₄BrFMg

【分子量】199.3051632

【元素组成】C 36.16% H 2.02% Br 40.09% F 9.53% Mg 12.19%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-4-one (I) with 3-fluorophenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.

参考文献中间体

合成目标

【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26.
【2】 Okubo, T.; Tanaka, H.; Chaki, S.; Okuyama, S.; Tomisawa, K.; Kumagai, T.; Nakazato, A.; Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor1 receptor antagonists. Bioorg Med Chem 2000, 8, 5, 1183.
【3】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10925	Iodoethane;ethyl iod	75-03-6	C₂H₅I	详情	详情
(I)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(II)	35384	bromo(3-fluorophenyl)magnesium		C₆H₄BrFMg	详情	详情
(III)	35385	tert-butyl 4-(3-fluorophenyl)-4-hydroxy-1-piperidinecarboxylate		C₁₆H₂₂FNO₃	详情	详情
(IV)	35386	4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine		C₁₁H₁₂FN	详情	详情
(V)	35387	2,4-dichloro-6-methylpyrimidine	5424-21-5	C₅H₄Cl₂N₂	详情	详情
(VI)	35388	2-chloro-4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methylpyrimidine		C₁₆H₁₅ClFN₃	详情	详情
(VII)	35389	4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline		C₁₀H₁₅NS	详情	详情
(VIII)	35390	N-[4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methyl-2-pyrimidinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]amine; 4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methyl-2-pyrimidinamine		C₂₆H₂₉FN₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The desired enantiomer was prepared by two chiral routes. Monoalkylation of (S)-alpha-methylbenzylamine (I) with benzyl bromide in N,N'-dimethylpropyleneurea gave the chiral secondary amine (II). Diastereoselective Michael addition of the lithium amide of (II) to benzyl crotonate (III) provided adduct (IV). The chiral ester (IV) was then reacted with the Grignard reagent (V) to yield the diaryl carbinol (VI). This was subsequently dehydrated to (VII) using H2SO4 in glacial HOAc. Double bond reduction and N-debenzylation of (VII) over Pearlman抯 catalyst provided the target primary amine, which was finally isolated as the hydrochloride salt.

参考文献中间体

合成目标

【1】 Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411.
【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 .
【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 .
【4】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 .

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)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(II)	38470	(1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine	38235-77-7	C₁₅H₁₇N	详情	详情
(III)	46908	benzyl (E)-2-butenoate		C₁₁H₁₂O₂	详情	详情
(IV)	46909	benzyl (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]butanoate		C₂₆H₂₉NO₂	详情	详情
(V)	35384	bromo(3-fluorophenyl)magnesium		C₆H₄BrFMg	详情	详情
(VI)	46910	(3S)-3-[benzyl[(1S)-1-phenylethyl]amino]-1,1-bis(3-fluorophenyl)-1-butanol		C₃₁H₃₁F₂NO	详情	详情
(VII)	46911	(2S)-N-benzyl-4,4-bis(3-fluorophenyl)-N-[(1S)-1-phenylethyl]-3-buten-2-amine; N-benzyl-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methyl-2-propenyl]-N-[(1S)-1-phenylethyl]amine		C₃₁H₂₉F₂N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Piperonal (I) is brominated by means of Br2 in AcOH to produce (II). Subsequent Suzuki coupling of aryl bromide (II) with 4-(methylsulfanyl)benzeneboronic acid (III) furnishes adduct (IV). Addition of 3-fluorophenylmagnesium bromide (V) to aldehyde (IV) leads to carbinol (VI). The sulfide group is further oxidized to sulfone (VII) employing oxone in aqueous MeOH. Finally, oxidation of alcohol (VII) with pyridinium chlorochromate provides the target ketone. (1,2)

参考文献中间体

合成目标

【1】 Ezawa, M.; Khanapure, S.P.; Garvey, D.S.; Young, D.; Earl, R.; Gaston, R.; Fang, F.; Marek, P.; Shumway, M.; Trocha, M.; Tam, S.W.; Janero, D.R.; Letts, L.G.; Design and synthesis of novel benzo-dioxolane cyclooxygenase (COX-2) selective inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 243.
【2】 Earl, R.A.; Garvey, D.S.; Khanapure, S.P.; Gaston, R.D.; Fang, X.; Ezawa, M. (NitroMed Inc.); Substd. aryl cpds. as novel cyclooxygenase-2 selective inhibitors, compsns. and methods of use. US 2002119977; WO 0260378 .

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)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(II)	46376	ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate		C₃₀H₂₈BrNO₈	详情	详情
(III)	18561	4-(methylsulfanyl)phenylboronic acid	98546-51-1	C₇H₉BO₂S	详情	详情
(IV)	64023	6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxole-5-carbaldehyde		C₁₅H₁₂O₃S	详情	详情
(V)	35384	bromo(3-fluorophenyl)magnesium		C₆H₄BrFMg	详情	详情
(VI)	64024	(3-fluorophenyl){6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxol-5-yl}methanol		C₂₁H₁₇FO₃S	详情	详情
(VII)	64025	(3-fluorophenyl){6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-5-yl}methanol		C₂₁H₁₇FO₅S	详情	详情

Extended Information