(3-bromophenoxy)(tert-butyl)dimethylsilane; 3-bromophenyl tert-butyl(dimethyl)silyl ether -Drug Synthesis Database

【结构式】

【分子编号】20705

【品名】(3-bromophenoxy)(tert-butyl)dimethylsilane; 3-bromophenyl tert-butyl(dimethyl)silyl ether

【CA登记号】65423-56-5

【分子式】C₁₂H₁₉BrOSi

【分子量】287.27176

【元素组成】C 50.17% H 6.67% Br 27.81% O 5.57% Si 9.78%

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：(XIX)

The title compound was synthesized by two related procedures. 3-Fluoro-N-methylaniline (XIV) was obtained from 3-fluoroaniline (XI) by condensation with 1-(hydroxymethyl)benzotriazole (XII), followed by reduction of the anilinomethylbenzotriazole (XIII) with NaBH4. Subsequent condensation with 3-formylbenzoyl chloride (XV) (prepared from the corresponding acid and SOCl2) provided amide (XVI). Then, condensation of (XVI) with piperazine (V) and benzotriazole in the presence of a catalytic amount of Et3N in refluxing toluene furnished (XVII) as a mixture of epimers. 3-Bromophenol (XVIII) was protected as the silyl ether (XIX) with tert-butyldimethylsilyl chloride and imidazole. This compound was converted to the organolithium derivative with n-butyllithium in THF at -78 C, and further transformed to the arylmagnesium reagent (XX) by treatment with magnesium bromide etherate in THF. Condensation of (XVII) with organometallic compound (XX) afforded the benzhydrylpiperazine (XXI) as a 10:1 mixture of epimers. Desilylation of (XXI) by treatment with HCl in aqueous THF, followed by recrystallization of the major isomer from EtOAc/hexane yielded the title compound.

参考文献中间体

合成目标

【1】 Chang, K.; Boswell, G.E.; Bubacz, D.G.; Collins, M.A.; Davis, A.O.; McNutt, R.W. (Delta Pharmaceuticals, Inc.); Opioid diarylmethylpiperazines and piperidines. JP 1995503247; US 5658908; US 5681830; WO 9315062 .
【2】 Chang, K.-J.; Bishop, M.J.; Bubacz, D.G.; McNutt, R.W. Jr. (Glaxo Wellcome plc); Piperazine cpds. used in therapy. EP 0711289; JP 1997501156; WO 9504051 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	20690	(2R,5S)-1-allyl-2,5-dimethylpiperazine		C₉H₁₈N₂	详情	详情
(XI)	20697	3-fluoroaniline; 3-fluorophenylamine	372-19-0	C₆H₆FN	详情	详情
(XII)	20698	1H-1,2,3-benzotriazol-1-ylmethanol	28539-02-8	C₇H₇N₃O	详情	详情
(XIII)	20699	N-(1H-1,2,3-benzotriazol-1-ylmethyl)-3-fluoroaniline; N-(1H-1,2,3-benzotriazol-1-ylmethyl)-N-(3-fluorophenyl)amine		C₁₃H₁₁FN₄	详情	详情
(XIV)	20700	3-fluoro-N-methylaniline; N-(3-fluorophenyl)-N-methylamine		C₇H₈FN	详情	详情
(XV)	20701	3-formylbenzoyl chloride		C₈H₅ClO₂	详情	详情
(XVI)	20702	N-(3-fluorophenyl)-3-formyl-N-methylbenzamide		C₁₅H₁₂FNO₂	详情	详情
(XVII)	20703	3-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](1H-1,2,3-benzotriazol-1-yl)methyl]-N-(3-fluorophenyl)-N-methylbenzamide		C₃₀H₃₃FN₆O	详情	详情
(XVIII)	20704	3-bromophenol	591-20-8	C₆H₅BrO	详情	详情
(XIX)	20705	(3-bromophenoxy)(tert-butyl)dimethylsilane; 3-bromophenyl tert-butyl(dimethyl)silyl ether	65423-56-5	C₁₂H₁₉BrOSi	详情	详情
(XX)	20706	bromo(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)magnesium		C₁₂H₁₉BrMgOSi	详情	详情
(XXI)	20707	3-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]-N-(3-fluorophenyl)-N-methylbenzamide		C₃₆H₄₈FN₃O₂Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

In an alternative procedure, the silylether of 3-bromophenol (XIX) was converted to the organolithium compound (XXII) and then coupled to 3-bromobenzaldehyde (XXIII) in THF at -78 C. The resulting benzhydrol (XXIV) was treated with SOCl2 to give chloride (XXV), which was subsequently condensed with piperazine (V) in refluxing acetonitrile. The diastereomeric mixture of benzhydryl piperazines (XXVI) was desilylated with tetraethylammonium fluoride, and the major isomer (XXVII) was isolated by recrystallization from acetonitrile. The bromo substituent of (XXVII) was then substituted for a cyano group upon treatment with CuCN in N-methylpyrrolidinone at 170 C. Basic hydrolysis of nitrile (XXVIII) gave acid (XXIX), which was protected as the tert-butyldimethylsilyl ether and further converted to acid chloride (XXX) by reaction with oxalyl chloride and a catalytic amount of DMF. Finally, acid chloride (XXX) was condensed with N-methyl-3-fluoroaniline (XIV), and the silyl protecting group was removed by treatment with tetraethylammonium fluoride in acetonitrile.

参考文献中间体

合成目标

【1】 Chang, K.-J.; Bishop, M.J.; Bubacz, D.G.; McNutt, R.W. Jr. (Glaxo Wellcome plc); Piperazine cpds. used in therapy. EP 0711289; JP 1997501156; WO 9504051 .
【2】 Chang, K.; Boswell, G.E.; Bubacz, D.G.; Collins, M.A.; Davis, A.O.; McNutt, R.W. (Delta Pharmaceuticals, Inc.); Opioid diarylmethylpiperazines and piperidines. JP 1995503247; US 5658908; US 5681830; WO 9315062 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	20690	(2R,5S)-1-allyl-2,5-dimethylpiperazine		C₉H₁₈N₂	详情	详情
(XIV)	20700	3-fluoro-N-methylaniline; N-(3-fluorophenyl)-N-methylamine		C₇H₈FN	详情	详情
(XIX)	20705	(3-bromophenoxy)(tert-butyl)dimethylsilane; 3-bromophenyl tert-butyl(dimethyl)silyl ether	65423-56-5	C₁₂H₁₉BrOSi	详情	详情
(XXII)	20708	(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)lithium		C₁₂H₁₉LiOSi	详情	详情
(XXIII)	10477	3-Bromobenzaldehyde; m-Bromobenzaldehyde	3132-99-8	C₇H₅BrO	详情	详情
(XXIV)	20710	(3-bromophenyl)(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methanol		C₁₉H₂₅BrO₂Si	详情	详情
(XXV)	20711	3-[(3-bromophenyl)(chloro)methyl]phenyl tert-butyl(dimethyl)silyl ether; [3-[(3-bromophenyl)(chloro)methyl]phenoxy](tert-butyl)dimethylsilane		C₁₉H₂₄BrClOSi	详情	详情
(XXVI)	20712	(2R,5S)-1-allyl-4-[(3-bromophenyl)(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]-2,5-dimethylpiperazine; 3-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-bromophenyl)methyl]phenyl tert-butyl(dimethyl)silyl ether		C₂₈H₄₁BrN₂OSi	详情	详情
(XXVII)	20713	3-[(S)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-bromophenyl)methyl]phenol		C₂₂H₂₇BrN₂O	详情	详情
(XXVIII)	20714	3-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-hydroxyphenyl)methyl]benzonitrile		C₂₃H₂₇N₃O	详情	详情
(XXIX)	20715	3-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-hydroxyphenyl)methyl]benzoic acid		C₂₃H₂₈N₂O₃	详情	详情
(XXX)	20716	3-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]benzoyl chloride		C₂₉H₄₁ClN₂O₂Si	详情	详情

Extended Information