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【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

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.

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.

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