【结 构 式】 |
【分子编号】38430 【品名】tert-butyl[[3-(3,4-dichlorophenyl)-3-butenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(3,4-dichlorophenyl)-3-butenyl ether 【CA登记号】 |
【 分 子 式 】C16H24Cl2OSi 【 分 子 量 】331.35686 【元素组成】C 58% H 7.3% Cl 21.4% O 4.83% Si 8.48% |
合成路线1
该中间体在本合成路线中的序号:(XII)The intermediate 3-(3,4-dichlorophenyl)-3-buten-1-ol silyl ether (XII) was prepared by several procedures: 1) Addition of the organozinc reagent (IX) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) to diketene (X) in the presence of palladium catalyst, followed by esterification with MeOH and H2SO4 furnished 3-arylbutenoate methyl ester (XI), which was reduced to alcohol with LiAlH4 and then silylated with tert-butyldimethylsilyl chloride to give silyl ether (XII). 2) In an alternative procedure, ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate (XIII) was protected with triethyl orthoformate in the presence of p-toluenesulfonic acid and then reduced to alcohol (XIV) with LiAlH4. Ketal deprotection of (XIV) with trifluoroacetic acid provided hydroxy ketone (XV). After silylation of (XV) with tert-butyldimethylsilyl chloride, subsequent Wittig condensation with methylene triphenylphosphorane gave intermediate silyl eher (XII). 3) In a further procedure, the Grignard reagent (XVI) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) was coupled with 3-iodo-3-buten-1-ol silyl ether (XVII) in the presence of palladium catalyst to furnish intermediate ether (XII).
【1】 Kurata, H.; Ito, K.; Nakajima, K.; Yamaguchi, T.; Ishibashi, K.; Fukuzawa, T.; Nishi, T. (Sankyo Co., Ltd.); Azaheterocyclic cpds. having tachykinin receptor antagonist activity; NK1 and NK2. EP 0776893; JP 1998152478; JP 1998182649; JP 1998182650 . |
【2】 Nishi, T.; Yamaguchi, T. (Sankyo Co., Ltd.); Salts of optically active sulfoxide deriv.. EP 0987269; JP 1999043490; WO 9854191 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIII) | 38427 | 4-bromo-1,2-dichlorobenzene | 18282-59-2 | C6H3BrCl2 | 详情 | 详情 |
(IX) | 38428 | chloro(3,4-dichlorophenyl)zinc | C6H3Cl3Zn | 详情 | 详情 | |
(X) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
(XI) | 38429 | methyl 3-(3,4-dichlorophenyl)-3-butenoate | C11H10Cl2O2 | 详情 | 详情 | |
(XII) | 38430 | tert-butyl[[3-(3,4-dichlorophenyl)-3-butenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(3,4-dichlorophenyl)-3-butenyl ether | C16H24Cl2OSi | 详情 | 详情 | |
(XIII) | 38431 | ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate | C11H10Cl2O3 | 详情 | 详情 | |
(XIV) | 38432 | 3-(3,4-dichlorophenyl)-3,3-diethoxy-1-propanol | C13H18Cl2O3 | 详情 | 详情 | |
(XV) | 38433 | 1-(3,4-dichlorophenyl)-3-hydroxy-1-propanone | C9H8Cl2O2 | 详情 | 详情 | |
(XVI) | 10069 | Bromo(3,4-dichlorophenyl)magnesium | 79175-35-2 | C6H3BrCl2Mg | 详情 | 详情 |
(XVII) | 38434 | tert-butyl[(3-iodo-3-butenyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-iodo-3-butenyl ether | C10H21IOSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XII)Asymmetric dihydroxylation of intermeddiate silylated olefin (XII) employing potassium ferricyanide in the presence of osmium tetraoxide and the chiral auxiliary hydroquinidine 1,4-phthalazindiyl diether produced diol (XVIII). After conversion of the primary hydroxyl group of (XVIII) to the corresponding tosylate (XIX), displacement with ethanolamine yielded hydroxy amine (XX). Protection of (XX) as the Boc derivative (XXI), followed by cyclization under Mitsunobu conditions gave rise to morpholine (XXII). The Boc and silyl groups of (XXII) were then deprotected with HCl in dioxan, and the deprotected morpholine (XXIII) was acylated with 3,4,5-trimethoxybenzoyl chloride (XXIV) to produce amide (XXV). The alcohol group of (XXV) was then converted to mesylate (XXVI) using methanesulfonyl chloride and triethylamine. Optionally, the alchohol group was subjected to Swern oxidation, affording aldehyde (XXVII).
【1】 Kurata, H.; Ito, K.; Nakajima, K.; Yamaguchi, T.; Ishibashi, K.; Fukuzawa, T.; Nishi, T. (Sankyo Co., Ltd.); Azaheterocyclic cpds. having tachykinin receptor antagonist activity; NK1 and NK2. EP 0776893; JP 1998152478; JP 1998182649; JP 1998182650 . |
【2】 Nishi, T.; Yamaguchi, T. (Sankyo Co., Ltd.); Salts of optically active sulfoxide deriv.. EP 0987269; JP 1999043490; WO 9854191 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
(XII) | 38430 | tert-butyl[[3-(3,4-dichlorophenyl)-3-butenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(3,4-dichlorophenyl)-3-butenyl ether | C16H24Cl2OSi | 详情 | 详情 | |
(XVIII) | 38435 | (2R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3,4-dichlorophenyl)-1,2-butanediol | C16H26Cl2O3Si | 详情 | 详情 | |
(XIX) | 38436 | (2R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3,4-dichlorophenyl)-2-hydroxybutyl 4-methylbenzenesulfonate | C23H32Cl2O5SSi | 详情 | 详情 | |
(XX) | 38437 | (2R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3,4-dichlorophenyl)-1-[(2-hydroxyethyl)amino]-2-butanol | C18H31Cl2NO3Si | 详情 | 详情 | |
(XXI) | 38438 | tert-butyl (2R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3,4-dichlorophenyl)-2-hydroxybutyl(2-hydroxyethyl)carbamate | C23H39Cl2NO5Si | 详情 | 详情 | |
(XXII) | 38439 | tert-butyl (2R)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-(3,4-dichlorophenyl)-4-morpholinecarboxylate | C23H37Cl2NO4Si | 详情 | 详情 | |
(XXIII) | 38440 | 2-[(2R)-2-(3,4-dichlorophenyl)morpholinyl]-1-ethanol | C12H15Cl2NO2 | 详情 | 详情 | |
(XXIV) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
(XXV) | 38441 | [(2R)-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)morpholinyl](3,4,5-trimethoxyphenyl)methanone | C22H25Cl2NO6 | 详情 | 详情 | |
(XXVI) | 38442 | 2-[(2R)-2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholinyl]ethyl methanesulfonate | C23H27Cl2NO8S | 详情 | 详情 | |
(XXVII) | 38443 | 2-[(2R)-2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholinyl]acetaldehyde | C22H23Cl2NO6 | 详情 | 详情 |