【结 构 式】 |
【分子编号】63502 【品名】1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether 【CA登记号】5414-19-7 |
【 分 子 式 】C4H8Br2O 【 分 子 量 】231.91492 【元素组成】C 20.72% H 3.48% Br 68.91% O 6.9% |
合成路线1
该中间体在本合成路线中的序号:(VII)Alkylation of the spiro lactone (VI) with dibromide (VII) in the presence of lithium hexamethyldisilazide gives rise to the tricyclic spiro compound (VIII). After acidic Boc group cleavage in (VIII), the resultant secondary amine (IX) is reductively alkylated with aldehyde (V) to produce (X) as a diastereomeric mixture. Partial reduction of lactone (X) with DIBAL provides lactol (XI), which is further converted to nitrile (XII) upon treatment with cyanotrimethylsilane and boron trifluoride. Acidic hydrolysis of nitrile (XII), followed by esterification of the resultant carboxylic acid (XIII) furnishes the methyl ester (XIV)
【1】 Pyrrolidine antagonists of the CCR3 chemokine receptor. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 250. |
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) | 63500 | 1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinecarbaldehyde | C16H17NOS | 详情 | 详情 | |
(VI) | 63501 | 1,1-dimethylethyl 2-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate | C13H21NO4 | 详情 | 详情 | |
(VII) | 63502 | 1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether | 5414-19-7 | C4H8Br2O | 详情 | 详情 |
(VIII) | 63503 | 1,1-dimethylethyl 15-oxo-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-11-carboxylate | C17H27NO5 | 详情 | 详情 | |
(IX) | 63504 | 3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-one | C12H19NO3 | 详情 | 详情 | |
(X) | 63505 | 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-one | C28H36N2O3S | 详情 | 详情 | |
(XI) | 63506 | 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-ol | C28H38N2O3S | 详情 | 详情 | |
(XII) | 63507 | 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carbonitrile | C29H37N3O2S | 详情 | 详情 | |
(XIII) | 63508 | 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid | C29H38N2O4S | 详情 | 详情 | |
(XIV) | 63509 | methyl 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate | C30H40N2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)Friedel–Crafts acylation of 2-tert-butylphenol (I) with acetyl chloride (II) in the presence of AlCl3 in cold toluene gives 1-(3-tert-butyl-4-hydroxyphenyl)ethanone (III) (1, 2), which by nitration with HNO3 in cold H2O/CH2Cl2 provides 1-(3-tert-butyl-4-hydroxy-5-nitrophenyl)ethanone (IV). O-Alkylation of phenol (IV) with methyl iodide by means of K2CO3 in DMF produces the methyl ether (V), which is reduced at the nitro group with Fe and NH4Cl in EtOH/H2O to afford the corresponding amine (VI). Cyclocondensation of the aniline derivative (VI) with bis(2-bromoethyl) ether (VII) by means of NaI and K2CO3 in DMF provides the 3-morpholino-acetophenone derivative (VIII). α-Halogenation of acetophenone (VIII) with NBS by means of Et3N and TBDMSOTf in THF yields the corresponding bromoacetophenone (IX) , which is finally condensed with isoindole derivative (X) in THF or DMF .
The isoindole intermediate (X) is prepared by dialkylation of 3-fluorocatechol (XI) with ethyl iodide (XII) in the presence of K2CO3 in DMF to give 1,2-diethoxy-3-fluorobenzene (XIII), which is brominated with Br2 by means of NaOAc in AcOH at 70 °C to yield 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (XIV). Bromide substitution in intermediate (XIV) with CuCN in DMF at 150 °C affords 4,5-diethoxy-3-fluorophthalonitrile (XV), which is finally submitted to reductive cyclization with H2 over PtO2 in EtOAc/EtOH/MeOH .
【1】 Suzuki, S., Naoe, Y., Miyamoto, M. et al. (Eisai R&D Management Co., Ltd.). 2-Iminopyrrolidine derivatives. EP 1391451, EP 2385039, US 2005004204, US 7244730, WO 2002085855. |
【2】 Shimomura, N., Sasho, M., Kayano, A., Yoshizawa, K., Tsujii, M., Kuroda,H., Furukawa, K. (Eisai R&D Management Co., Ltd.). Processes for producing cyclic benzamidine derivative. CA 2515715, EP 1602646, US 2006058370, US 7375236, WO 2004078721. |
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) | 67678 | 2-tert-butylphenol;o-t-Butylphenol;o-tert-Butylphenol;2-tert-Butyl-1-hydroxybenzene;2-(1,1-Dimethylethyl)phenol | 88-18-6 | C10H14O | 详情 | 详情 |
(II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
(III) | 68400 | 1-(3-tert-butyl-4-hydroxyphenyl)ethanone | C12H16O2 | 详情 | 详情 | |
(IV) | 68401 | 1-(3-(tert-butyl)-4-hydroxy-5-nitrophenyl)ethanone | C12H15NO4 | 详情 | 详情 | |
(V) | 68402 | 1-(3-(tert-butyl)-4-methoxy-5-nitrophenyl)ethanone | C13H17NO4 | 详情 | 详情 | |
(VI) | 68403 | 1-(3-amino-5-(tert-butyl)-4-methoxyphenyl)ethanone | C13H19NO2 | 详情 | 详情 | |
(VII) | 63502 | 1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether | 5414-19-7 | C4H8Br2O | 详情 | 详情 |
(VIII) | 68404 | 1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone | C17H25NO3 | 详情 | 详情 | |
(IX) | 68405 | 2-bromo-1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone | C17H24BrNO3 | 详情 | 详情 | |
(X) | 68406 | 5,6-diethoxy-4-fluoro-1H-isoindol-3-amine | C12H15FN2O2 | 详情 | 详情 | |
(XI) | 68407 | 3-fluorocatechol;3-FLUORO-1,2-DIHYDROXYBENZENE;3-FLUOROBENZENE-1,2-DIOL;1-FLUORO-2,3-DIHYDROXYBENZENE;1,2-Dihydroxy-3-fluoroBenzene | 363-52-0 | C6H5FO2 | 详情 | 详情 |
(XII) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
(XIII) | 68408 | 1,2-diethoxy-3-fluorobenzene | C10H13FO2 | 详情 | 详情 | |
(XIV) | 68409 | 1,2-dibromo-4,5-diethoxy-3-fluorobenzene | C10H11Br2FO2 | 详情 | 详情 | |
(XV) | 68410 | 4,5-diethoxy-3-fluorophthalonitrile;6-(aminomethyl)-3,4-diethoxy-2-fluorobenzonitrile | 474554-45-5 | C12H11FN2O2 | 详情 | 详情 |