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【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%

与该中间体有关的原料药合成路线共 3 条

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2

该中间体在本合成路线中的序号:(VI)

中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成

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
Extended Information