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【结 构 式】 
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【药物名称】E-5555;Atopaxar 【化学名称】1-[3-tert-Butyl-4-methoxy-5-(4-morpholino)phenyl]-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-1H-isoindol-2-yl)ethanone 【CA登记号】751475-53-3;474544-83-7 (hydrochloride) 【 分 子 式 】C29H38FN3O5 【 分 子 量 】527.6275 |
【开发单位】Eisai Co., Ltd. (JP) 【药理作用】Protease-Activated Receptor PAR1 Antagonist;Thrombin Inhibitor;Treatment of Acute Coronary Syndrome;Treatment of Arterial Thrombosis |
合成路线1
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 |
合成路线2
Bromination of 1,2-diethoxy-3-fluorobenzene (XIII) with NBS in acetonitrile gives 1-bromo-3,4-diethoxy-2-fluorobenzene (XVI), which undergoes bromide displacement with CuCN in DMF at 155 °C to yield 3,4-diethoxy-2-fluorobenzonitrile (XVII). Metalation of compound (XVII) with BuLi in the presence of tetramethylpiperidine (TMP) in THF at –10 °C followed by reaction with DMF and quenching with AcOH leads to 3,4-diethoxy-2-fluoro-6-formylbenzonitrile (XVIII). Reduction of aldehyde (XVIII) with NaBH(OAc)3 in EtOAc at 40 °C provides the benzylic alcohol (XIX), which is then activated as the mesylate (XX) by means of MsCl and Et3N in DME. Condensation of mesylate (XX) with phthalimide (XXI) by means of t-BuOK in DMF furnishes the N-substituted phthalimide (XXII), which is finally subsubjected to hydrazinolysis and subsequent cyclization in the presence of HCl in THF. Also, the isoindole (X) can be obtained by direct cyclization of the cyano mesylate (XX) with NH3 in toluene in a pressure vessel .
Alternatively, isoindole (X) can be prepared by metalation of 3,4-diethoxy-2-fluorobenzonitrile (XVII) with MeLi in the presence of TMP in THF, followed by alkylation with MeI to afford 3,4-diethoxy-2-fluoro-6-methylbenzonitrile (XXIII), which is then brominated with NBS by means of AIBN in refluxing CCl4 to yield 6-(bromomethyl)-3,4-diethoxy-2-fluorobenzonitrile (XXIV). Benzylic bromide (XXIV) can also be prepared by treatment of primary alcohol (XIX) with PBr3 in DME. Subsequent cyclization of the benzonitrile (XXIV) with NH3 in toluene affords 3-amino-5,6-diethoxy-4-fluoroisoindole (X) .
| 【1】 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 |
|---|---|---|---|---|---|---|
| (X) | 68406 | 5,6-diethoxy-4-fluoro-1H-isoindol-3-amine | C12H15FN2O2 | 详情 | 详情 | |
| (XIII) | 68408 | 1,2-diethoxy-3-fluorobenzene | C10H13FO2 | 详情 | 详情 | |
| (XVI) | 68411 | 1-bromo-3,4-diethoxy-2-fluorobenzen | C10H12BrFO2 | 详情 | 详情 | |
| (XVII) | 68412 | 3,4-diethoxy-2-fluorobenzonitrile | C11H12FNO2 | 详情 | 详情 | |
| (XVIII) | 68413 | 3,4-diethoxy-2-fluoro-6-formylbenzonitrile | C12H12FNO3 | 详情 | 详情 | |
| (XIX) | 68414 | 3,4-diethoxy-2-fluoro-6-(hydroxymethyl)benzonitrile | C12H14FNO3 | 详情 | 详情 | |
| (XX) | 68415 | 2-cyano-4,5-diethoxy-3-fluorobenzyl methanesulfonate | C13H16FNO5S | 详情 | 详情 | |
| (XXI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (XXII) | 68416 | 6-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-diethoxy-2-fluorobenzonitrile | C20H17FN2O4 | 详情 | 详情 | |
| (XXIII) | 68417 | 3,4-diethoxy-2-fluoro-6-methylbenzonitrile;3,4-diethoxy-2-fluoro-6-methylbenzonitrile | C12H14FNO2 | 详情 | 详情 | |
| (XXIV) | 68418 | 6-(bromomethyl)-3,4-diethoxy-2-fluorobenzonitrile | C12H13BrFNO2 | 详情 | 详情 |
合成路线3
Bromination of 1-(3-tert-butyl-4-hydroxyphenyl)ethanone (III) with NBS in acetonitrile yields 1-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone (XXV), which by protection with trimethyl orthoformate (XXVI) in the presence of (±)-CSA in MeOH affords the dimethyl acetal (XXVII). O-Methylation of phenol (XXVII) with MeI by means of K2CO3 in DMF provides 1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene (XXVIII), which by Buchwald–Hartwig condensation with morpholine (XXIX) in the presence of Pd(OAc)2, BINAP and t-BuONa in DME leads to the Narylmorpholine (XXX). Bromination of compound (XXX) with PhNMe3Br3 in THF/MeOH generates the α-bromoacetal (XXXI), which, without isolation, is finally hydrolyzed by quenching in aqueous Na2S2O3 to give bromo ketone (IX) .
| 【1】 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 |
|---|---|---|---|---|---|---|
| (XXX） | 68422 | 4-(3-(tert-butyl)-5-(1,1-dimethoxyethyl)-2-methoxyphenyl)morpholine | C19H31NO4 | 详情 | 详情 | |
| (III) | 68400 | 1-(3-tert-butyl-4-hydroxyphenyl)ethanone | C12H16O2 | 详情 | 详情 | |
| (IX) | 68405 | 2-bromo-1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone | C17H24BrNO3 | 详情 | 详情 | |
| (XXV) | 68419 | 1-(3-bromo-5-(tert-butyl)-4-hydroxyphenyl)ethanone | C12H15BrO2 | 详情 | 详情 | |
| (XXVI) | 27311 | trimethoxymethane;Trimethyl orthoformate;Methyl orthoformate | 149-73-5 | C4H10O3 | 详情 | 详情 |
| (XXVII) | 68420 | 2-bromo-6-(tert-butyl)-4-(1,1-dimethoxyethyl)phenol | C14H21BrO3 | 详情 | 详情 | |
| (XXVIII) | 68421 | 1-bromo-3-(tert-butyl)-5-(1,1-dimethoxyethyl)-2-methoxybenzene;1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene | C15H23BrO3 | 详情 | 详情 | |
| (XXIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXXI) | 68423 | 4-(5-(2-bromo-1,1-dimethoxyethyl)-3-(tert-butyl)-2-methoxyphenyl)morpholine | C19H30BrNO4 | 详情 | 详情 |