1,2-diethoxy-3-fluorobenzene -Drug Synthesis Database

【结构式】

【分子编号】68408

【品名】1,2-diethoxy-3-fluorobenzene

【CA登记号】　

【分子式】C₁₀H₁₃FO₂

【分子量】184.21042

【元素组成】C 65.2% H 7.11% F 10.31% O 17.37%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIII)

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 .

参考文献中间体

合成目标

【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

该中间体在本合成路线中的序号：(XIII)

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) .

参考文献中间体

合成目标

【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

Extended Information