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【结 构 式】 
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【分子编号】67678 【品名】2-tert-butylphenol；o-t-Butylphenol；o-tert-Butylphenol；2-tert-Butyl-1-hydroxybenzene；2-(1,1-Dimethylethyl)phenol 【CA登记号】88-18-6 |
【 分 子 式 】C10H14O 【 分 子 量 】150.22056 【元素组成】C 79.96% H 9.39% O 10.65% |
合成路线1
该中间体在本合成路线中的序号：(I)Iodination of 2-tert-butylphenol (I) with excess NaI and NaOCl in the presence of NaOH in MeOH gives 2-tert-butyl-4,6-diiodophenol (II), which is O-alkylated with Me2SO4 and K2CO3 or with MeI and NaOH in refluxing acetone to yield 1-tert-butyl-3,5-diiodo-2-methoxybenzene (III). goldberg reaction of aryl iodide (III) with uracil (Iv) by means of CuI, K3PO4 and N-(2-cyanophenyl)picolinamide in DMSO at 60 °C affords 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil (v) (1-4), which by Suzuki coupling with 6-hydroxy-2-naphthylboronic acid (vI) in the presence of Pd2dba3, K3PO4 and meCgPPh (1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.113,7]decane) in THF provides adduct (vII). Condensation of naphthol (vII) with perfluoro-butanesulfonyl fluoride (vIII) and K2CO3 in acetonitrile/DMF produces sulfonate (IX), which is finally condensed with methanesulfonamide (X) using Pd2dba3, K3PO4 and t-BuBrettPhos in t-amyl alcohol at 60 °C, THF, 2-MeTHF or EtOAc .
In a related procedure, dasabuvir is obtained by Suzuki coupling of aryl iodide (v) with pinacol 6-(methylsulfonamido)-2-naphth-ylboronate (XI) using K3PO4, Pd2dba3 and meCgPPh in THF/H2O at 50 °C .
| 【1】 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146. |
| 【3】 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134. |
| 【4】 Shekhar, S., Franczyk, T.S., Barnes, D.M., Dunn, T.B., Haight, A.R., Chan, v.S. (Abbvie, Inc.) Process for preparing antiviral compounds. CN 103097360, EP 2593439, JP 2013532636, KR 2013043195, US 2012014913, WO 2012009699. |
| 【2】 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127. |
| 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) | 67679 | 2-tert-butyl-4,6-diiodophenol | C10H12I2O | 详情 | 详情 | |
| (III) | 67680 | 1-tert-butyl-3,5-diiodo-2-methoxybenzene | C11H14I2O | 详情 | 详情 | |
| (IV) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (V) | 67681 | 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil | C15H17IN2O3 | 详情 | 详情 | |
| (VI) | 67682 | 6-hydroxy-2-naphthylboronic acid | 173194-95-1 | C10H9BO3 | 详情 | 详情 |
| (VII) | 67683 | 1-(3-(tert-butyl)-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione | C25H24N2O4 | 详情 | 详情 | |
| (VIII) | 67684 | perfluoro-butanesulfonyl fluoride | 375-72-4 | C4F10O2S | 详情 | 详情 |
| (IX) | 67685 | 6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate | C29H23F9N2O6S | 详情 | 详情 | |
| (X) | 39701 | methanesulfonamide | 3144-09-0 | CH5NO2S | 详情 | 详情 |
| (XI) | 67686 | N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide | C17H22BNO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |