Telaprevir intermediate and preparation method thereof
A telaprevir and intermediate technology, applied in the field of drug synthesis, can solve problems such as inability to produce sustained virological response and adverse reactions
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Embodiment 1
[0071] Preparation of Compound C (according to the method in J.Org.Chem., Vol.59, No.10, 1994):
[0072]
[0073] At 20°C, add 4-methyl-5-hydroxyethylthiazole (40g, 0.27mol), ethyl bromoacetate (37.1ml, 0.33mol), and EtOH400ml into a three-necked flask, heat up to reflux, and stir for 3 hours , the heating was stopped, and the solvent was removed by rotary evaporation. use CH 2 Cl 2 Recrystallized with ether to obtain 50 g of white solid B.
[0074] in N 2 Under protection, compound B (20g, 64.5mmol), 2-cyclopentenone (25g, 304.5mmol) and anhydrous acetonitrile were added to the reaction flask, and triethylamine ( 7.17g, 70.9mmol), the dropwise addition was completed, and the reaction was carried out at room temperature under nitrogen protection for 24h. Add 100ml of water to the reaction solution to quench the reaction, extract the aqueous phase with ether, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and ...
Embodiment 2
[0081] n is 0, R 1 When is ethyl, Z is benzyloxycarbonyl, the preparation of compound 1:
[0082]
[0083] in N 2 Under protection, compound E (2g, 6.04mmol), 1,2-ethanedithiol (0.8ml, 9.05mmol) and anhydrous dichloromethane (20ml) were added to the three-necked flask, and slowly added to the reaction solution at 20°C Add boron trifluoride ether (0.5ml, 3.13mmol) dropwise, after the dropwise addition, stir for 0.5h, add saturated sodium bicarbonate to quench the reaction, extract the aqueous phase with dichloromethane, combine the organic phases, and use saturated brine for the organic phases Washed, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.6 g of light yellow oil. Column chromatography gave 2.3 g of compound 1 as a colorless oil, with a yield of 92%. m / z (M+Na + )430.01, 1 H NMR (400MHz, CDCl 3 )δ1.16-1.27(m,3H),1.69(s,1H),2.15-2.35(m,3H),2.81-2.86(m,1H),3.01-3.06(m,1H),3.28(s, 4H), 3.51-3.59(m, 1H), 3.75-3.82(m, 1H), 4.07-4.30(m, 3H), 5.04-5....
Embodiment 3
[0085] n is 1, R 1 When is ethyl, Z is benzyloxycarbonyl, the preparation of compound 1:
[0086]
[0087] in N 2 Under protection, compound E (0.5g, 1.51mmol), 1,3-propanedithiol (0.25ml, 2.26mmol) and anhydrous dichloromethane (8ml) were added to the three-necked flask, Slowly add boron trifluoride ether (0.2ml, 1.25mmol) dropwise, after the dropwise addition is complete, stir for 0.5h, add saturated sodium bicarbonate (20ml) to quench the reaction, extract the aqueous phase with dichloromethane, combine the organic phase, organic phase Washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.6 g of light yellow oil. After purification by silica gel column chromatography, 0.5 g of compound 1 was obtained as a colorless oil with a yield of 93%. m / z (M+Na + )444.01, 1 HNMR (400MHz, CDCl 3 )δ1.16-1.27(m,3H),1.69(s,1H),1.88-1.97(m,1H),2.11-2.13(m,3H),2.31-2.41(m,1H),2.72-2.91( m,3H),2.92-3.01(m,2H),3.26-3.32(m,1H),3.62-3.79(m,2H),4.0...
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