4-(2-trimethylsilylethynyl)phenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 382 mg of p-[(trimethylsilyl)ethynyl]-phenol (prepared according to Example 10) in 15 ml of a 1:1 mixture of methanol and 1N aqueous potassium hydroxide solution was stirred at room temperature for 45 minutes in a round flask under argon gasification. Methanol was subsequently removed on a rotary evaporator and the residue, after the addition of 30 ml of 1N hydrochloric acid, was extracted three times with 30 ml of diethyl ether each time. The organic phases were washed twice with 30 ml of water each time and once with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 207 mg (88%) of p-ethynylphenol as a colourless oil (decomposing rapidly in the pure state) which was taken up immediately in 50 ml of diethyl ether and treated with 436 mg of trans-4-pentylcyclohexanecarboxylic acid, 454 mg of N,N'-dicyclohexylcarbodiimide and 24.4 mg of 4-(dimethylamino)pyridine. This mixture was stirred at room temperature for 18 hours and subsequently filtered. The filtrate was treated with 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (847 mg) on silica gel with 3% ethyl acetate petroleum ether gave 277 mg (46%) of trans-4-pentylcyclohexanecarboxylic acid p-ethynylphenyl ester as colourless crystals (purity 98.5%) which were recrystallized further from methanol (purity 99.1%); m.p. (C-N) 50.6° C., cl.p. (N-I) 78.5° C. Methanol was subsequently removed on a rotary evaporator the residue, after the addition of 30 ml of 1N hydrochloric acid was extracted three times with 30 ml of diethyl ether each time The organic phases were washed twice with 30 ml of water each time once with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 381 mg of p-[(trimethylsilyl)ethynyl]phenol in 5 ml of hexamethylphosphoric acid triamide was treated at -5° C. in a sulphonation flask under argon gasification with 2.5 ml of a 1.75M solution of methyl lithium in diethyl ether. 15 minutes after completion of the addition the mixture, which had become a red slurry, was diluted with 5 ml of absolute tetrahydrofuran and subsequently stirred at room temperature for 3 hours. The mixture was then cooled to -30° C. and 322 μl of phenyl cyanate were added. The new brown-orange clear solution was warmed to 0° C. within 60 minutes, then poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the orange residue (570 mg) on silica gel with 15% ethyl acetate/petroleum ether followed by 20% ethyl acetate/petroleum ether gave 160 mg (56%) of (p-hydroxyphenyl)propiolonitrile as light yellowish crystals; m.p. 134°-137° C. 15 minutes after completion of the addition the mixture, which The mixture was then cooled to -30° C. The new brown-orange clear solution was warmed to 0° C. within 60 minutes extracted three times with 50 ml of diethyl ether each time The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-BPT was prepared in a similar manner as 3-BPT, using 4-TMSE-phenol (3.50 g, 18.4 mmol) and 4-azidophenol (3.73 g, 27.9 mmol) instead of 3-TMSE-phenol and 3-azidophenol. This gave 2.79 g (60% yield) of a purple crystal. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.62 (s, 1H, triazol-H), 7.75-7.68 (m, 4H, Ar—H), 6.99 (d, 2H, J=9.0 Hz, Ar—H), 6.90 (d, 2H, J=8.7 Hz, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 159.7, 159.3, 149.8, 131.0, 128.4, 123.4, 123.0, 119.4, 117.3, 116.9. 4-BPT was prepared in a similar manner as 3-BPT,

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-TMSE-phenol was prepared in a similar manner as 3-TMSE-phenol, using 4-iodophenol (5.0 g) instead of 3-iodophenol. This gave 3.5 g (82% yield) of a brown oil. 1H NMR (acetone-d6, 300 MHz, ppm): 8.80 (s, 1H, Ar—OH), 7.34 (d, 2H, J=8.4 Hz, Ar—H), 6.85 (d, 2H, J=8.4 Hz, Ar—H), 0.21 (s, 9H, TMS). 13C NMR (CDCl3, 75 MHz, ppm): 156.1, 133.9, 115.6, 115.5, 105.3, 92.7, 0.2.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5 mmol of 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylic acid tert-butyl ester and 5 mmol of 4-(2-(trimethylsilyl)-1-ethynyl)phenol (for the preparation see the literature mentioned in Example 122) are treated as described in Example 122. are treated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (400 mg, 0.61 mol), copper iodide (14 mg, 70 μmol), tetrakis(triphenylphosphine)palladium(0) (71 mg, 60 μmol) and 4-[(trimethylsilyl)ethynyl]phenol (234 mg, 1.23 mmol) in 1,2-dimethoxyethan (3.5 mL) and n-butyl amine (0.91 mL) was added a 1 M tetra-n-butyl ammonium fluoride solution in THF (800 μL, 0.8 mmol) over 60 minutes at 80° C. After 10 additional minutes at 80° C. the mixture was diluted with water after cooling to room temperature and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 338 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate extracted with ethyl acetate The organic phase was dried over sodium sulfate concentrated in vacuum The residue was purified by preparative HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 382 mg of p-[(trimethylsilyl)ethynyl]-phenol (prepared according to Example 10) in 15 ml of a 1:1 mixture of methanol and 1N aqueous potassium hydroxide solution was stirred at room temperature for 45 minutes in a round flask under argon gasification. Methanol was subsequently removed on a rotary evaporator and the residue, after the addition of 30 ml of 1N hydrochloric acid, was extracted three times with 30 ml of diethyl ether each time. The organic phases were washed twice with 30 ml of water each time and once with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 207 mg (88%) of p-ethynylphenol as a colourless oil (decomposing rapidly in the pure state) which was taken up immediately in 50 ml of diethyl ether and treated with 436 mg of trans-4-pentylcyclohexanecarboxylic acid, 454 mg of N,N'-dicyclohexylcarbodiimide and 24.4 mg of 4-(dimethylamino)pyridine. This mixture was stirred at room temperature for 18 hours and subsequently filtered. The filtrate was treated with 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (847 mg) on silica gel with 3% ethyl acetate petroleum ether gave 277 mg (46%) of trans-4-pentylcyclohexanecarboxylic acid p-ethynylphenyl ester as colourless crystals (purity 98.5%) which were recrystallized further from methanol (purity 99.1%); m.p. (C-N) 50.6° C., cl.p. (N-I) 78.5° C. Methanol was subsequently removed on a rotary evaporator the residue, after the addition of 30 ml of 1N hydrochloric acid was extracted three times with 30 ml of diethyl ether each time The organic phases were washed twice with 30 ml of water each time once with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 381 mg of p-[(trimethylsilyl)ethynyl]phenol in 5 ml of hexamethylphosphoric acid triamide was treated at -5° C. in a sulphonation flask under argon gasification with 2.5 ml of a 1.75M solution of methyl lithium in diethyl ether. 15 minutes after completion of the addition the mixture, which had become a red slurry, was diluted with 5 ml of absolute tetrahydrofuran and subsequently stirred at room temperature for 3 hours. The mixture was then cooled to -30° C. and 322 μl of phenyl cyanate were added. The new brown-orange clear solution was warmed to 0° C. within 60 minutes, then poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the orange residue (570 mg) on silica gel with 15% ethyl acetate/petroleum ether followed by 20% ethyl acetate/petroleum ether gave 160 mg (56%) of (p-hydroxyphenyl)propiolonitrile as light yellowish crystals; m.p. 134°-137° C. 15 minutes after completion of the addition the mixture, which The mixture was then cooled to -30° C. The new brown-orange clear solution was warmed to 0° C. within 60 minutes extracted three times with 50 ml of diethyl ether each time The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-BPT was prepared in a similar manner as 3-BPT, using 4-TMSE-phenol (3.50 g, 18.4 mmol) and 4-azidophenol (3.73 g, 27.9 mmol) instead of 3-TMSE-phenol and 3-azidophenol. This gave 2.79 g (60% yield) of a purple crystal. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.62 (s, 1H, triazol-H), 7.75-7.68 (m, 4H, Ar—H), 6.99 (d, 2H, J=9.0 Hz, Ar—H), 6.90 (d, 2H, J=8.7 Hz, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 159.7, 159.3, 149.8, 131.0, 128.4, 123.4, 123.0, 119.4, 117.3, 116.9. 4-BPT was prepared in a similar manner as 3-BPT,

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-BPT was prepared in a similar manner as 3-BPT, using 4-TMSE-phenol (3.50 g, 18.4 mmol) and 4-azidophenol (3.73 g, 27.9 mmol) instead of 3-TMSE-phenol and 3-azidophenol. This gave 2.79 g (60% yield) of a purple crystal. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.62 (s, 1H, triazol-H), 7.75-7.68 (m, 4H, Ar—H), 6.99 (d, 2H, J=9.0 Hz, Ar—H), 6.90 (d, 2H, J=8.7 Hz, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 159.7, 159.3, 149.8, 131.0, 128.4, 123.4, 123.0, 119.4, 117.3, 116.9. 4-BPT was prepared in a similar manner as 3-BPT,