tert-butyl-(4-iodobutoxy)-dimethylsilane

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: In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.358 ml, 0.562 mmol) was added to a tetrahydrofuran (4 ml) solution of the 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (250 mg, 0.511 mmol) obtained in Example 15. The temperature of the resulting mixture was raised to room temperature. After cooling to −78° C., 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.146 ml, 0.562 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid. After cooling to −78° C. followed by extraction with diethyl ether washed successively with water and brine dried over MgSO4 concentrated The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid

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

実験手順: In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.358 ml, 0.562 mmol) was added to a tetrahydrofuran (4 ml) solution of the 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (250 mg, 0.511 mmol) obtained in Example 15. The temperature of the resulting mixture was raised to room temperature. After cooling to −78° C., 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.146 ml, 0.562 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid. After cooling to −78° C. followed by extraction with diethyl ether washed successively with water and brine dried over MgSO4 concentrated The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a dimethoxyethane (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1 hour and then, at room temperature for 30 minutes. The reaction mixture was cooled to −78° C., followed by the dropwise addition of 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.260 ml, 1.00 mmol). While elevating the temperature of the reaction mixture to room temperature, stirring was conducted for 15 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (8% ethyl acetate-hexane), whereby the title compound (401 mg, 82%) was obtained as a colorless solid. The resulting solid was recrystallized from hexane to yield colorless needle crystals. at room temperature for 30 minutes The reaction mixture was cooled to −78° C. to room temperature stirring was conducted for 15 hours followed by extraction with diethyl ether washed successively with water and brine dried over MgSO4 concentrated The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (8% ethyl acetate-hexane), whereby the title compound (401 mg, 82%) was obtained as a colorless solid The resulting solid was recrystallized from hexane to yield colorless needle crystals

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

実験手順: A mixture of Example 11A (0.1302 g, 0.352 mmol) and potassium carbonate (0.058 g, 0.422 mmol) in acetonitrile (2 mL) was heated at reflux for 30 minutes, then (4-iodobutoxy)-tert-butyldimethylsilane (0.122 g, 0.387 mmol) was added and the resultant mixture was stirred at reflux for 0.5 hour. The reaction mixture became thick so additional acetonitrile (2 mL) and dimethyl sulfoxide (2 mL) were added, and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil that was taken up in ethyl acetate (100 mL) and washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo leaving a yellow oil. Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes afforded the title compound (0.135 g, 69%). at reflux for 30 minutes at reflux for 0.5 hour were added The reaction mixture was concentrated in vacuo to a yellow oil that washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl The organic phase was dried over anhydrous Na2SO4 filtered concentrated in vacuo leaving a yellow oil Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes

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

実験手順: A mixture of Example 11A (0.1302 g, 0.352 mmol) and potassium carbonate (0.058 g, 0.422 mmol) in acetonitrile (2 mL) was heated at reflux for 30 minutes, then (4-iodobutoxy)-tert-butyldimethylsilane (0.122 g, 0.387 mmol) was added and the resultant mixture was stirred at reflux for 0.5 hour. The reaction mixture became thick so additional acetonitrile (2 mL) and dimethyl sulfoxide (2 mL) were added, and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil that was taken up in ethyl acetate (100 mL) and washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo leaving a yellow oil. Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes afforded the title compound (0.135 g, 69%). at reflux for 30 minutes at reflux for 0.5 hour were added The reaction mixture was concentrated in vacuo to a yellow oil that washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl The organic phase was dried over anhydrous Na2SO4 filtered concentrated in vacuo leaving a yellow oil Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes

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

実験手順: In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (70.0 mg, 0.226 mmol) was dissolved in DMF (2.1 mL), and the solution was treated with potassium carbonate (93.8 mg, 0.679 mmol) and tert-butyl(4-iodobutoxy)dimethylsilane (0.176 mL, 0.679 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1) to obtain 4-chloro-5-[4-(tert-butyldimethylsiloxy)butoxy]-7-iodoisoindolinone (94.2 mg, yield 84%). followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 26, 250 mg, 1.2 mmol) in DMF (10 mL), 60% NaH (58 mg, 1.44 mmol) was added portionwise. The reaction was then heated to 70° C. and this temperature was maintained for 1.5 hour. After cooling to room temperature, (4-iodo-butoxy)-tert-butyl-dimethyl-silane (452 mg, 1.44 mmol) was then added dropwise and the reaction was stirred for 24 hours. Water (30 mL) was added and the product was extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85) followed by DCM/MeOH (70:30) to give the title compound as a yellow oil (110 mg, 23% yield). this temperature was maintained for 1.5 hour After cooling to room temperature the product was extracted with Et2O The organic phase was dried (Na2SO4) evaporated The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85)

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: In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (70.0 mg, 0.226 mmol) was dissolved in DMF (2.1 mL), and the solution was treated with potassium carbonate (93.8 mg, 0.679 mmol) and tert-butyl(4-iodobutoxy)dimethylsilane (0.176 mL, 0.679 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1) to obtain 4-chloro-5-[4-(tert-butyldimethylsiloxy)butoxy]-7-iodoisoindolinone (94.2 mg, yield 84%). followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 26, 250 mg, 1.2 mmol) in DMF (10 mL), 60% NaH (58 mg, 1.44 mmol) was added portionwise. The reaction was then heated to 70° C. and this temperature was maintained for 1.5 hour. After cooling to room temperature, (4-iodo-butoxy)-tert-butyl-dimethyl-silane (452 mg, 1.44 mmol) was then added dropwise and the reaction was stirred for 24 hours. Water (30 mL) was added and the product was extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85) followed by DCM/MeOH (70:30) to give the title compound as a yellow oil (110 mg, 23% yield). this temperature was maintained for 1.5 hour After cooling to room temperature the product was extracted with Et2O The organic phase was dried (Na2SO4) evaporated The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85)