(2,5-dioxopyrrolidin-1-yl) 2-bromoacetate

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

実験手順: A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) and 4-methylmorpholine (0.108 ml, 0.985 mmol) in N,N-diisopropylethylamine (0.5 ml) was added to 2,5-dioxopyrrolidin-1-yl 2-bromoacetate (0.056 g, 0.236 mmol) in N,N-diisopropylethylamine (0.5 ml) and stirred at room temperature. After 1 hour, (R)-2-amino-3-mercaptopropanoic acid (0.119 g, 0.985 mmol) as a solution in water (1 ml) was added. After stirring an additional 1 hour, a few drops of TFA were added to form a homogeneous solution which was purified by revere phase chromatography. The product containing peaks were lyophilized to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J=6.0 Hz, 1H), 8.86 (d, J=7.0 Hz, 1H), 8.44 (bs, 2H), 8.32 (d, J=2.0 Hz, 1H), 8.18-8.11 (m, 2H), 7.86-7.77 (m, 3H), 7.46 (dd, J=7.0, 1.5 Hz, 1H), 7.27 (dd, J=3.7, 1.8 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 4.21-4.13 (m, 1H), 4.13-4.02 (m, 2H), 4.02-3.92 (m, 1H), 3.87-3.57 (m, 3H), 3.42-3.29 (m, 1H), 3.29-3.18 (m, 1H), 3.10 (dd, J=14.6, 4.7 Hz, 1H), 2.98 (dd, J=14.6, 7.6 Hz, 1H), 1.60-1.18 (m, 4H), 0.96 (s, 3H); MS (ESI(+)) m/e 596 (M+H)+. After stirring an additional 1 hour to form a homogeneous solution which was purified by revere phase chromatography The product containing peaks

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

実験手順: 2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1). reacted overnight

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

実験手順: 2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1). reacted overnight

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

実験手順: Bromoacetic acid (4.30 g) and N-hydroxysuccinimide (4.03 g) were dissolved in DCM (25 ml). The mixture was stirred on a magnetic stirrer at room temperature. DCC was added (7.42 g) in one portion and the mixture was reacted overnight. The reaction mixture was filtered to remove dicyclohexylurea. The filter cake washed several times with DCM. The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/each wash), dried over anhydrous magnesium sulfate, and filtered. The title compound was obtained as a white solid (5 g) after rotary evaporation in vacuo. the mixture was reacted overnight The reaction mixture was filtered to remove dicyclohexylurea The filter cake washed several times with DCM The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/ each wash), dried over anhydrous magnesium sulfate filtered

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

実験手順: The NHS (N-hydroxy succinimide) ester of bromoacetic acid was prepared as follows: 100 mmoles of (13.9 g) of bromoacetic acid were dissolved in 50 ml of anhydrous DMF, to this solution 100 mmoles (20.6 g) of N—N-Dicyclohexylcarbodiimide were added with stirring followed by 100 mmoles of N-hydroxysuccinimide (11.9 g adjusted for 100% purity), and the mixture was stirred for 6 hours at 37° C. The mixture was then placed for 2 hours at −20° C. to accelerate the precipitation of hydroxyurea, which was removed by filtration. In the filtrate the DMF was removed under reduced pressure at 45° C. and the active ester was recrystallized from 2-propanal. were added the mixture was stirred for 6 hours at 37° C the precipitation of hydroxyurea, which was removed by filtration In the filtrate the DMF was removed under reduced pressure at 45° C. the active ester was recrystallized from 2-propanal

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

実験手順: The NHS (N-hydroxy succinimide) ester of bromoacetic acid was prepared as follows: 100 mmoles of (13.9 g) of bromoacetic acid were dissolved in 50 ml of anhydrous DMF, to this solution 100 mmoles (20.6 g) of N—N-Dicyclohexylcarbodiimide were added with stirring followed by 100 mmoles of N-hydroxysuccinimide (11.9 g adjusted for 100% purity), and the mixture was stirred for 6 hours at 37° C. The mixture was then placed for 2 hours at −20° C. to accelerate the precipitation of hydroxyurea, which was removed by filtration. In the filtrate the DMF was removed under reduced pressure at 45° C. and the active ester was recrystallized from 2-propanal. were added the mixture was stirred for 6 hours at 37° C the precipitation of hydroxyurea, which was removed by filtration In the filtrate the DMF was removed under reduced pressure at 45° C. the active ester was recrystallized from 2-propanal

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

実験手順: Bromoacetic acid (20 mmoles) was treated with dicyclohexyl-carbodiimide (22 mmoles, 1.1 equivalents) and N-hydroxysuccinimide (22 mmoles) in 30 ml CH2Cl2 at 4° C. according to the procedure of M. S. Bernatowicz and G. R. Matsueda (Anal. Biochem. 155:95, 1986) to give the N-succinimidyl bromoacetate as a white solid.

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

実験手順: Bromoacetic acid (20 mmoles) was treated with dicyclohexyl-carbodiimide (22 mmoles, 1.1 equivalents) and N-hydroxysuccinimide (22 mmoles) in 30 ml CH2Cl2 at 4° C. according to the procedure of M. S. Bernatowicz and G. R. Matsueda (Anal. Biochem. 155:95, 1986) to give the N-succinimidyl bromoacetate as a white solid.

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

実験手順: 2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1). reacted overnight

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

実験手順: Bromoacetic acid (4.30 g) and N-hydroxysuccinimide (4.03 g) were dissolved in DCM (25 ml). The mixture was stirred on a magnetic stirrer at room temperature. DCC was added (7.42 g) in one portion and the mixture was reacted overnight. The reaction mixture was filtered to remove dicyclohexylurea. The filter cake was washed several times with DCM. The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/each wash), dried over anhydrous magnesium sulfate, and filtered. The title compound was obtained as a white solid (5 g) after rotary evaporation in vacuo. the mixture was reacted overnight The reaction mixture was filtered to remove dicyclohexylurea The filter cake was washed several times with DCM The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/ each wash), dried over anhydrous magnesium sulfate filtered

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

実験手順: A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) and 4-methylmorpholine (0.108 ml, 0.985 mmol) in N,N-diisopropylethylamine (0.5 ml) was added to 2,5-dioxopyrrolidin-1-yl 2-bromoacetate (0.056 g, 0.236 mmol) in N,N-diisopropylethylamine (0.5 ml) and stirred at room temperature. After 1 hour, (R)-2-amino-3-mercaptopropanoic acid (0.119 g, 0.985 mmol) as a solution in water (1 ml) was added. After stirring an additional 1 hour, a few drops of TFA were added to form a homogeneous solution which was purified by revere phase chromatography. The product containing peaks were lyophilized to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J=6.0 Hz, 1H), 8.86 (d, J=7.0 Hz, 1H), 8.44 (bs, 2H), 8.32 (d, J=2.0 Hz, 1H), 8.18-8.11 (m, 2H), 7.86-7.77 (m, 3H), 7.46 (dd, J=7.0, 1.5 Hz, 1H), 7.27 (dd, J=3.7, 1.8 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 4.21-4.13 (m, 1H), 4.13-4.02 (m, 2H), 4.02-3.92 (m, 1H), 3.87-3.57 (m, 3H), 3.42-3.29 (m, 1H), 3.29-3.18 (m, 1H), 3.10 (dd, J=14.6, 4.7 Hz, 1H), 2.98 (dd, J=14.6, 7.6 Hz, 1H), 1.60-1.18 (m, 4H), 0.96 (s, 3H); MS (ESI(+)) m/e 596 (M+H)+. After stirring an additional 1 hour to form a homogeneous solution which was purified by revere phase chromatography The product containing peaks

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

実験手順: 2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1). reacted overnight