2,2-dimethylbutanedioic acid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g of 3,3-dimethyl succinic acid and 102.7 g of urea were mixed and stirred at 160° C. for 10 hours. Then water was added to the reaction mixture which was cooled to about 100° C., and further cooled to about room temperature, then extracted with ethyl acetated three times. The organic layers were joined, washed with saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethyl-2,5-pyrrolidine dion. was cooled to about 100° C. further cooled to about room temperature extracted with ethyl washed with saturated aqueous solution of sodium chloride dried with anhydrous magnesium sulfate concentrated

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The mixture of 10 g of 3,3-dimethylsuccinic acid and 102.7 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethylpyrrolidin-2,5-dione. the mixture was cooled to near room temperature The mixture was extracted with ethyl acetate three times The organic layers were washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The mixture of 10 g of 3,3-dimethylsuccinic acid and 102.7 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethylpyrrolidin-2,5-dione. the mixture was cooled to near room temperature The mixture was extracted with ethyl acetate three times The organic layers were washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated

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

実験手順: 174(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (303.0 mg, 1.0 mmol) and 2,2-dimethylbutanedioic acid (146.0 mg, 1.0 mmol) were dissolved in DCM (10 mL), followed by the addition of HOBt (1.0 eq, 153.0 mg) and EDC (1.0 eq, 192.0 mg). The resultant solution was stirred overnight. The solution was purified by reverse phase HPLC using a Gilson to yield 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-4-oxobutanoic acid and 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3,3-dimethyl-4-oxobutanoic acid mixture 120 mg. The solution was purified by reverse phase HPLC

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

実験手順: 174(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (303.0 mg, 1.0 mmol) and 2,2-dimethylbutanedioic acid (146.0 mg, 1.0 mmol) were dissolved in DCM (10 mL), followed by the addition of HOBt (1.0 eq, 153.0 mg) and EDC (1.0 eq, 192.0 mg). The resultant solution was stirred overnight. The solution was purified by reverse phase HPLC using a Gilson to yield 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-4-oxobutanoic acid and 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3,3-dimethyl-4-oxobutanoic acid mixture 120 mg. The solution was purified by reverse phase HPLC

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

実験手順: A solution of o-phenylenediamine (5.4 g, 0.05 mole) and 2,2-dimethylsuccinic acid (7.5 g, 0.05 mole) in 50 mL of 4.8 N HCl was refluxed without condenser until the total volume was reduced to about 20 mL. Evaporation at 100° and 40 torr afforded a green paste which was taken up in 100 mL H2O and made alkaline (pH 9) with 20% NaOH. The mixture was filtered removing tarry matter and the clear yellow filtrate was concentrated, cooled and the pH adjusted to about 6 by addition of acetic acid. A light yellow solid precipitated and was isolated by filtration and dried in air to give 9 g of α,α-dimethyl-1H-2-benzimidazolepropanoic acid, m.p. 223°-226° (dec). Recrystallization from acetonitrile-methyl ethyl ketone-methanol (30-30-40) afforded 6.7 g (61%) of colorless needles, m.p. 266°-267° (dec). Evaporation at 100° 40 torr afforded a green paste which The mixture was filtered removing tarry matter the clear yellow filtrate was concentrated cooled the pH adjusted to about 6 by addition of acetic acid A light yellow solid precipitated was isolated by filtration dried in air

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

実験手順: Sixty-nine grams (0.5 mole) of m-nitroaniline and 76 grams (g.) (0.52 mole) of 2,2-dimethylsuccinic acid were mixed with 200 milliliters (ml.) of xylene and heated to reflux until approximately 20 ml. of water was removed in a modified Dean Stark apparatus. On cooling, the product crystallized from solution. The mixture was diluted with 300 ml. of ether, the solid filtered off, washed with an additional 100 ml. of ether and dried. Yield was 117.5 g. of a product having a melting point (m.p.) of 134°-134.5° C. The product was identified as the title compound by analysis of infrared spectra. heated to reflux until approximately 20 ml of water was removed in a modified Dean Stark apparatus On cooling the product crystallized from solution The mixture was diluted with 300 ml of ether, the solid filtered off washed with an additional 100 ml of ether and dried a melting point (m.p.) of 134°-134.5° C

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

実験手順: 50 g of 2,2-dimethylsuccinic acid and 70 ml of acetic anhydride were reacted at 140° C. for 3 hours and, after removing acetic acid and acetic anhydride under reduced pressure, the residue was subjected to vacuum distillation to obtain 37 g of 2,2-dimethylsuccinic anhydride. after removing acetic acid and acetic anhydride under reduced pressure the residue was subjected to vacuum distillation

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

実験手順: 50 g of 2,2-dimethylsuccinic acid and 70 ml of acetic anhydride were reacted at 140° C. for 3 hours and, after removing acetic acid and acetic anhydride under reduced pressure, the residue was subjected to vacuum distillation to obtain 37 g of 2,2-dimethylsuccinic anhydride. after removing acetic acid and acetic anhydride under reduced pressure the residue was subjected to vacuum distillation

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g of 3,3-dimethyl succinic acid and 102.7 g of urea were mixed and stirred at 160° C. for 10 hours. Then water was added to the reaction mixture which was cooled to about 100° C., and further cooled to about room temperature, then extracted with ethyl acetated three times. The organic layers were joined, washed with saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethyl-2,5-pyrrolidine dion. was cooled to about 100° C. further cooled to about room temperature extracted with ethyl washed with saturated aqueous solution of sodium chloride dried with anhydrous magnesium sulfate concentrated

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The mixture of 10 g of 3,3-dimethylsuccinic acid and 102.7 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethylpyrrolidin-2,5-dione. the mixture was cooled to near room temperature The mixture was extracted with ethyl acetate three times The organic layers were washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated