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Warm a mixture OF 4- [2- (6-METHYL-PYRIDIN-2-YL)-5, 6-dihydro-4H-pyrrolo [1, 2- B] PYRAZOL-3-YL] -QUINOLINE-6-CARBOXYLIC ACID METHYL ESTER IN 60 ML 7 N AMMONIA IN methanol to 90 °C in a stainless steel pressure vessel for 66 hours. The pressure will rise to about 80 PSI. Maintain the pressure for the duration of the reaction. Cool the vessel and concentrate the brown mixture in vacuo. Purify the residual solid on two 12 g Redi- Pak cartridges coupled in series eluting with acetone. Combine appropriate fractions and concentrate in vacuo. Suspend the resulting nearly white solid in methylene chloride, dilute with hexane, and filter. The collected off-white solid yields 1.104 g (63.8percent) of the desired title product. MS ES+ = 370 (M+1).
With ammonia; In methanol; at 90℃; under 4137.29 Torr; for 66h;
Warm a mixture OF 4- [2- (6-METHYL-PYRIDIN-2-YL)-5, 6-dihydro-4H-pyrrolo [1, 2- B] PYRAZOL-3-YL] -QUINOLINE-6-CARBOXYLIC ACID METHYL ESTER IN 60 ML 7 N AMMONIA IN methanol to 90 C in a stainless steel pressure vessel for 66 hours. The pressure will rise to about 80 PSI. Maintain the pressure for the duration of the reaction. Cool the vessel and concentrate the brown mixture in vacuo. Purify the residual solid on two 12 g Redi- Pak cartridges coupled in series eluting with acetone. Combine appropriate fractions and concentrate in vacuo. Suspend the resulting nearly white solid in methylene chloride, dilute with hexane, and filter. The collected off-white solid yields 1.104 g (63.8%) of the desired title product. MS ES+ = 370 (M+1).
With water; In acetone; at 60℃; for 0.5 - 0.75h;Heating / reflux;Product distribution / selectivity;
Suspend 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H- pyrrolo[l,2-b]pyrazole in 28 vol. of a 75%/25% acetone/purified water solution. Heat this slurry to reflux (60 C) and stir for 30-45 minutes after the product dissolves. Filter the product solution. Start the distillation, and add milled seed when the pot temperature reaches 63 0C. Continue distilling until the distillate volume is 50% of the initial volume. Cool the slurry to 20-25 0C over 90 minutes. Then cool the slurry to 0-5 0C over 30-40 minutes. Stir for 2-3 hours at 0-50C. Filter the slurry and rinse the product cake on the filter with purified water. Dry the product under vacuum at 45 0C to furnish the title compound. The reaction yield is >80%. Product purity is >98% with low total related substances.
With water; at 20℃; for 1 - 2h;Product distribution / selectivity;
2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazole monohydrate EPO <DP n="16"/>Prepare 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H- pyrrolo[l,2-b]rhoyrazole monohydrate by stirring the compound or active pharmaceutical ingredient (API) in 10 volumes of water at room temperature for 1-2 hours, filtering, and drying at 45 0C under vacuum.
Took 45 mg of LY2157299 monohydrate and mixed with 8.3 mg succinic acid, added 0.3 mL of methanol, ground at 10 C. to dryness, and obtained 46 mg succinate cocrystal form, yield 89%.
Took 50 mg of LY2157299 monohydrate and mixed with 18.3 mg fumaric acid, added 1 mL of methanol to form a suspension, stirred at 10 C. for 16 hrs, filtered, dried at room temperature for 1 hr and obtained 51 mg fumarate cocrystal form, yield 89%.
In chloroform; acetonitrile at 60℃; Cooling with ice;
3 Galunisertib Monomer
Galunisertib (1.676 g, 4.53 mmol) was dissolved in CHCl3 (42.8 mL) and added dropwise to oxalyl chloride (540.5 uL, 6.35 mmol, 1.4 equiv) in MeCN (12.5 mL) that was placed in an ice-bath. Caution-this reaction is highly exothermic. The solution is then stirred on ice for a further 45 min before refluxing at 60° C. for 2.5 hr. Next, the reaction mixture is once again placed in an ice-bath. The benzylalcohol methacrylate monomer (2.135 g, 6.35 mmol, 1.4 equiv) in CHCl3 (2.0 mL) is then added dropwise to the reaction mixture containing galunisertib-carboxyisocyanate. After addition of the benzylalcohol methacrylate monomer is complete the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction is then diluted with CHCl3 (60 mL), quenched with a saturated solution of KHCO3 (100 mL). The organic layer is collected, washed with water (100 mL), with brine (100 mL), dried over NaSO4 and filtered. Rotary evaporation of the filtrate yielded a viscous brown liquid. Further evacuation of residual solvent yielded a brown solid. Rf=0.4. Dry silica (0.020-0.045 micron) flash chromatography with CHCl3→CHCl3/MeOH (92/8 v/v) as eluent. Co-elution of unreacted benzylalcohol methacrylate can be removed by isolation of product from diethyl ether/pentane (1/1 v/v). Centrifugation (5000 rpm) resulted in efficient recovery of precipitated product (90%). NMR spectra and mass spectrometry was performed to confirm synthesis of the monomer (FIGS. 7B-7D).
In chloroform; acetonitrile at 60℃; for 3.25h; Cooling with ice;
2 Galunisertib Monomer
Galunisertib (1.676 g, 4.53 mmol) was dissolved in CHCl3 (42.8 mL) and added dropwise to oxalyl chloride (540.5 uL, 6.35 mmol, 1.4 equiv) in MeCN (12.5 mL) that was placed in an ice-bath. Caution-this reaction is highly exothermic. The solution is then stirred on ice for a further 45 min before refluxing at 60° C. for 2.5 hr. Next, the reaction mixture is once again placed in an ice-bath. The benzylalcohol methacrylate monomer (2.135 g, 6.35 mmol, 1.4 equiv) in CHCl3 (2.0 mL) is then added dropwise to the reaction mixture containing galunisertib-carboxyisocyanate. After addition of the benzylalcohol methacrylate monomer is complete the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction is then diluted with CHCl3 (60 mL), quenched with a saturated solution of KHCO3 (100 mL). The organic layer is collected, washed with water (100 mL), with brine (100 mL), dried over NaSO4 and filtered. Rotary evaporation of the filtrate yielded a viscous brown liquid. Further evacuation of residual solvent yielded a brown solid. Rf=0.4. Dry silica (0.020-0.045 micron) flash chromatography with CHCl3→CHCl3/MeOH (92/8 v/v) as eluent. Co-elution of unreacted benzylalcohol methacrylate can be removed by isolation of product from diethyl ether/pentane (1/1 v/v). Centrifugation (5000 rpm) resulted in efficient recovery of precipitated product (90%). NMR spectra and mass spectrometry was performed to confirm synthesis of the monomer (FIGS. 27B-27D).
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