4-Acetamidobutyric acid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oily suspension (50% by weight; 0.96 g) of sodium hydride is added in the course of 15 minutes to a suspension of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.15 g) in anhydrous dimethylformamide (50 cc) while the temperature is maintained in the region of 0° C., the mixture then being stirred again for 30 minutes at 0° C. Diethyl chlorophosphate (2.9 cc) is then added dropwise in the course of 30 minutes while the temperature is maintained in the region of 0° C. A solution of sodium 4-acetylaminobutanoate, prepared from 4-acetamidobutyric acid (2.9 g) in anhydrous dimethylformamide (30 cc) and an oily suspension (50% by weight; 0.96 g) of sodium hydride, is added at a temperature in the region of 0° C. to the solution obtained. The mixture is stirred for 1 hour at 0° C., then 20 hours at a temperature in the region of 20° C., and finally 4 hours at 80° C. The reaction mixture is poured into water (400 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) contained in a column 5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 100-cc fractions. Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.; the residue is recrystallized in acetonitrile. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-acetylaminobutyrate (2 g), m.p. 190° C., is thereby obtained. is maintained in the region of 0° C obtained The mixture is stirred for 1 hour at 0° C. 20 hours in the region of 20° C., and finally 4 hours at 80° C extracted with methylene chloride (3×200 cc) washed with water dried concentrated to dryness under reduced pressure (2.7 kPa) The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) collecting 100-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. the residue is recrystallized in acetonitrile

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oily suspension (50% by weight; 0.96 g) of sodium hydride is added in the course of 15 minutes to a suspension of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.15 g) in anhydrous dimethylformamide (50 cc) while the temperature is maintained in the region of 0° C., the mixture then being stirred again for 30 minutes at 0° C. Diethyl chlorophosphate (2.9 cc) is then added dropwise in the course of 30 minutes while the temperature is maintained in the region of 0° C. A solution of sodium 4-acetylaminobutanoate, prepared from 4-acetamidobutyric acid (2.9 g) in anhydrous dimethylformamide (30 cc) and an oily suspension (50% by weight; 0.96 g) of sodium hydride, is added at a temperature in the region of 0° C. to the solution obtained. The mixture is stirred for 1 hour at 0° C., then 20 hours at a temperature in the region of 20° C., and finally 4 hours at 80° C. The reaction mixture is poured into water (400 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) contained in a column 5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 100-cc fractions. Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.; the residue is recrystallized in acetonitrile. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-acetylaminobutyrate (2 g), m.p. 190° C., is thereby obtained. is maintained in the region of 0° C obtained The mixture is stirred for 1 hour at 0° C. 20 hours in the region of 20° C., and finally 4 hours at 80° C extracted with methylene chloride (3×200 cc) washed with water dried concentrated to dryness under reduced pressure (2.7 kPa) The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) collecting 100-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. the residue is recrystallized in acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of hemiaminal A1 (2.6 g, 5.5 mmol) in dichloromethane (30 mL) was added triethylamine (2.3 mL, 16.4 mmol), followed by addition of methanesulfonyl chloride (0.47 g, 6.0 mmol) over 3 min. The reaction mixture was stirred for 25 min and then N-acetyl-4-aminobutyric acid (1.6 g, 10.1 mmol) added. The reaction mixture was then heated at reflux for 18 h, cooled and washed with sat. NaHCO3 (aq). The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with 1:1:0.1 to 1:1:0.2 dichloromethane/ethyl acetate/methanol to give the title compound as an off white solid (1.1 g, 34%). The reaction mixture was then heated at reflux for 18 h cooled washed with sat. NaHCO3 (aq) The organic phase was dried over MgSO4 filtered evaporated The residue was further purified on silica eluting with 1:1:0.1 to 1:1:0.2 dichloromethane/ethyl acetate/methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Method as example 127 using 4-acetamidobutanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials. Purified by Prep HPLC at low pH to afford a white solid (46.5 mg, 0.089 mmol, 39%). Purified by Prep HPLC at low pH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to the method of the preceding example, there are obtained, starting from 3.36 g of apovincamine and 1.45 g of 4-acetamidobutyric acid, 4.4 g of a product, having melting point of 128° C. and insoluble in water and alcohol. The apovincamine content of the salt is 56%. are obtained

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oily suspension (50% by weight; 0.96 g) of sodium hydride is added in the course of 15 minutes to a suspension of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.15 g) in anhydrous dimethylformamide (50 cc) while the temperature is maintained in the region of 0° C., the mixture then being stirred again for 30 minutes at 0° C. Diethyl chlorophosphate (2.9 cc) is then added dropwise in the course of 30 minutes while the temperature is maintained in the region of 0° C. A solution of sodium 4-acetylaminobutanoate, prepared from 4-acetamidobutyric acid (2.9 g) in anhydrous dimethylformamide (30 cc) and an oily suspension (50% by weight; 0.96 g) of sodium hydride, is added at a temperature in the region of 0° C. to the solution obtained. The mixture is stirred for 1 hour at 0° C., then 20 hours at a temperature in the region of 20° C., and finally 4 hours at 80° C. The reaction mixture is poured into water (400 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) contained in a column 5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 100-cc fractions. Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.; the residue is recrystallized in acetonitrile. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-acetylaminobutyrate (2 g), m.p. 190° C., is thereby obtained. is maintained in the region of 0° C obtained The mixture is stirred for 1 hour at 0° C. 20 hours in the region of 20° C., and finally 4 hours at 80° C extracted with methylene chloride (3×200 cc) washed with water dried concentrated to dryness under reduced pressure (2.7 kPa) The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) collecting 100-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. the residue is recrystallized in acetonitrile