4-fluoro-2-methyl-2,3-dihydro-1H-indole

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

Procedure: 8.2 ml of concentrated hydrochloric acid are added to a solution of 1.69 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (2) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 200 ml of water, alkalinized with concentrated sodium hydroxide until the pH is 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.56 g of (−)-4-fluoro-2-methylindoline is thus obtained in the form of a very pale yellow oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution

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

Procedure: 8 ml of concentrated hydrochloric acid are added to a solution of 1.66 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (1) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 250 ml of water, alkalinized with concentrated sodium hydroxide until the pH is 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure heptane and then with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclochexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.50 g of (+)-4-fluoro-2-methylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution

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

Procedure: 8 ml of concentrated hydrochloric acid are added to a solution of 1.66 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (1) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 250 ml of water, alkalinized with concentrated sodium hydroxide until the pH is 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure heptane and then with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclochexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.50 g of (+)-4-fluoro-2-methylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution

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

Procedure: 8 ml of concentrated hydrochloric acid are added to a solution of 1.66 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (1) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 250 ml of water, alkalinized with concentrated sodium hydroxide until the pH is 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure heptane and then with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclochexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.50 g of (+)-4-fluoro-2-methylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution

Conditions: temp:14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.63 g of sodium cyanoborohydride are gradually added to a solution of 2.87 g of 4-fluoro-2-methylindole in 98 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is allowed to warm up to ambient temperature. After 2 hours, the reaction mixture is poured into a mixture of water and ice, and is then treated with a 28% aqueous ammonia solution until the pH is 9. The mixture is then extracted twice with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 300 g silica column, elution being carried out with a 100/0 to 90/10 v/v heptane/ethyl acetate gradient. 2.19 g of 4-fluoro-2-methyl-2,3-dihydro-1H-indole are thus obtained in the form of a colorless oil, the characteristics of which are the following: to warm up to ambient temperature The mixture is then extracted twice with dichloromethane dried over anhydrous magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified on a 300 g silica column, elution

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

Procedure: The product is prepared by following the procedure described in example 29c using 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c), 0.11 g of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c], and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 120 μl of pyridine and 3.0 ml of N,N-dimethylformamide. 79 mg of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

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

Procedure: 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 120 μl of pyridine are added to a solution of 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c) in 3 ml of N,N-dimethylformamide. The resulting suspension is stirred at ambient temperature for 15 minutes and then 0.11 g of (+)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] is rapidly added. The reaction mixture is stirred at ambient temperature for 64 hours and is then treated with a mixture of 20 ml of water and 2 ml of ethyl acetate, and then stirred at ambient temperature for 2 hours. The precipitate formed is filtered off, and then rinsed successively with 3 ml of water and 3×6 ml of diethyl ether. The solid obtained is dried with suction, then dried under reduced pressure at 40° C. 82 mg of (−)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following: The reaction mixture is stirred at ambient temperature for 64 hours stirred at ambient temperature for 2 hours The precipitate formed is filtered off rinsed successively with 3 ml of water and 3×6 ml of diethyl ether The solid obtained is dried with suction dried under reduced pressure at 40° C

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

Procedure: The product is prepared by following the procedure described in example 29c using 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c), 0.11 g of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c], and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 120 μl of pyridine and 3.0 ml of N,N-dimethylformamide. 79 mg of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

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

Procedure: The product is prepared by following the procedure described in example 1c using 0.22 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 116 mg of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

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

Procedure: The product is prepared by following the procedure described in example 1c using 0.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 127 mg of (+)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.20 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (−)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

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

Procedure: 8.2 ml of concentrated hydrochloric acid are added to a solution of 1.69 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (B) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 200 ml of water, alkalinized with concentrated sodium hydroxide to pH 14, and the mixture is then extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.56 g of (−)-4-fluoro-2-methylindoline is thus obtained in the form of a very pale yellow oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is then extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution

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

Procedure: 8 ml of concentrated hydrochloric acid are added to a solution of 1.66 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (A) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 250 ml of water, alkalinized with concentrated sodium hydroxide to pH 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure heptane and then with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.50 g of (+)-4-fluoro-2-methylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following: The reaction mixture is refluxed concentrated to dryness under reduced pressure the mixture is extracted with 3×200 ml of dichloromethane washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution