1-chloro-3-fluoro-2-methylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The starting material may be prepared as follows: A mixture of 98 g (0.678 mole) of 6-chloro-2-fluorotoluene, 91.5 g (0.678 mole) of sulfuryl chloride and 0.2 g of dibenzoyl peroxide is stirred for 3 hours at 100°-110° C. and then distilled, affording 6-chloro-2-fluorobenzyl chloride with a boiling point in the range from 78°-82° C. The starting material may be prepared distilled

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (2.5M in hexane, 100 ml) was added to a cooled solution of 2-chloro-6-fluorotoluene (36.1 g) in dry tetrahydrofuran while maintaining the temperature below -60° C. The mixture was stirred at -78° C. overnight then poured onto solid carbon dioxide pellets. The mixture was stirred and allowed to warm to room temperature. It was acidified to pH 1 and extracted with ether. The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water. The combined aqueous extracts were acidified to pH 1 and the solid formed was filtered off and washed with water and n-hexane to give 4-chloro-2-fluoro-3-methylbenzoic acid (40.35 g) as a white solid, NMR (DMSO-d6) 2.3(d,3H), 7.4(d,1H) 7.7(t,1H). while maintaining the temperature below -60° C The mixture was stirred to warm to room temperature extracted with ether The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water the solid formed was filtered off washed with water and n-hexane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (2.5M in hexane, 100 ml) was added to a cooled solution of 2-chloro-6-fluorotoluene (36.1 g) in dry tetrahydrofuran while maintaining the temperature below -60° C. The mixture was stirred at -78° C. overnight then poured onto solid carbon dioxide pellets. The mixture was stirred and allowed to warm to room temperature. It was acidified to pH 1 and extracted with ether. The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water. The combined aqueous extracts were acidified to pH 1 and the solid formed was filtered off and washed with water and n-hexane to give 4-chloro-2-fluoro-3-methylbenzoic acid (40.35 g) as a white solid, NMR (DMSO-d6) 2.3(d,3H), 7.4(d, 1H) 7.7(t, 1H). while maintaining the temperature below -60° C The mixture was stirred to warm to room temperature extracted with ether The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water the solid formed was filtered off washed with water and n-hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (2.5M in hexane, 100 ml) was added to a cooled solution of 2-chloro-6-fluorotoluene (36.1 g) in dry tetrahydrofuran while maintaining the temperature below -60° C. The mixture was stirred at -78° C. overnight then poured onto solid carbon dioxide pellets. The mixture was stirred and allowed to warm to room temperature. It was acidified to pH 1 and extracted with ether. The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water. The combined aqueous extracts were acidified to pH 1 and the solid formed was filtered off and washed with water and n-hexane to give 4-chloro-2-fluoro-3-methylbenzoic acid (40.35 g) as a white solid, NMR (DMSO-d6) 2.3(d,3H), 7.4(d, 1H) 7.7(t, 1H). while maintaining the temperature below -60° C The mixture was stirred to warm to room temperature extracted with ether The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water the solid formed was filtered off washed with water and n-hexane

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vigorously stirred mixture of sulphuric acid (136 ml) and nitric acid (134 ml), maintained at 15° C. was added dropwise 2-chloro-6-fluorotoluene (100 g) over a period of 30 minutes. The mixture was alllowed to attain room temperature (20° C.), stirred for 70 minutes, then poured onto crushed ice. Solid 2-chloro-6-fluoro-3-nitrotoluene (70 g) was obtained after filtering and drying. to attain room temperature (20° C.) poured onto crushed ice

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

Procedure: 1-Chloro-3-fluoro-2-methylbenzene (1.00 mL, 8.24 mmol) was dissolved in sulfuric acid (18 M, 10 mL) and cooled in an ice bath. Potassium nitrate (0.87 g, 8.65 mmol) dissolved in sulfuric acid (18 M, 10 mL) was added dropwise to the cold solution. The reaction mixture was stirred for 5 min, then the ice bath was removed and stirring was continued for another 2 h. The reaction mixture was poured onto ice (25 g) stirred for 5 min and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a clear yellow oil (1.34 g, purity 85%). The product was used without further purification in the next reaction step. cooled in an ice bath was added dropwise to the cold solution the ice bath was removed stirring was continued for another 2 h The reaction mixture was poured onto ice (25 g) stirred for 5 min extracted with ethyl acetate (3×25 mL) The combined organic layers were dried over sodium sulfate filtered evaporated to give a clear yellow oil (1.34 g, purity 85%) The product was used without further purification in the next reaction step

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

Procedure: 2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1 g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1 mmol) was added slowly in 3 portions with 1 min between each addition. The reaction was stirred for additional 15 min. Then dichloromethane (50 ml) was added, the reaction mixture transferred to a separation funnel and washed with a sodium thiosulphate solution (10%, 30 mL) until it had turned colorless. The layers were separated and the organic layer was washed with sat. sodium hydrogen carbonate (30 mL), dried and evaporated to give the title compound as a colorless oil (7.57 g, 98%) containing 15% 3-bromo-5-chloro-2-fluorotoluene (calc. by 1H-NMR). The compound was used in the next step without further purification. the reaction mixture transferred to a separation funnel washed with a sodium thiosulphate solution (10%, 30 mL) until it The layers were separated the organic layer was washed with sat. sodium hydrogen carbonate (30 mL) dried evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (31 mg, 130 μmol) was dissolved in DMF (470 μL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 10.1 mg, 169 μmol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0 μL, 390 μmol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the solvent was removed. 1.2M HCl in EtOH (630 μL, 760 μmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H20C1NO, 266.12. found 266.0. The reaction was quenched with MeOH the solvent was removed the mixture was stirred overnight The product was concentrated purified by preparative HPLC

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

Procedure: (S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12. found 266.0. Washed separate portions the mixture was stirred overnight at 70° C The mixture was concentrated was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) the desired fractions were isolated concentrated stirred overnight at room temperature The product was concentrated under vacuum purified by preparative HPLC