1,3,2-dioxathiolane 2,2-dioxide

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

Procedure: Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained. the resulting mixture was stirred at room temperature After 1 hour again, and the resulting mixture was stirred for 30 minutes the resulting mixture was stirred at room temperature for 1 hour After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration the filtrate was concentrated again To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added the resulting mixture was stirred at 60° C. for 16 hours The reaction was cooled to room temperature dissolved in ethyl acetate washed with water and saturated saline The organic layer was dried over anhydrous sodium sulfate filtered Then, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained

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

Procedure: 2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.6 mmol, European Journal of Organic Chemistry, (18), 3793-3798, 2004) was dissolved in tetrahydrofuran (9.0 mL) and cooled to −78° C. 2.5 M n-Butyllithium in hexanes (0.98 mL, 2.4 mmol) was added dropwise. The reaction was stirred at −78° C. for 45 minutes, at which time 1,3,2-dioxathiolane 2,2-dioxide (0.24 g, 2.0 mmol, Aldrich) in Tetrahydrofuran (2.2 mL) was added. The mixture was then allowed to warm to ambient temperature and stir over 1.5 hours. 12.0 M hydrogen chloride in water (0.81 mL, 9.8 mmol) was added to the mixture and the reaction was stirred overnight. 1N NaOH was then added to achieve a pH between 8 and 9, and brine was also added. The product was extracted with EtOAc, and the organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 40 g silica gel cartridge, eluting with a gradient from 0-40% EtOAc in hexanes afforded product as a mixture of isomers, which contained about 50% of the desired isomer (0.09 g, 24%). LCMS (M+H)+: 226.0/228.1. was added to warm to ambient temperature the reaction was stirred overnight was also added The product was extracted with EtOAc the organic layer was dried over sodium sulfate filtered concentrated eluting with a gradient from 0-40% EtOAc in hexanes afforded product as a mixture of isomers, which

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

Procedure: 2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.6 mmol, European Journal of Organic Chemistry, (18), 3793-3798, 2004) was dissolved in tetrahydrofuran (9.0 mL) and cooled to −78° C. 2.5 M n-Butyllithium in hexanes (0.98 mL, 2.4 mmol) was added dropwise. The reaction was stirred at −78° C. for 45 minutes, at which time 1,3,2-dioxathiolane 2,2-dioxide (0.24 g, 2.0 mmol, Aldrich) in Tetrahydrofuran (2.2 mL) was added. The mixture was then allowed to warm to ambient temperature and stir over 1.5 hours. 12.0 M hydrogen chloride in water (0.81 mL, 9.8 mmol) was added to the mixture and the reaction was stirred overnight. 1N NaOH was then added to achieve a pH between 8 and 9, and brine was also added. The product was extracted with EtOAc, and the organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 40 g silica gel cartridge, eluting with a gradient from 0-40% EtOAc in hexanes afforded product as a mixture of isomers, which contained about 50% of the desired isomer (0.09 g, 24%). LCMS (M+H)+: 226.0/228.1. was added to warm to ambient temperature the reaction was stirred overnight was also added The product was extracted with EtOAc the organic layer was dried over sodium sulfate filtered concentrated eluting with a gradient from 0-40% EtOAc in hexanes afforded product as a mixture of isomers, which

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

Procedure: 2.5 M n-Butyllithium in hexanes (1.2 mL, 2.9 mmol) was added dropwise to a solution of tert-butyl 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.50 g, 1.4 mmol, from Step 1) in tetrahydrofuran (8.0 mL) at −78° C. The reaction was stirred at this temperature for 1.5 hours, and 1,3,2-dioxathiolane 2,2-dioxide (0.36 g, 2.9 mmol, Aldrich) in Tetrahydrofuran (2.0 mL) was added. The mixture was allowed to warm to room temperature and stir overnight. 12 N Hydrogen chloride in water (0.72 mL, 8.7 mmol) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was then treated with saturated sodium bicarbonate to pH between 7 and 8, and brine was added. The mixture was then extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) was used to purify the product. It was the second peak to elute having the desired mass. 1H NMR (300 MHz, CD3OD) δ 7.24 (s, 1H), 6.86 (s, 1H), 5.16 (tt, J=8.4, 3.9 Hz, 1H), 3.80 (t, J=6.3 Hz, 2H), 3.06 (dt, J=12.6, 4.6 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.73 (ddd, J=12.7, 9.5, 3.2 Hz, 2H), 2.13-1.93 (m, 2H), 1.68 (dtd, J=13.0, 9.1, 3.9 Hz, 2H). 19F NMR (282 MHz, CD3OD) δ −70.29 (s). LCMS (M+H)+: 291.1 stir overnight The mixture was stirred at room temperature for 4 hours was added The mixture was then extracted with DCM four times The combined extracts were dried over sodium sulfate filtered concentrated Preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to purify the product to elute

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

Procedure: 2.5 M n-Butyllithium in hexanes (1.2 mL, 2.9 mmol) was added dropwise to a solution of tert-butyl 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.50 g, 1.4 mmol, from Step 1) in tetrahydrofuran (8.0 mL) at −78° C. The reaction was stirred at this temperature for 1.5 hours, and 1,3,2-dioxathiolane 2,2-dioxide (0.36 g, 2.9 mmol, Aldrich) in Tetrahydrofuran (2.0 mL) was added. The mixture was allowed to warm to room temperature and stir overnight. 12 N Hydrogen chloride in water (0.72 mL, 8.7 mmol) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was then treated with saturated sodium bicarbonate to pH between 7 and 8, and brine was added. The mixture was then extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) was used to purify the product. It was the second peak to elute having the desired mass. 1H NMR (300 MHz, CD3OD) δ 7.24 (s, 1H), 6.86 (s, 1H), 5.16 (tt, J=8.4, 3.9 Hz, 1H), 3.80 (t, J=6.3 Hz, 2H), 3.06 (dt, J=12.6, 4.6 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.73 (ddd, J=12.7, 9.5, 3.2 Hz, 2H), 2.13-1.93 (m, 2H), 1.68 (dtd, J=13.0, 9.1, 3.9 Hz, 2H). 19F NMR (282 MHz, CD3OD) δ −70.29 (s). LCMS (M+H)+: 291.1 stir overnight The mixture was stirred at room temperature for 4 hours was added The mixture was then extracted with DCM four times The combined extracts were dried over sodium sulfate filtered concentrated Preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to purify the product to elute

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

Procedure: Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained. the resulting mixture was stirred at room temperature After 1 hour again, and the resulting mixture was stirred for 30 minutes the resulting mixture was stirred at room temperature for 1 hour After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration the filtrate was concentrated again To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added the resulting mixture was stirred at 60° C. for 16 hours The reaction was cooled to room temperature dissolved in ethyl acetate washed with water and saturated saline The organic layer was dried over anhydrous sodium sulfate filtered Then, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained

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

Procedure: Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained. the resulting mixture was stirred at room temperature After 1 hour again, and the resulting mixture was stirred for 30 minutes the resulting mixture was stirred at room temperature for 1 hour After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration the filtrate was concentrated again To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added the resulting mixture was stirred at 60° C. for 16 hours The reaction was cooled to room temperature dissolved in ethyl acetate washed with water and saturated saline The organic layer was dried over anhydrous sodium sulfate filtered Then, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained

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

Procedure: Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained. the resulting mixture was stirred at room temperature After 1 hour again, and the resulting mixture was stirred for 30 minutes the resulting mixture was stirred at room temperature for 1 hour After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration the filtrate was concentrated again To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added the resulting mixture was stirred at 60° C. for 16 hours The reaction was cooled to room temperature dissolved in ethyl acetate washed with water and saturated saline The organic layer was dried over anhydrous sodium sulfate filtered Then, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained

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

Procedure: Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained. the resulting mixture was stirred at room temperature After 1 hour again, and the resulting mixture was stirred for 30 minutes the resulting mixture was stirred at room temperature for 1 hour After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration the filtrate was concentrated again To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added the resulting mixture was stirred at 60° C. for 16 hours The reaction was cooled to room temperature dissolved in ethyl acetate washed with water and saturated saline The organic layer was dried over anhydrous sodium sulfate filtered Then, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained

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

Procedure: Potassium tert-butoxide in THF (0.510 mL, 0.510 mmol) was added to a solution of 3-bromo-1H-pyrazole (50.0 mg, 0.340 mmol) in DMF (3 mL) and stirred at r.t. for 10 min, and then 1,3,2-dioxathiolane 2,2-dioxide (0.0633 g, 0.510 mmol) was added and the stirred at r.t. for 1 h. At this time, conc. HCl (0.3 mL) was added to the above reaction mixture and then stirred at r.t. overnight. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product which was directly used in the next reaction without further purification. LCMS (M+H)+: m/z=191.0. the stirred at r.t. for 1 h stirred at r.t. overnight washed with saturated NaHCO3, water and brine dried over Na2SO4 filtered concentrated

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 160 ml of tetrahydrofuran was dissolved 40 g of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylate and after adding to the solution 5.2 g of 50% oil dispersion of sodium hydride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. Then, the mixture was cooled to temperatures of from -10° C. to -20° C., and after adding dropwise thereto a solution of 20 g ethylene sulfate in 80 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at -10° C., and the temperature of the system was raised gradually till room temperature. After further adding 4.0 g of 50% oil dispersion of sodium hydride, the mixture was stirred for 3 hrs. at room temperature. The reaction mixture was cooled to -10° C., and after adding dropwise a solution of 5.0 g ethylene sulfate in 10 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at the same temperature. The reaction mixture was cooled and 800 ml of ether was added thereto and further 100 ml of water was added. The separated aqueous layer was subjected to a silica gel column chromatography (12 cm × 5.0 cm). After eluting the small amount of raw material using 50 ml of ethyl acetate as an elute, the product was then developed by using 1:1 ethyl acetate-methanol mixed solvent as an elute. The solvent of the effluent was distilled away under reduced pressure, and to the residue obtained was added 30 ml of water and after cooling, the crystal formed was filtered to provide 35 g of sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)- 1,4-dihydropyridine-1-yl]-ethyl sulfate. By recrystallizing this product from water, scale-shaped yellow crystal was obtained. Then, the mixture was cooled to temperatures of from -10° C. to -20° C. after adding dropwise at room temperature The reaction mixture was cooled to -10° C. the mixture was stirred for 1 hr The reaction mixture was cooled After eluting the small amount of raw material The solvent of the effluent was distilled away under reduced pressure to the residue obtained after cooling the crystal formed was filtered

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 160 ml of tetrahydrofuran was dissolved 40 g of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylate and after adding to the solution 5.2 g of 50% oil dispersion of sodium hydride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. Then, the mixture was cooled to temperatures of from -10° C. to -20° C., and after adding dropwise thereto a solution of 20 g ethylene sulfate in 80 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at -10° C., and the temperature of the system was raised gradually till room temperature. After further adding 4.0 g of 50% oil dispersion of sodium hydride, the mixture was stirred for 3 hrs. at room temperature. The reaction mixture was cooled to -10° C., and after adding dropwise a solution of 5.0 g ethylene sulfate in 10 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at the same temperature. The reaction mixture was cooled and 800 ml of ether was added thereto and further 100 ml of water was added. The separated aqueous layer was subjected to a silica gel column chromatography (12 cm × 5.0 cm). After eluting the small amount of raw material using 50 ml of ethyl acetate as an elute, the product was then developed by using 1:1 ethyl acetate-methanol mixed solvent as an elute. The solvent of the effluent was distilled away under reduced pressure, and to the residue obtained was added 30 ml of water and after cooling, the crystal formed was filtered to provide 35 g of sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)- 1,4-dihydropyridine-1-yl]-ethyl sulfate. By recrystallizing this product from water, scale-shaped yellow crystal was obtained. Then, the mixture was cooled to temperatures of from -10° C. to -20° C. after adding dropwise at room temperature The reaction mixture was cooled to -10° C. the mixture was stirred for 1 hr The reaction mixture was cooled After eluting the small amount of raw material The solvent of the effluent was distilled away under reduced pressure to the residue obtained after cooling the crystal formed was filtered