(3S,4S)-1-Benzylpyrrolidine-3,4-diol

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 32.2 ml (0.6 mole) sulfuric acid in 100 ml DME was added dropwise to a suspension of 66.4 g (0.3 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidine dione (IIb) and 45.6 g (1.2 moles) sodium boron hydride in 400 ml 1,2-dimethoxyethane (DME) within 2.5 h at room temperature. The mixture was then agitated 4 h at 75° C. After it cooled off, 75 ml MeOH were added and the mixture rotated in to dryness. The residue was taken up in 300 ml water and compounded with 50 ml conc. hydrochloric acid. The mixture was then made alkaline and extracted with 200 ml toluene twice at 65° C. The extraction residue was taken up in 100 ml each of water and toluene, adjusted to be strongly acidic with hydrochloric acid and agitated overnight at room temperature. It was then made alkaline with 30% sodium hydroxide solution. After the addition of 200 ml toluene the organic phase was separated at 65° C. The aqueous phase was extracted again with 200 ml methylene chloride. After the organic phases were rotated in, 85 g oil remained. The latter was taken up in 400 ml ethyl acetate and washed twice with 80 ml water at 65° C. The ethyl-acetate phase was rotated in after drying over sodium sulfate. 60 g residue remained which was recrystallized from 150 ml ethyl acetate. 30.2 g (52.1%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb) were obtained in two fractions. After it cooled off extracted with 200 ml toluene twice at 65° C agitated overnight at room temperature After the addition of 200 ml toluene the organic phase was separated at 65° C The aqueous phase was extracted again with 200 ml methylene chloride washed twice with 80 ml water at 65° C in after drying over sodium sulfate was recrystallized from 150 ml ethyl acetate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 32.2 ml (0.6 mole) sulfuric acid in 100 ml DME was added dropwise to a suspension of 66.4 g (0.3 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidine dione (IIb) and 45.6 g (1.2 moles) sodium boron hydride in 400 ml 1,2-dimethoxyethane (DME) within 2.5 h at room temperature. The mixture was then agitated 4 h at 75° C. After it cooled off, 75 ml MeOH were added and the mixture rotated in to dryness. The residue was taken up in 300 ml water and compounded with 50 ml conc. hydrochloric acid. The mixture was then made alkaline and extracted with 200 ml toluene twice at 65° C. The extraction residue was taken up in 100 ml each of water and toluene, adjusted to be strongly acidic with hydrochloric acid and agitated overnight at room temperature. It was then made alkaline with 30% sodium hydroxide solution. After the addition of 200 ml toluene the organic phase was separated at 65° C. The aqueous phase was extracted again with 200 ml methylene chloride. After the organic phases were rotated in, 85 g oil remained. The latter was taken up in 400 ml ethyl acetate and washed twice with 80 ml water at 65° C. The ethyl-acetate phase was rotated in after drying over sodium sulfate. 60 g residue remained which was recrystallized from 150 ml ethyl acetate. 30.2 g (52.1%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb) were obtained in two fractions. After it cooled off extracted with 200 ml toluene twice at 65° C agitated overnight at room temperature After the addition of 200 ml toluene the organic phase was separated at 65° C The aqueous phase was extracted again with 200 ml methylene chloride washed twice with 80 ml water at 65° C in after drying over sodium sulfate was recrystallized from 150 ml ethyl acetate

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

Procedure: A solution of 50.7 g (0.2 mole) iodine in 200 ml THF was added dropwise to a suspension of 22.1 g (0.1 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione (IIb) and 15.2 g (0.4 mole) sodium boron hydride in 500 ml THF within 1 h at 12°-15° C. The mixture was then heated 2 d under argon on a reflux. After cooling off, 50 ml methanol were added and after the end of the development of gas the mixture was evaporated to dryness. The residue was taken up in 60 ml water and compounded with 15 ml conc. hydrochloric acid until an acidic reaction. After 30 min agitation, 150 ml 20% potash lye were added and [the mixture] extracted twice with 250 ml MTBE each time. After evaporation, 19.2 g colorless, crystalline residue remained. Recrystallization from 60 ml ethyl acetate yielded in 2 fractions 10.4 g (53.9%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb). The mixture was then heated 2 d under argon on a reflux After cooling off after the end of the development of gas the mixture was evaporated to dryness compounded with 15 ml conc. hydrochloric acid until an acidic reaction [the mixture] extracted twice with 250 ml MTBE each time After evaporation, 19.2 g colorless Recrystallization from 60 ml ethyl acetate

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C11H15NO2 194.2 (M+H)+. to maintain the temperature between 20° C. and 25° C was ramped to 60° C. held for 1 hr The reaction mixture was then heated to reflux concentrated to a low stir volume cooled to 5° C. to crystallize the product

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

Procedure: To a suspension of LiAlH4 (18.33 g, 219.2 mmol) in 200 mL THF, (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (23.1 g, 104.4 mmol) was added and the mixture was refluxed for 12 hours. The mixture was cooled down to room temperature and carefully quenched with 3 mL EtOAc and 3 mL MeOH. Wet silica gel was added to the mixture following by addition of MeOH—CHCl3, 1:1, and the mixture was filtered. The filtrate was evaporated giving the title compound that was used for the next step without additional purification. was added the mixture was refluxed for 12 hours carefully quenched with 3 mL EtOAc and 3 mL MeOH Wet silica gel was added to the mixture following by addition of MeOH—CHCl3, 1:1 the mixture was filtered The filtrate was evaporated

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

Procedure: Compound VI-10 (966 mg, 54.1%) was obtained in the same manner as that in Reference Example 1, by using (3S,4S)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 500 mg, 2.59 mmol) and (9Z,12Z)-octadec-9,12-dienyl methanesulfonate (Nu-Chek Prep, Inc; 2.23 g, 6.47 mmol). Compound VI-10 (966 mg, 54.1%) was obtained in the same manner as that in Reference Example 1

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 32.2 ml (0.6 mole) sulfuric acid in 100 ml DME was added dropwise to a suspension of 66.4 g (0.3 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidine dione (IIb) and 45.6 g (1.2 moles) sodium boron hydride in 400 ml 1,2-dimethoxyethane (DME) within 2.5 h at room temperature. The mixture was then agitated 4 h at 75° C. After it cooled off, 75 ml MeOH were added and the mixture rotated in to dryness. The residue was taken up in 300 ml water and compounded with 50 ml conc. hydrochloric acid. The mixture was then made alkaline and extracted with 200 ml toluene twice at 65° C. The extraction residue was taken up in 100 ml each of water and toluene, adjusted to be strongly acidic with hydrochloric acid and agitated overnight at room temperature. It was then made alkaline with 30% sodium hydroxide solution. After the addition of 200 ml toluene the organic phase was separated at 65° C. The aqueous phase was extracted again with 200 ml methylene chloride. After the organic phases were rotated in, 85 g oil remained. The latter was taken up in 400 ml ethyl acetate and washed twice with 80 ml water at 65° C. The ethyl-acetate phase was rotated in after drying over sodium sulfate. 60 g residue remained which was recrystallized from 150 ml ethyl acetate. 30.2 g (52.1%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb) were obtained in two fractions. After it cooled off extracted with 200 ml toluene twice at 65° C agitated overnight at room temperature After the addition of 200 ml toluene the organic phase was separated at 65° C The aqueous phase was extracted again with 200 ml methylene chloride washed twice with 80 ml water at 65° C in after drying over sodium sulfate was recrystallized from 150 ml ethyl acetate

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

Procedure: A solution of 50.7 g (0.2 mole) iodine in 200 ml THF was added dropwise to a suspension of 22.1 g (0.1 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione (IIb) and 15.2 g (0.4 mole) sodium boron hydride in 500 ml THF within 1 h at 12°-15° C. The mixture was then heated 2 d under argon on a reflux. After cooling off, 50 ml methanol were added and after the end of the development of gas the mixture was evaporated to dryness. The residue was taken up in 60 ml water and compounded with 15 ml conc. hydrochloric acid until an acidic reaction. After 30 min agitation, 150 ml 20% potash lye were added and [the mixture] extracted twice with 250 ml MTBE each time. After evaporation, 19.2 g colorless, crystalline residue remained. Recrystallization from 60 ml ethyl acetate yielded in 2 fractions 10.4 g (53.9%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb). The mixture was then heated 2 d under argon on a reflux After cooling off after the end of the development of gas the mixture was evaporated to dryness compounded with 15 ml conc. hydrochloric acid until an acidic reaction [the mixture] extracted twice with 250 ml MTBE each time After evaporation, 19.2 g colorless Recrystallization from 60 ml ethyl acetate

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C11H15NO2 194.2 (M+H)+. to maintain the temperature between 20° C. and 25° C was ramped to 60° C. held for 1 hr The reaction mixture was then heated to reflux concentrated to a low stir volume cooled to 5° C. to crystallize the product

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

Procedure: To a suspension of LiAlH4 (18.33 g, 219.2 mmol) in 200 mL THF, (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (23.1 g, 104.4 mmol) was added and the mixture was refluxed for 12 hours. The mixture was cooled down to room temperature and carefully quenched with 3 mL EtOAc and 3 mL MeOH. Wet silica gel was added to the mixture following by addition of MeOH—CHCl3, 1:1, and the mixture was filtered. The filtrate was evaporated giving the title compound that was used for the next step without additional purification. was added the mixture was refluxed for 12 hours carefully quenched with 3 mL EtOAc and 3 mL MeOH Wet silica gel was added to the mixture following by addition of MeOH—CHCl3, 1:1 the mixture was filtered The filtrate was evaporated