| 17.88 g |
Stage #1: 3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-3-ol dihydrochloride In ethanol at 20℃; for 0.166667h;
Stage #2: With potassium phosphate In ethanol; water at 10 - 20℃; for 0.483333h;
Stage #3: 2,3,4-trifluoro-benzoyl chloride In ethanol; water at 10 - 20℃; for 0.533333h; |
4 Example 4{3-Hydroxy-3-[ (S)-1-( (S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanone
{3-Hydroxy-3-[ (S)-1-( (S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanone The aqueous solution of 3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-3-ol di hydrochloride (43.5 g) was treated with EtOH (24 mL) and stirred for 10 min atroom temperature. To this mixture was added a solution oftripotassium phosphate (28.8 g, 136mmol, 4.7 eq.) in 261 mL water within 14 min at a batch temperature of 10 to 20 oc and themixture was stirred for 15 min at 15 oc (pH 11.9). To this solution was added via droppingfunnel34 g of the above described 2,3,4-Trifluoro-benzoyl chloride solution (34.0 g, 29.8 mmol,1.0 eq.) over 32 min at a batch temperature of 10 to 20 oc while vigorously stirring. Thedropping funnel was rinsed with toluene ( 1.2 ml) and the biphasic mixture was stirred at roomtemperature for 60 min. The layers were allowed to separate, and the aqueous phase wasdiscarded. The organic phase was washed with a solution of sodium carbonate (3.36 g, 31.5mmol, 1.09 eq.) in water (42 g) and stirred for 30 min at room temperature. The layers wereallowed to separate, and the organic phase was washed with aqueous sodium chloride (30 g,1 0%-w/w). In the rotary evaporator (bath temperature 50 °C, pressure < 200 mbar), the organicphase was concentrated to a volume of approximately 30%. The residue was taken up in EtOH(23 mL) and stirred for 5 min at 40 to 50 °C. The solution was again concentrated in the rotaryevaporator (bath temperature 50 °C, pressure less than 200 mbar, 17 ml distillate), resulting in avery viscous oil. The residue was again taken up in EtOH (23 mL) and stirred for 10 min andagain further diluted with EtOH (12 mL) in order to reach the target volume (53 mL, 46.06 g).HPLC purity: 85.0%-are For analytical purposes, the product solution (90 mL) was filtered and the filterresidue was washed with EtOH (15 ml). In the rotary evaporator (bath temperature 40°C,pressure< 150 mbar), the solution was completely concentrated, and the residue was taken up in MTBE ( 40 mL ), subsequently again fully concentrated, then taken up in a mixture of ethylacetate (29 mL) and heptane ( 40 mL ), then fully concentrated, then again taken up in a mixtureofMTBE (20 mL) and heptane (50 mL) and again fully concentrated resulting, finally, in afoamy solid (32.5 g). The solid residue (32.0 g) was dissolved in ethyl acetate (20 mL) andpurified by flash chromatography over silica gel (150 g) using ethyl acetate as eluent. After aforerun of 200 mL, 6 fractions (800 mL) were combined and completely concentrated in therotary evaporator (bath temperature: 40 °C, pressure~ 20m bar) resulting in 28.0 g of a slightlyyellowish oil. At room temperature, the oily residue was taken up in dichloromethane (20 mL ),diluted with heptane (150 mL) and again fully concentrated in the rotary evaporator, followed bydissolving the residue in MTBE (20 mL) and again by complete removal of the solvent in therotary evaporator resulting in a rubber-like foam. This foam was dissolved in toluene (30 mL,room temperature) and dosed over 20 min added drop-wise by dropping funnel at roomtemperature to heptane (400 mL), whereupon the product started to precipitate. The droppingfunnel was rinsed with toluene (4 mL) and the suspension was kept stirring for 1 hat roomtemperature. The solids were filtered off and the reactor and filter cake were twice rinsed withthe filtrate and subsequently with heptane (15 mL). Drying under vacuum at 35°C until weightconstancy resulted in 17.88 g of a colorless solid. HPLC purity: 97 .0%-area, residual solvents:toluene (1.2%-w/w) and heptane (2.3%-w/w). Mp (visually): Tonset: 55- 73°C (meltingaccompanied by exothermic decomposition). 1H NMR ( 400 MHz, DMSO-d6, 120°C): 8 7.41 -7.47 (m, 2 H), 7.27-7.32 (m, 2 H), 7.21 -7.26 (m, 2 H), 7.12- 7.19 (m, 1 H), 5.21 (bs, 1 H),4.35 (bd, 1 H), 4.22 (bs, 1 H), 4.05 (dd, 1 H), 3.91 - 4.01 (m, 1 H), 3.74- 3.90 (m, 4 H), 3.01 (dd,1 H), 2. 75 - 2.84 (m, 1 H), 2.49 - 2.59 (m, 1 H), 1.68- 1.81 (m, 1 H), 1.51 - 1.65 (m, 1 H), 1.23 -1.50 (m, 3 H), 1.09- 1.22 (m, 1 H). MS (EI): mlz = 435 ([M+Ht, 100%). EA for C23H2sF3N203,corrected for residual toluene (1.2%-w/w) and heptane (2.3%-w/w): calcd: C 64.38, H 6.07, F12.66, N 6.22; found C 64.01, H 6.04, F 12.63, N 6.35. |
| 17.88 g |
Stage #1: 3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-3-ol dihydrochloride With potassium phosphate In ethanol; water at 10 - 20℃; for 0.483333h;
Stage #2: 2,3,4-trifluoro-benzoyl chloride In ethanol; water at 10 - 20℃; for 0.533333h; |
4 {3-hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenylethyl)piperidin-2-yl]azetidin-1-yl}(2,3,4-trifluorophenyl)methanone:
The aqueous solution of 3-[(S)- 1 -((5)-2-hydroxy- 1 -phenyl-ethyl)-piperidin-2-yl]- azetidin-3-ol di hydrochloride (43.5 g) was treated with EtOH (24 mL) and stirred for 10 min at room temperature. To this mixture was added a solution of tripotassium phosphate (28.8 g, 136 mmol, 4.7 eq.) in 261 mL water within 14 min at a batch temperature of 10 to 20 °C and the mixture was stirred for 15 min at 15 °C (pH 11.9). To this solution was added via dropping funnel 34 g of the above described 2,3,4-Trifluoro-benzoyl chloride solution (34.0 g, 29.8 mmol, 1.0 eq.) over 32 min at a batch temperature of 10 to 20 °C while vigorously stirring. The dropping funnel was rinsed with toluene (1.2 ml) and the biphasic mixture was stirred at room temperature for 60 min. The layers were allowed to separate, and the aqueous phase was discarded. The organic phase was washed with a solution of sodium carbonate (3.36 g, 31.5 mmol, 1.09 eq.) in water (42 g) and stirred for 30 min at room temperature. The layers were allowed to separate, and the organic phase was washed with aqueous sodium chloride (30 g, 10%-w/w). In the rotary evaporator (bath temperature 50 °C, pressure < 200 mbar), the organic phase was concentrated to a volume of approximately 30%. The residue was taken up in EtOH (23 mL) and stirred for 5 min at 40 to 50 °C. The solution was again concentrated in the rotary evaporator (bath temperature 50 °C, pressure less than 200 mbar, 17 ml distillate), resulting in a very viscous oil. The residue was again taken up in EtOH (23 mL) and stirred for 10 min and again further diluted with EtOH (12 mL) in order to reach the target volume (53 mL, 46.06 g). HPLC purity: 85.0%-area.For analytical purposes, the product solution (90 mL) was filtered and the filter residue was washed with EtOH (15 ml). In the rotary evaporator (bath temperature 40°C, pressure 20mbar) resulting in 28.0 g of a slightly yellowish oil. At room temperature, the oily residue was taken up in dichloromethane (20 mL), diluted with heptane (150 mL) and again fully concentrated in the rotary evaporator, followed by dissolving the residue in MTBE (20 mL) and again by complete removal of the solvent in the rotary evaporator resulting in a rubber-like foam. This foam was dissolved in toluene (30 mL, room temperature) and dosed over 20 min added drop-wise by dropping funnel at room temperature to heptane (400 mL), whereupon the product started to precipitate. The dropping funnel was rinsed with toluene (4 mL) and the suspension was kept stirring for 1 h at room temperature. The solids were filtered off and the reactor and filter cake were twice rinsed with the filtrate and subsequently with heptane (15 mL). Drying under vacuum at 35°C until weight constancy resulted in 17.88 g of a colorless solid. HPLC purity: 97.0%-area, residual solvents: toluene (1.2%-w/w) and heptane (2.3%- w/w). Mp (visually): TonSet: 55 - 73°C (melting accompanied by exothermic decomposition). NMR (400 MHz, OMSO-d6, 120°C): δ 7.41 - 7.47 (m, 2 H), 7.27 - 7.32 (m, 2 H), 7.21 - 7.26 (m, 2 H), 7.12 - 7.19 (m, 1 H), 5.21 (bs, 1 H), 4.35 (bd, 1 H), 4.22 (bs, 1 H), 4.05 (dd, 1 H), 3.91 - 4.01 (m, 1 H), 3.74 - 3.90 (m, 4 H), 3.01 (dd, 1 H), 2.75 - 2.84 (m, 1 H), 2.49 - 2.59 (m, 1 H), 1.68 - 1.81 (m, 1 H), 1.51 - 1.65 (m, 1 H), 1.23 - 1.50 (m, 3 H), 1.09 - 1.22 (m, 1 H). MS (EI): m/z = 435 ([M+H]+, 100%). EA for CzsH^l^Os, corrected for residual toluene (1.2%-w/w) and heptane (2.3%-w/w): calcd: C 64.38, H 6.07, F 12.66, N 6.22; found C 64.01, H 6.04, F 12.63, N 6.35. |
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