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1. A mixture of 1X kg the compound of Formula A, 5X L EtOH and 5X L 3N aq HCI was agitated for 1.5 hours at 50C.HCI Solution Preparation: Dilute 1.25X L 37% HCI solution with 3.75X L water.2. It was then sampled for In-Process Control: Formula A≤ 0.5% LC Area (For sample Prep, a 0.25 ml aliquot was dissolved in 100 ml Acetonitriie Water).Agitation was continued, if needed, for an additional 1 hour and sampled again.3. The batch pH was adjusted to between 5-7 using 15% KOH (Charge about 4. OX L) at 50C. For KOH Solution Preparation, 1.05X kg KOH pellets were dissolved in 5.95X L water.4. 12X L ethanol was added to the reaction mixture while maintaining batch temperature at 50C.5. The batch was heated to reflux (78C).6. The pH was adjusted to be between 10.0 -11.0 by adding 0.5X L 15% KOH.7. It was then cooled to 72C (at 0.3C/min) over 20 minutes.8. It was then seeded with the compound of Formula I (0.008X).9. It was the held at 72C for 45 minutes.10. The it was cooled to 5C (0.3 C/min) over 4 hours.11. 3X water was added while maintaining batch temperature at 5C.12. It was then held at 5C for an hour.13. The wet cake was filtered and washed with 20X water in 3 shots of 6.6X.14. The wet cake was dried under vacuum at 25C to give 0.7X-0.8X of the compound of Formula I.15. It was dried until the moisture content (measured by, for example, Karl Fisher) < 6.0% and EtOH < 0.1%.16. The dry cake was sampled for HPLC (15 mg dry cake was dissolved in 100 ml 1 :1 Acetonitrile: Water).HPLC Purity was 98-100%.17. The dry cake was sampled for chiral HPLC (50 mg dry cake was dissolved in 100 ml EtOH).18. The wt/wt% purity was determined by NMR assay (Solvent: MeOD).19. The filtrate was sampled for any additional compound of Formula I (0.5 ml aliquot was dissolved in 10 mi 1 :1 Acetonitrile:Water).Typical yield was about 90% (mole percent) based on the compound of Formula A, and the HPLC based purity about 98-100%.
To a solution of the compound from Preparative Example 2-5 (l.Og, 1.0 equiv.) in CH2C12 (20 mL) at 0C was added TFA dropwise. The solution was stirred at 0C for 30 minutes and warmed to room temperature for 15 minutes. The mixture was concentrated under reduced pressure adding several portions of CH2CI2 to azeotrope trace TFA. The resulting oil was dried under high vacuum for 1 hour and treated with 7M NH3 in MeOH (50 mL) and stirred for 4 hours at room temperature. The resulting solution was concentrated under reduced pressure and the crude product purified by Analogix BSR pump using a 40g Isco column on 35% speed using a gradient of 20:1 CH2Cl2/MeOH to 40:1 CH2C12/7M H3 in MeOH to 20:1 CH2C12/7M NH3 in MeOH to afford pure product. LCMS: M+ = 376
Preparative Example 2- To a solution of the compound from Preparative Example 2-5 (l .Og, 1.0 equiv.) in CH2C12 (20 mL) at 0C was added TFA dropwise. The solution was stirred at 0C for 30 minutes and warmed to room temperature for 15 minutes. The mixture was concentrated under reduced pressure adding several portions of CH2C12 to azeotrope trace TFA. The resulting oil was dried under high vacuum for 1 hour and treated with 7M NH3 in MeOH (50 mL) and stirred for 4 hours at room temperature. The resulting solution was concentrated under reduced pressure and the crude product purified by Analogix BSR pump using a 40g Isco column on 35% speed using a gradient of 20: 1 CH2Cl2/MeOH to 40: 1 CH2C12/7M NH3 in MeOH to 20: 1 CH2C12/7M NH3 in MeOH to afford pure product. LCMS: M+ = 376
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