Hydrochloric Acid → HCID 131735357, compound

Temperature

60 °C

To a three-neck 250 mL round bottom flask, equipped with a mechanical stirrer, a nitrogen inlet, and a thermocouple was charged tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.8 g, 29.3 mmol), 2-propanol (41.6 mL) and 2.75 M HCl in 2-propanol (32 mL, 88 mmol). The mixture was heated to 55-65° C. until reaction completion. Distilled 2-propanol (−13%) to remove excess HCl. The reaction mixture was cooled to 5° C. and added 4-methylmorpholine (21 mL, 191 mmol) at a rate maintaining the temperature below 25° C. The mixture was stirred at room temperature for 30 min. (S)-3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (10.5 g, 30.8 mmol) and 2-propanol (24.5 mL) were added and the reaction mixture was cooled 0-5° C. Additional 2-propanol was added as required for rinse and to dilute reaction mixture to 10 vol total. Propanephosphonic anhydride (T3P) (50 wt % in EtOAc) (19.2 mL, 32.2 mmol) was added at a rate maintaining the temperature ≦10° C. The reaction mixture was warmed to room temperature. Upon reaction completion, water (10 mL, 1 vol) was added. CPME (100 mL) and then 1N aqueous NaOH (100 mL) were added. The mixture was stirred for 30 min and the layers were cut. The organic layer was consecutively washed with 1N aqueous NaOH (100 mL), 1N aqueous NH4OH (2×100 mL), and saturated aqueous NH4Cl (50 mL). The organic layer was washed with 14% aqueous NaCl (25 mL) and then concentrated to minimum stir volume at 65° C. under vacuum. CPME (100 mL) was added and the solution was distilled to minimum stir volume. CPME (100 mL) was added and the solution is distilled to minimum stir volume. CPME (100 mL) was added and the solution was heated to 50° C. Charcoal (7.35 g) was added. The mixture was stirred at 50° C. for 12 hours. The charcoal was filtered and the solution was distilled to minimum stir volume and CPME and heptane were added to obtain a final solution of 80 mL (8 vol) of a 35% CPME/heptane mixture. The mixture was heated to 70° C. to obtain a solution, and then cooled to 55° C. then seeded with 50 mg ((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate. The mixture was held at 55° C. for 1 h and then cooled to room temperature. Heptane (29 mL) was added and the mixture was cooled to 0-5° C., filtered and washed with 15% CPME/Heptane (2×15 mL) and heptane (2×15 mL). The filter cake was dried at ≦55° C. to give tert-butyl ((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate, isolated 14.1 g, 86% yield.

1. customTo a three-neck 250 mL round bottom flask, equipped with a mechanical stirrer, a nitrogen inlet
2. customDistilled 2-propanol (−13%) to remove excess HCl
3. temperatureThe reaction mixture was cooled to 5° C.
4. temperaturemaintaining the temperature below 25° C
5. additionwere added
6. temperaturethe reaction mixture was cooled 0-5° C
7. washfor rinse
8. additionto dilute
9. customreaction mixture to 10 vol total
10. temperaturemaintaining the temperature ≦10° C
11. temperatureThe reaction mixture was warmed to room temperature
12. additionwas added
13. washThe organic layer was consecutively washed with 1N aqueous NaOH (100 mL), 1N aqueous NH4OH (2×100 mL), and saturated aqueous NH4Cl (50 mL)
14. washThe organic layer was washed with 14% aqueous NaCl (25 mL)
15. concentrationconcentrated to minimum stir volume at 65° C. under vacuum
16. additionCPME (100 mL) was added
17. distillationthe solution was distilled to minimum stir volume
18. additionCPME (100 mL) was added
19. distillationthe solution is distilled to minimum stir volume
20. additionCPME (100 mL) was added
21. temperaturethe solution was heated to 50° C
22. additionCharcoal (7.35 g) was added
23. stirringThe mixture was stirred at 50° C. for 12 hours
24. filtrationThe charcoal was filtered
25. distillationthe solution was distilled to minimum stir volume and CPME and heptane
26. additionwere added

ORD record

ord-cdd4d5ea253a4a1faa6d36f23c9a08bd

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315471B2