Hydrochloric Acid → HCID 86724153, compound

Temperature

120 °C

A microwave vial was charged with 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoic acid (2.00 g, 4.94 mmol), potassium ferrocyanide trihydrate (3.14 g, 7.42 mmol), diacetoxypalladium (0.112 g, 0.494 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.472 g, 0.990 mmol) and potassium carbonate (1.71 g, 12.36 mmol). The vial was evacuated and backfilled with argon. 1,4-Dioxane (10 mL) and H2O (10 mL) were added then argon was bubbled through the mixture for about 15 min. The mixture was heated at about 120° C. for about 40 h then cooled to rt and partitioned between EtOAc (600 mL) and 20% citric acid (400 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The collected solids were triturated with EtOAc (200 mL) and 20% citric acid (200 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The combined organic layers were washed with H2O (600 mL) and brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was treated with potassium ferrocyanide trihydrate (1.31 g, 3.09 mmol), diacetoxypalladium (0.056 g, 0.247 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.236 g, 0.495 mmol) and potassium carbonate (0.769 g, 5.57 mmol). The flask was evacuated and backfilled with argon. 1,4-Dioxane (5 mL) and H2O (5 mL) were added and argon was bubbled through the reaction for about 15 min. The mixture was heated at about 120° C. for about 8 h then cooled to rt and partitioned between EtOAc (300 mL) and 20% citric acid (200 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The collected solids were triturated with EtOAc (100 mL) and 20% citric acid (100 mL), filtered then the filtrate layers were separated. The combined organic layers were washed with H2O (300 mL) and brine (300 mL), dried over Na2SO4, filtered and concentrated u in vacuo. The residue was semi-purified by column chromatography (SiO2, 0-2% MeOH/DCM) and the product-containing fractions were concentrated in vacuo. The residue was dissolved in dioxane (30 mL) then 4 N aqueous NaOH (40 mL, 160 mmol) was added. The mixture was heated at about 100° C. for about 16 h then allowed to cool to rt. The mixture was neutralized by the dropwise addition of concentrated hydrochloric acid (4.85 mL, 160 mmol). The layers were separated and the organic layer was washed with 20% citric acid (300 mL), H2O (2×300 mL) and brine (300 mL) dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-5% MeOH/DCM) and the product containing fractions were concentrated in vacuo. The residue was dissolved in 2-Me THF (300 mL) and washed with H2O (3×400 mL) and brine (300 mL), dried with Na2SO4, filtered and concentrated in vacuo to give 4-(3-carboxy-1-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)propyl)-3-methylbenzoic acid (1.11 g, 2.68 mmol, 54%): LC-MS (Table 1, Method g) Rt=1.64 min, m/z 404/414 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.31 (s, 1H), 8.60-8.57 (m, 1H), 7.87-7.79 (m, 2H), 7.72-7.67 (m, 1H), 7.65-7.62 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.36-7.28 (m, 1H), 5.39-5.33 (m, 1H), 3.84 (s, 3H), 2.46-2.18 (m, 4H), 2.12 (s, 3H).

1. customThe vial was evacuated
2. addition1,4-Dioxane (10 mL) and H2O (10 mL) were added
3. customargon was bubbled through the mixture for about 15 min
4. temperaturethen cooled to rt
5. custompartitioned between EtOAc (600 mL) and 20% citric acid (400 mL)
6. customThe insoluble material was removed by filtration
7. customthe filtrate layers were separated
8. customThe collected solids were triturated with EtOAc (200 mL) and 20% citric acid (200 mL)
9. customThe insoluble material was removed by filtration
10. customthe filtrate layers were separated
11. washThe combined organic layers were washed with H2O (600 mL) and brine (600 mL)
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe flask was evacuated
16. addition1,4-Dioxane (5 mL) and H2O (5 mL) were added
17. customargon was bubbled through the reaction for about 15 min
18. temperatureThe mixture was heated at about 120° C. for about 8 h
19. temperaturethen cooled to rt
20. custompartitioned between EtOAc (300 mL) and 20% citric acid (200 mL)
21. customThe insoluble material was removed by filtration
22. customthe filtrate layers were separated
23. customThe collected solids were triturated with EtOAc (100 mL) and 20% citric acid (100 mL)
24. filtrationfiltered
25. customthe filtrate layers were separated
26. washThe combined organic layers were washed with H2O (300 mL) and brine (300 mL)
27. dry with materialdried over Na2SO4
28. filtrationfiltered
29. concentrationconcentrated u in vacuo
30. concentrationthe product-containing fractions were concentrated in vacuo
31. dissolutionThe residue was dissolved in dioxane (30 mL)
32. temperatureThe mixture was heated at about 100° C. for about 16 h
33. temperatureto cool to rt
34. customThe layers were separated
35. washthe organic layer was washed with 20% citric acid (300 mL), H2O (2×300 mL) and brine (300 mL)
36. dry with materialdried with Na2SO4
37. filtrationfiltered
38. concentrationconcentrated in vacuo
39. customThe residue was purified by column chromatography (SiO2, 0-5% MeOH/DCM)
40. additionthe product containing fractions
41. concentrationwere concentrated in vacuo
42. dissolutionThe residue was dissolved in 2-Me THF (300 mL)
43. washwashed with H2O (3×400 mL) and brine (300 mL)
44. dry with materialdried with Na2SO4
45. filtrationfiltered
46. concentrationconcentrated in vacuo

ORD record

ord-a58e8a8a833f4dcfb2ba3c8a6871dfd6

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09150592B2