4-Methylmorpholine → HCID 90233352, compound

Temperature

0 °C

A solution of 3-(4-bromo-2-methylphenyl)-3-(5-((tert-butoxycarbonyl)amino)-1,3-dimethyl-1H-pyrazol-4-yl)propanoic acid (0.452 g, 1.0 mmol, Prepared using W from 4-bromo-2-methylbenzaldehyde (Ark Pharm, Inc), X from 1,3-dimethyl-1H-pyrazol-5-amine then Y).) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.175 g, 1.0 mmol) in DCM (5 mL) was cooled to about 0° C. and treated with NMM (0.11 mL, 1.0 mmol) dropwise. The mixture was stirred under nitrogen at about 0° C. for about 3 h. Separately, into a new 50 mL Ehrlenmeyer flask, 1-methyl-3-nitro-1-nitrosoguanidine (2.94 g, 10 mmol) was added in portions to a stirred mixture of Et2O (27 mL) and 45% aq. KOH (12 mL) cooled to about 0° C. The mixture was stirred for about an additional 20 min after the reagent was added. The mixture was poured into a diazomethane separatory funnel and the aqueous layer was removed. The Et2O layer was poured into a new 50 mL Ehrlenmyer flask. The Et2O layer was decanted again to remove any residual water. The solids were filtered away from the acid chloride and the acid chloride was added to the stirring diazomethane solution. The reaction was allowed to warm to rt for about 90 min and then the solvents and excess diazomethane were removed with a stream of nitrogen. The residue was dissolved in MeOH (20 mL) and cooled at about 0° C. in sonic bath. A mixture of silver benzoate (0.069 g, 0.300 mmol) in TEA (0.98 mL, 7.0 mmol) was added dropwise. Sonication was continued for about 30 min, then let stand for about 16 h. The reaction was concentrated in vacuo, diluted with sat NaHCO3 solution (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with sat. aq. NaCl solution (25 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel using a gradient of 25-70% EtOAc in heptane. Product fractions were combined and concentrated to yield methyl 4-(4-Bromo-2-methylphenyl)-4-(5-((tert-butoxycarbonyl)amino)-1,3-dimethyl-1H-pyrazol-4-yl)butanoate as a tan foam (0.060 g, 0.13 mmol, 13%); LC-MS (Table 1, Method g) Rt=2.56 min, m/z 580/582 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.35-7.13 (m, 3H), 3.84 (t, J=7.4 Hz, 1H), 3.54 (s, 3H), 3.42 (s, 3H), 2.26-2.19 (m, 2H), 2.16 (s, 3H), 2.14-2.02 (m, 2H), 1.92 (s, 3H), 1.39 (s, 9H).

1. temperaturecooled to about 0° C
2. stirringThe mixture was stirred for about an additional 20 min after the reagent
3. additionwas added
4. additionThe mixture was poured into a diazomethane separatory funnel
5. customthe aqueous layer was removed
6. additionThe Et2O layer was poured into a new 50 mL Ehrlenmyer flask
7. customThe Et2O layer was decanted again
8. customto remove any residual water
9. filtrationThe solids were filtered away from the acid chloride
10. additionthe acid chloride was added to the stirring diazomethane solution
11. temperatureto warm to rt for about 90 min
12. customthe solvents and excess diazomethane were removed with a stream of nitrogen
13. dissolutionThe residue was dissolved in MeOH (20 mL)
14. temperaturecooled at about 0° C. in sonic bath
15. additionwas added dropwise
16. customSonication
17. waitwas continued for about 30 min
18. waitlet stand for about 16 h
19. concentrationThe reaction was concentrated in vacuo
20. additiondiluted with sat NaHCO3 solution (25 mL)
21. extractionextracted with EtOAc (2×25 mL)
22. washThe organic layer was washed with sat. aq. NaCl solution (25 mL)
23. dry with materialdried over Na2SO4
24. filtrationfiltered
25. concentrationconcentrated in vacuo
26. customThe residue was purified on silica gel using a gradient of 25-70% EtOAc in heptane
27. concentrationconcentrated

ORD record

ord-2bce7c8a35304e399151561f21e803a0

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09150592B2