Sodium Azide → 1-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide

Temperature

60 °C

A suspension of [5-({[1-(4-Chloromethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (100 mg, 0.207 mmol, prepared according to step a) of example 17), sodium azide (13.43 mg, 0.207 mmol), ethynyltrimethylsilane (20.29 mg, 0.207 mmol), DIPEA (3.61 μL, 0.021 mmol), copper sulfate (3.30 mg, 0.021 mmol) and sodium ascorbate (4.09 mg, 0.021 mmol) in 2.5 mL of DMSO and 0.5 mL of water was stirred for 3 hours at 60° C. The mixture was allowed to cool to room temperature, was diluted with ethyl acetate and washed with water. The organic solution was concentrated under reduced pressure. The residue was dissolved in mL of methanol and 2 mL of concentrated aqueous HCl was added. This solution was stirred for 2 hours at 60° C. The volatiles were evaporated under reduced pressure. The residue was adjusted to basic pH with 1N NaOH. The resulting aqueous solution was extracted with ethyl acetate. The organic solution was dried of MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Macherey Nagel C18 100×10 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min, then ACN/water (0.1% TFA) 5/95-100/0 over 15 min). The fractions containing product were pooled, freeze-dried and redissolved in methanol. This solution was filtered over a methanol-flushed PL-HCO3-MP resin column, which was subsequently washed twice with 5 mL methanol. The methanolic solution was concentrated under reduced pressure. The residue was taken up in ACN—water and freeze dried to afford the title compound. LCMS (Method A) RtA=0.316; [M+H]+=417.1.

1. customprepared
2. temperatureto cool to room temperature
3. washwashed with water
4. concentrationThe organic solution was concentrated under reduced pressure
5. dissolutionThe residue was dissolved in mL of methanol and 2 mL of concentrated aqueous HCl
6. additionwas added
7. stirringThis solution was stirred for 2 hours at 60° C
8. customThe volatiles were evaporated under reduced pressure
9. extractionThe resulting aqueous solution was extracted with ethyl acetate
10. dry with materialThe organic solution was dried of MgSO4
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe residue was purified by preparative HPLC (Macherey Nagel C18 100×10 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min
14. waitACN/water (0.1% TFA) 5/95-100/0 over 15 min)
15. additionThe fractions containing product
16. customfreeze-dried
17. dissolutionredissolved in methanol
18. filtrationThis solution was filtered over a methanol-
19. customflushed PL-HCO3-MP resin column, which
20. washwas subsequently washed twice with 5 mL methanol
21. concentrationThe methanolic solution was concentrated under reduced pressure
22. customfreeze dried

ORD record

ord-5a50b22a1ecf4a83ad421ab1d817a109

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290485B2