Hydrochloric Acid → HCID 71537059, compound

Temperature

70 °C

A solution of methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (40 mg, 0.076 mmol) in Tetrahydrofuran (THF) (0.2 mL), Methanol (0.200 mL), Water (0.200 mL) was treated with NaOH (24.21 mg, 0.605 mmol) and heated at 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL), treated with KHMDS (0.757 mL, 0.378 mmol) and stirred at ambient temperature for one hour. Additional KHMDS (0.757 mL, 0.378 mmol) was added and the mixture was heated to 70° C. for 2 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in N,N-Dimethylformamide (DMF) (0.5 mL), treated with MeI (0.024 mL, 0.378 mmol) and potassium carbonate (52.3 mg, 0.378 mmol) and then stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL), Methanol (0.200 mL) and Water (0.200 mL), treated with NaOH (24.21 mg, 0.605 mmol) and then heated to 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1 M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(tert-butoxy)-2-(1,6-dimethyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid (6 mg, 0.013 mmol, 17.72% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.28-7.33 (m, 1H) 6.96-7.02 (m, 1H) 6.92-6.96 (m, 1H) 6.70-6.81 (m, 1H) 5.70-5.81 (m, 1H) 5.15-5.46 (m, 1H) 4.17-4.25 (m, 5H) 3.66-3.68 (m, 3H) 2.60-2.77 (m, 2H) 2.06-2.16 (m, 2H) 1.92-2.05 (m, 3H) 0.98-1.05 (m, 9H); LCMS (m/z) ES+=439 (M+1).

1. temperatureThe mixture was cooled to 0° C.
2. extractionextracted with ethyl acetate
3. washThe combined extracts were washed with brine
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL)
8. temperaturethe mixture was heated to 70° C. for 2 hours
9. temperatureThe mixture was cooled to 0° C.
10. extractionextracted with ethyl acetate
11. washThe combined extracts were washed with brine
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated
15. dissolutionThe resultant was dissolved in N,N-Dimethylformamide (DMF) (0.5 mL)
16. stirringstirred at ambient temperature overnight
17. extractionthe mixture was extracted with ethyl acetate
18. washThe combined extracts were washed with brine
19. dry with materialdried over Na2SO4
20. filtrationfiltered
21. concentrationconcentrated
22. dissolutionThe resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL)
23. temperatureheated to 70° C. for 3 hours
24. temperatureThe mixture was cooled to 0° C.
25. extractionextracted with ethyl acetate
26. washThe combined extracts were washed with brine
27. dry with materialdried over Na2SO4
28. filtrationfiltered
29. concentrationconcentrated
30. customThe residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min)

ORD record

ord-81c0ab24b89e49cd89dcc6a52e37f60a

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012642B2