Sodium Hydroxide → HCID 46209424, compound

Temperature

30 °C

To a solution of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid methyl ester (12.0 g, 25.4 mmol) in methanol was added 5.0 M NaOH (25 mL) and the reaction mixture was heated at 30° C. for 8 h and then at 25° C. overnight. Most of the methanol solvent was removed by rotary evaporation at 25° C., water (100 mL) and isopropyl acetate (100 mL) was added and the resulting mixture was stirred for 15 min. The bottom two of three layers were extracted with isopropyl acetate (100 mL). Bottom layers were cooled to −5° C. and MeTHF (200 mL) was added and then concentrated HCl (˜15 mL) was added in portions until pH ˜2. Phases were separated, water layer was washed with MeTHF (100 mL) and combined organic layers were dried with Na2SO4. Most of the organic solvent was removed by rotary evaporation, ethyl acetate (200 mL) was added and the volume was reduced to 50 mL. Ethyl acetate (200 mL) was added and the resulting slurry was stirred/triturated at RT for 3 h. Product was filtered under nitrogen and dried under vacuum for 48 h to yield the hydrochloride salt of the title compound (11 g, 98.2% purity) as a white solid. 1H NMR (DMSO-d6): δ (ppm) 0.54 (t, 3H), 0.63 (t, 3H), 0.82 (m, 2H), 1.05-1.3 (m, 6H), 1.45 (m, 1H), 1.55-2.0 (m, 10H), 2.40 (m, 1H), 2.67 (dd, 1H), 3.06 (m, 1H), 3.22 (m, 1H), 3.30 (dd, 1H), 3.41 (s, 3H), 3.45 (dd, 1H), 4.05 (m, 1H), 7.19 (d, 1H), 7.50 (br, 1H), 7.69 (d, 1h), 7.70 (s, 1H), 7.95 (br, 2H), 9.26 (br, 1H).

1. customat 25° C.
2. customovernight
3. customMost of the methanol solvent was removed by rotary evaporation at 25° C.
4. additionwater (100 mL) and isopropyl acetate (100 mL) was added
5. extractionThe bottom two of three layers were extracted with isopropyl acetate (100 mL)
6. temperatureBottom layers were cooled to −5° C.
7. additionMeTHF (200 mL) was added
8. additionconcentrated HCl (˜15 mL) was added in portions until pH ˜2
9. customPhases were separated
10. washwater layer was washed with MeTHF (100 mL)
11. dry with materialwere dried with Na2SO4
12. customMost of the organic solvent was removed by rotary evaporation, ethyl acetate (200 mL)
13. additionwas added
14. additionEthyl acetate (200 mL) was added
15. customthe resulting slurry was stirred/triturated at RT for 3 h
16. filtrationProduct was filtered under nitrogen
17. customdried under vacuum for 48 h

ORD record

ord-aa1d6845bdd94f53a3a0fe0274ca0a97

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969367B2