Hydrochloric Acid → HCID 71237313, compound

Temperature

25 °C

Combine tert-butyl N-[(1S)-2-[[5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]carbamate (54.0 g, 0.12 mol) and acetonitrile (212.7 mL) under a nitrogen atmosphere. Add hydrochloric acid (317.5 mL, 4N, 1.27 mol) drop-wise to maintain the internal temperature below 30° C., and stir the reaction mixture for 16-18 hours at 20-30° C. Add water (324.0 mL) and dichloromethane (430 mL) and separate the layers. Discard the organic layer and to the aqueous phase add dichloromethane (645 mL) and adjust the pH to approximately 10 using aqueous sodium hydroxide (20%, 252 mL). Separate the layers, extract the aqueous layer with additional dichloromethane (2×430 mL), and combine the organic phases. Concentrate the organic under reduced pressure below 45° C. to an approximate volume of 130-150 mL, and add tetrahydrofuran (322 mL). Concentrate the solution under reduced pressure below 45° C. to an approximate volume of 200-220 mL, and add additional tetrahydrofuran (213 mL). Concentrate the reaction mixture under reduced pressure to an approximate volume of 250-270 mL, and heat to 60-65° C. for 2-3 hours. Cool the reaction mixture to 5-15° C. slowly and stir for 5-8 hours. Filter the resulting solids, wash the filter cake with ethyl acetate (56 mL). Transfer the solids to a clean reaction vessel, add ethyl acetate (150 mL), and heat to 60-65° C. for 2-3 hours, then cool the solution to 5-15° C. slowly. Stir for 2-3 hours at this temperature and collect the resulted solids by filtration. Wash the filter cake with ethyl acetate (45 mL) and dry the solids in an oven under reduced pressure below 60° C. to provide the title compound (21.0 g, 99.2% de, 100% ee, 51.0% yield) as an off white solid. MS (m/z): 341 (M+1).

1. customAdd water (324.0 mL) and dichloromethane (430 mL) and separate the layers
2. additionDiscard the organic layer and to the aqueous phase add dichloromethane (645 mL)
3. customSeparate the layers
4. extractionextract the aqueous layer with additional dichloromethane (2×430 mL)
5. concentrationConcentrate the organic under reduced pressure below 45° C. to an approximate volume of 130-150 mL
6. additionadd tetrahydrofuran (322 mL)
7. concentrationConcentrate the solution under reduced pressure below 45° C. to an approximate volume of 200-220 mL
8. additionadd additional tetrahydrofuran (213 mL)
9. concentrationConcentrate the reaction mixture under reduced pressure to an approximate volume of 250-270 mL
10. temperatureheat to 60-65° C. for 2-3 hours
11. temperatureCool the reaction mixture to 5-15° C. slowly
12. stirringstir for 5-8 hours
13. filtrationFilter the resulting solids
14. washwash the filter cake with ethyl acetate (56 mL)
15. additionTransfer the solids to a clean reaction vessel, add ethyl acetate (150 mL)
16. temperatureheat to 60-65° C. for 2-3 hours
17. temperaturecool the solution to 5-15° C. slowly
18. stirringStir for 2-3 hours at this temperature
19. customcollect the resulted solids
20. filtrationby filtration
21. washWash the filter cake with ethyl acetate (45 mL)
22. customdry the solids in an oven under reduced pressure below 60° C.

ORD record

ord-c82396e9930b4324b13b7d5cd4b79493

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569286B2