Hexane → 6-((2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanamido)-N,N-dimethylnicotinamide

Temperature

0 °C

Trimethylaluminium (2M in hexane, 0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (CAS no. 827588-33-0) (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (Intermediate L1) (256 mg, 0.65 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. 2M Trimethylaluminium in hexane (0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. The residue from the above evaporation was dissolved in toluene (6 mL) and added dropwise. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product.

1. customat 0° C.
2. additionAfter the addition
3. temperatureto warm to ambient temperature
4. temperaturewas then heated
5. temperatureto reflux for 16 hours
6. temperatureAllowed to cool to ambient temperature
7. concentrationThe reaction mixture was concentrated
8. additiondiluted with EtOAc (100 mL)
9. washwashed with saturated brine (50 mL)
10. dry with materialThe organic layer was dried (MgSO4)
11. filtrationfiltered
12. customevaporated
13. stirringThe resulting solution was stirred at 0° C. for 20 minutes
14. customThe residue from the above evaporation
15. dissolutionwas dissolved in toluene (6 mL)
16. additionadded dropwise
17. additionAfter the addition
18. temperatureto warm to ambient temperature
19. temperaturewas then heated
20. temperatureto reflux for 16 hours
21. temperatureAllowed to cool to ambient temperature
22. concentrationThe reaction mixture was concentrated
23. additiondiluted with EtOAc (100 mL)
24. washwashed with saturated brine (50 mL)
25. dry with materialThe organic layer was dried (MgSO4)
26. filtrationfiltered
27. customevaporated
28. customto afford crude product

ORD record

ord-ccc42f852965467db8ffc6d8d7faa1bb

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143263B2