HCID 90093186, compound → HCID 90093723, compound

Temperature

0 °C

Isopropyl magnesium chloride (8.16 mL, 1.28 mmol, 2M in diethyl ether) was added to 3-iodo-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 53, 4.45 g, 14.8 mmol) in THF (90 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 2-[(diphenylmethylene)amino]-N-methoxy-N-methylisonicotinamide (Preparation 51, 5.12 g, 14.8 mmol) in THF (30 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM/MeOH 95:5 (7×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM followed by a second purification by silica gel column chromatography eluting with 30-50% EtOAc in DCM. The residue was dissolved in THF (90 mL) and 0.5M HCl (90 mL) was added followed by stirring at room temperature for 30 minutes. The reaction was quenched by the addition of 1N NaOH to pH 6-7 and the mixture eluted through an SCX cartridge washing through with MeOH followed by ammonia in MeOH (300 mL, 2M solution). The filtrate was concentrated in vacuo, azeotroping with toluene. The residue was dissolved in DCM:MeOH 90:10 (20 mL) and poured into diethyl ether (1000 mL) to precipitate a white solid. After filtering the white solid was dried to afford the title compound.

1. temperatureThe mixture was warmed to room temperature
2. stirringstirred at this temperature for 16 hours
3. customThe reaction mixture was quenched with water (200 mL)
4. extractionextracted with DCM/MeOH 95:5 (7×100 mL)
5. washThe combined organic extracts were washed with brine
6. dry with materialdried over magnesium sulphate
7. customevaporated in vacuo
8. customThe residue was purified
9. washeluting with 0-5% MeOH in DCM
10. customfollowed by a second purification by silica gel column chromatography
11. washeluting with 30-50% EtOAc in DCM
12. dissolutionThe residue was dissolved in THF (90 mL)
13. addition0.5M HCl (90 mL) was added
14. stirringby stirring at room temperature for 30 minutes
15. customThe reaction was quenched by the addition of 1N NaOH to pH 6-7
16. washthe mixture eluted through an SCX cartridge
17. washwashing through with MeOH
18. concentrationThe filtrate was concentrated in vacuo
19. customazeotroping with toluene
20. dissolutionThe residue was dissolved in DCM:MeOH 90:10 (20 mL)
21. additionpoured into diethyl ether (1000 mL)
22. customto precipitate a white solid
23. filtrationAfter filtering the white solid
24. customwas dried

ORD record

ord-9ea9c9cdb5ff4475989c3d2752a29b3b

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09163021B2