Methanol → HCID 25265519, compound

(2S,3R)-2-Methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine (92 mg, 0.34 mmol) was dissolved in DCM (4 mL) and pyridine (1 mL). The solution was cooled in an ice-water bath. To this solution was added a solution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar, 0.48 g, 2.77 mmol, 1.6 equiv.) in DCM (2 mL). The solution was stirred at r.t. for 2 h. The reaction was judged to be complete when TLC (10% MeOH in DCM) and LC/MS did not detect the SM at 274, but detected only the product peak at 410.2 and at retention time of 3.02 min. Polymer bounded diethylenetriamine (4 mmol/g, 0.12 g) was added and stirred at r.t. for 30 min., then filtered and rinsed with DCM. The solvent was evaporated to dryness, re-dissolved in DCM and NaHCO3 aqueous solution. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were successively washed with sodium bicarbonate (5 mL) and brine (5 mL×2), dried (anhydrous potassium carbonate), passed through a silica gel pad (self packed, ˜10 g), rinsed with DCM (no product) and then with 10% MeOH in DCM (contain product). The solution was concentrated in vacuo to obtain a crude product, which was purified on a silica gel column by eluting with 0 to 10% MeOH in DCM to obtain 48 mg (34% yield) of the title compound as a semi-solid. LC/MS: t=3.020 min, MS: 410.2. 1H NMR (300 MHz, CDCl3), δ (ppm): 7.49 (m, 1H), 7.23 (m, 1H), 7.11 (m, 2H), 6.41 (m, 1H), 3.70 (m, 2H), 3.57 (t, 6.2 Hz, 1H), 3.39 (m, 2H), 3.32 (m, 1H), 3.16 (m, 1H), 3.06 (m, 1H), 2.95 (m, 2H), 2.65 (m, 1H), 2.62 (s, 1H), 2.61 (s, 3H), 2.49 (m, 1H), 2.38 (s, 3H), 2.05 (m, 2H), 1.90 (m, 2H), 1.80 (m, 1H), 1.40 (d, 6.5 Hz, 3H).

1. temperatureThe solution was cooled in an ice-water bath
2. additionwas added
3. stirringstirred at r.t. for 30 min.
4. filtrationfiltered
5. washrinsed with DCM
6. customThe solvent was evaporated to dryness
7. dissolutionre-dissolved in DCM
8. customThe two layers were separated
9. extractionthe aqueous layer was extracted with DCM (10 mL×2)
10. washThe combined DCM extracts were successively washed with sodium bicarbonate (5 mL) and brine (5 mL×2)
11. dry with materialdried (anhydrous potassium carbonate)
12. washrinsed with DCM (no product) and then with 10% MeOH in DCM (contain product)
13. concentrationThe solution was concentrated in vacuo
14. customto obtain a crude product, which
15. customwas purified on a silica gel column
16. washby eluting with 0 to 10% MeOH in DCM

ORD record

ord-330e6c646bb440579ba82231d61ce0db

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08227504B2