Dimethylcarbamoyl Chloride → 3-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-1,1-dimethyl-urea

Temperature

45 °C

N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-2,2,2-trifluoro-acetamide (78 mg, 0.15 mmol) and Potassium carbonate (125 mg, 0.904 mmol) were combined in Methanol (10 mL), and were then heated at 45° C. After stirring 3.5 d, the reaction had reached ˜60% completion. After an additional 3 d, the mixture had evaporated to dryness, but the reaction had gone to completion as determined by HPLC of resolubilized material (DCM:MeOH). The mixture was reconcentrated to dryness after filtering off the solids. 1,4-Dioxane (5 mL) was added followed by Triethylamine (0.2 mL, 1.4 mmol) and N,N-Dimethylcarbamoyl chloride (21 uL, 0.23 mmol), and the reaction was stirred under an atmosphere of Nitrogen. After O.N. stirring, 0.5 mL DMF was added, and the mixture was sonicated to aid in solubilizing all the contents. After an additional 24 h, N,N-Dimethylcarbamoyl chloride (50 uL, 0.5 mmol) was added and stirring was continued. After 24 h, N,N-Dimethylcarbamoyl chloride (50 uL, 0.5 mmol) was added along with 3 mL dichloromethane to aid in solubility and to rinse the sidewalls of the flask. After 5 h, the contents were concentrated onto Celite and chromatographed on an ISCO column, eluting with 10% (5% NH4OH:MeOH):DCM. The product elutes at 10% polar solvent mix, and was collected and concentrated to afford 3-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-1,1-dimethyl-urea (52 mg, 70%) as a yellow film. LCMS (m/e) 486 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.85 (s, 1H), 7.28 (m, 2H), 7.03 (m, 2H), 6.08 (d, 1H, J=7.1 Hz), 4.85 (d, 1H, J=7.2 Hz), 3.82 (m, 1H), 3.71 (m, 1H), 2.94 (m, 5H), 2.68 (s, 6H), 2.62 (m, 7H), 2.28 (m, 1H), 2.15 (m, 1H), 1.80 (m, 2H), 1.2-1.4 (m, 5H), 1.12 (t, 3H, J=7.1 Hz).

1. waitAfter an additional 3 d
2. customthe mixture had evaporated to dryness
3. filtrationafter filtering off the solids
4. addition1,4-Dioxane (5 mL) was added
5. stirringthe reaction was stirred under an atmosphere of Nitrogen
6. stirringstirring
7. customthe mixture was sonicated
8. waitAfter an additional 24 h
9. stirringstirring
10. waitAfter 24 h
11. washto rinse the sidewalls of the flask
12. waitAfter 5 h
13. concentrationthe contents were concentrated onto Celite
14. customchromatographed on an ISCO column
15. washeluting with 10% (5% NH4OH:MeOH)
16. additionmix
17. customwas collected
18. concentrationconcentrated

ORD record

ord-ec80e095c67a46619999b327816585aa

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08552186B2