Isopropanol → tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

HRID 2173052Notes

Reaction equation

HRID 2173052 reaction equation
[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](F)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CC(O)C.CN1CCOCC1>O>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 79724-MethylmorpholineHCID 68077633tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamateHCID 86727249HCID 86727249, compound

Product 1

HCID 86654748tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylateYield 93%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of tert-butyl 4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (42.5 g, 139 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (36.2 g, 167 mmol) was added IPA (425 mL) followed by 4-methylmorpholine (18.40 mL, 167 mmol). The reaction mixture was stirred at 60° C. for 20 hours under a nitrogen atmosphere. HPLC analysis indicated that the reaction was complete. The reaction mixture was subsequently cooled to room temperature and water (890 mL) was added slowly. The suspension was cooled in an ice/water bath to 6° C. and was stirred for 1 hour. The solids were collected by filtration and washed with water (30 mL) used to rinse the reaction vessel. The filter cake was washed with additional water (350 mL) and allowed to dry on the filter. The filter cake was subsequently dried in a vacuum oven at 60° C. over the weekend to afford the title compound (64.78 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.50 (s, 9H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49 (m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d, J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C22H30ClFN4O6, 501. found, 501.

Workup

  1. temperatureThe reaction mixture was subsequently cooled to room temperature
  2. temperatureThe suspension was cooled in an ice/water bath to 6° C.
  3. stirringwas stirred for 1 hour
  4. filtrationThe solids were collected by filtration
  5. washwashed with water (30 mL)
  6. washto rinse the reaction vessel
  7. washThe filter cake was washed with additional water (350 mL)
  8. customto dry on the filter
  9. customThe filter cake was subsequently dried in a vacuum oven at 60° C. over the weekend

Sources & evidence

ORD record
ord-be58bc26286547cc9a85f08ac4f2d21f
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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