Hydrochloric Acid → 6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

HRID 516127Notes

Reaction equation

HRID 516127 reaction equation
C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=3)[C:19]3[C:30](=[O:40])[N:31](C(OC(C)(C)C)=O)[CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl>CC(O)C>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:28])[F:29])[CH:26]=3)[C:19]3[C:30](=[O:40])[NH:31][CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 86654749tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 1

HCID 583175336-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-oneYield 96%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
75 °C

Procedure

tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (126 mg, 0.998 mmol) was dissolved in 2-propanol (5 mL) and the solution was heated to 75° C. with a heating block. Then 2M HCl (2.5 mL) was added, the temperature was lowered to 65° C., and the reaction mixture was stirred for 3 h. The solution was concentrated and purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 10-50% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (79 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 1 H), 2.09-2.12 (m, 1 H), 3.60-3.63 (m, 1 H), 3.76-3.77 (m, 1 H), 3.88-3.98 (m, 3 H), 4.44 (d, J=6.35 Hz, 2 H), 4.54-4.55 (m, 1 H), 7.17 (d, J=5.86 Hz, 1 H), 7.89 (br s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 9.43 (s, 1 H). [M+H] calc'd for C16H17F3N6O2, 383; found, 383.

Workup

  1. customwas lowered to 65° C.
  2. concentrationThe solution was concentrated
  3. custompurified by preparatory HPLC
  4. washeluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 10-50% gradient, 10 mM NH4HCO3)

Sources & evidence

ORD record
ord-d60aae2bc00c46b998a422a34c85ad34
Source dataset
uspto-grants-2015_08
Patent number
US09108970B2

Reaction notes

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