Sodium Carbonate → HCID 86727273, compound

HRID 2173103Notes

Reaction equation

HRID 2173103 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 642694trans-2-(4-Chlorophenyl)vinylboronic acidHCID 86654740tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 1

HCID 86727273HCID 86727273, compound

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-chlorostyrylboronic acid (54.8 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (31 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.82 Hz, 2H), 1.62 (d, J=7.58 Hz, 1H), 1.66-1.80 (m, 3H), 1.80-2.02 (m, 2H), 3.74 (br s, 1H), 4.41 (d, J=2.27 Hz, 1H), 4.50 (br s, 1H), 6.86 (d, J=5.56 Hz, 1H), 7.50 (d, J=8.59 Hz, 1H), 7.56-7.68 (m, 2H), 7.69 (s, 1H), 7.76 (br s, 3H), 8.21 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22ClFN4O, 401. found, 401.

Workup

  1. customIn a 30 mL sealed
  2. customThe cap was sealed
  3. extractionextracted with EtOAc (2×30 mL)
  4. dry with materialThe combined organic phase was dried over sodium sulfate
  5. customevaporated

Sources & evidence

ORD record
ord-007ac1f45e3d4134a60a06b9a758e197
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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