Sodium Carbonate → tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

HRID 2173096Notes

Reaction equation

HRID 2173096 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].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.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]([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[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]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 117363112-Phenyl-1-ethynylboronic acid pinacol esterHCID 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 86727269tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Reagents, catalysts & solvents 3

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

Conditions

Temperature
90 °C

Procedure

In a 30 mL 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), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and was extracted with EtOAc (2×50 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)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% 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 (32 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m, 5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H), 7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H21FN4O, 365. found, 365.

Workup

  1. customThe vessel was sealed with
  2. customa cap
  3. extractionwas extracted with EtOAc (2×50 mL)
  4. dry with materialThe combined organic phase was dried over sodium sulfate
  5. customevaporated

Sources & evidence

ORD record
ord-069c3c03efc1401b8484c4eca959d45e
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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