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Sodium Carbonate → 3-(5-Difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3-(5'-fluoro-[2,3']bipyridinyl-4-yl)-3H-isoindol-1-ylamine

HRID 1662272
Notes
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Reaction equation

HRID 1662272 reaction equation
Cl[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH:27]([F:29])[F:28])=[C:21]([CH3:30])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][CH:27]([F:29])[O:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([C:8]2([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:34]4[CH:35]=[N:36][CH:37]=[C:32]([F:31])[CH:33]=4)[CH:7]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)=[N:20][C:21]=1[CH3:30]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 44717403(5-Fluoropyridin-3-yl)boronic acidHCID 585795123-(2-Chloro-pyridin-4-yl)-3-(5-difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3H-isoindol-1-ylamine

Product 1

HCID 585795053-(5-Difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3-(5'-fluoro-[2,3']bipyridinyl-4-yl)-3H-isoindol-1-ylamineYield 14%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalyst
HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3-(2-chloro-pyridin-4-yl)-3-(5-difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3H-isoindol-1-ylamine 1 (0.14 g, 0.32 mmol), 5-fluoropyridine-3-boronic acid (0.068 g, 0.485 mmol), Pd(PPh3)4 (0.065 g, 0.056 mmol), aqueous Na2CO3 (2M, 1 mL, 2 mmol) in DME (4 mL) was degassed for 15 minutes using nitrogen and then heated in a sealed tube at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and washed with saturated NaHCO3 solution (10 mL) and H2O (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (22 mg, 14%). 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (br. s., 1 H) 8.61 (d, 1 H) 8.48 (br. s., 1 H) 8.00 (d, 2 H) 7.85 (s, 1 H) 7.54-7.61 (m, 1 H) 7.51 (s, 1 H) 7.40 (d, 1 H) 7.16 (t, 1 H) 6.36 (s, 1 H) 2.51 (s, 3 H) 2.30 (s, 3 H).

Workup

  1. customwas degassed for 15 minutes
  2. temperatureThe reaction mixture was cooled to room temperature
  3. additiondiluted with EtOAc (20 mL)
  4. washwashed with saturated NaHCO3 solution (10 mL) and H2O (20 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-199021452b1a4b49b8fcfcb6893e56d3
Source dataset
uspto-grants-2011_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08030500B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes