Potassium Carbonate → HCID 118195198, compound

HRID 924151Notes

Reaction equation

HRID 924151 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[C:25]1[C:26]([N:45]2[CH2:49][C@H:48]([OH:50])[C@@H:47]([OH:51])[CH2:46]2)=[N:27][CH:28]=[C:29]([CH:44]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([Cl:43])([F:42])[F:41])=[CH:35][CH:34]=1)=[O:31]>CN(C=O)C.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>[Cl:43][C:40]([F:41])([F:42])[O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:29]2[CH:44]=[C:25]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:26]([N:45]3[CH2:46][C@H:47]([OH:51])[C@@H:48]([OH:50])[CH2:49]3)=[N:27][CH:28]=2)=[O:31])=[CH:34][CH:35]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 159842973-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carbonitrileHCID 899065275-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 118195198HCID 118195198, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

4-Cyanopyridine-3-boronic acid pinacol ester (192 mg, 0.836 mmol), K2CO3 (0.418 mL, 0.836 mmol) and Pd(PPh3)4 (24.14 mg, 0.021 mmol) were added to a solution of 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 248.1, 200 mg, 0.418 mmol) in DMF (2.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and heated at 130° C. for 18 h. The RM was diluted with EtOAc (60 mL) and washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in MeOH (3 mL), stirred for at RT 15 min, filtered and washed with MeOH (2 mL). The filtrate was filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol) and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 21% to 26% in 6 min) to afford the title product as a yellow solid. HPLC (Condition 10) tR=5.90 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=502.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.95 (d, J=11.34 Hz, 2H) 3.14-3.39 (m, 2H) 3.86 (br. s, 2H) 5.02-5.07 (m, 1H) 5.09-5.14 (m, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 7.96-8.06 (m, 1H) 8.12 (d, J=17.60 Hz, 1H) 8.76-8.88 (m, 2H) 9.08 (br. s, 1H) 10.21 (d, J=4.69 Hz, 1H).

Workup

  1. customThe vial was evacuated/purged with argon
  2. customsealed
  3. additionThe RM was diluted with EtOAc (60 mL)
  4. washwashed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent was evaporated off under reduced pressure
  8. filtrationfiltered
  9. washwashed with MeOH (2 mL)
  10. filtrationThe filtrate was filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol)
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a residue which
  13. customwas purified by preparative SFC (Column 2-EP, from 21% to 26% in 6 min)

Sources & evidence

ORD record
ord-ea1dd91bb73941b89f1ce85ea586405d
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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