Sodium Bicarbonate → HCID 118195158, compound

HRID 923852Notes

Reaction equation

HRID 923852 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=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>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 27630812-Methylpyridine-5-boronic acidHCID 86702636(S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118195158HCID 118195158, compound

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 60 mg, 0.134 mmol) and (6-methylpyridin-3-yl)boronic acid (36.8 mg, 0.19 mmol) were dissolved in DME (0.5 mL). A solution of 2 M aq. NaHCO3 (0.2 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and then treated with Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol). The RM was stirred under argon at 90° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.09 min, UPLC-MS (Condition 7) m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.75 (m, 1H) 1.76-1.87 (m, 1H) 2.52 (s, 3H) 2.86 (d, J=11.73 Hz, 1H) 3.11-3.24 (m, 2H) 3.27-3.43 (m, 1H) 4.17 (br. s, br. s, 1H) 4.83 (br. s, br. s, 1H) 7.28-7.39 (m, 3H) 7.69 (dd, J=7.82, 1.96 Hz, 1H) 7.79-7.89 (m, 2H) 7.98 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

Workup

  1. customthe RM was flushed with argon
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH)
  7. additiontreated with Si-Thiol (50 mg) in MeOH

Sources & evidence

ORD record
ord-a025418ef8c847de9ff341091a219837
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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