Potassium Phosphate, Tribasic → HCID 118195395, compound

HRID 924152Notes

Reaction equation

HRID 924152 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]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[CH3:28])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 573700804-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 118195395HCID 118195395, compound

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
110 °C

Procedure

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 70 mg, 0.151 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49.7 mg, 0.227 mmol), Pd(Ph3P)4 (17.48 mg, 0.015 mmol) and K3PO4 (96 mg, 0.454 mmol) were added to a vial, flushed with argon, treated with toluene (1 mL), and stirred at 110° C. for 2 h followed by 4 h at 130° C. Dioxane (1 mL) was added and the RM was stirred for an additional 3 days at 130° C. The RM was diluted with dioxane and filtered on a pad of Hyflo®, followed by Si-Thiol scavenger treatment. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min). The purified product was lyophilized in water/min. vol. MeCN to afford the title product as an off-white powder. UPLC-MS (Condition 3), tR=0.97 min, m/z=475.1/477.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.62-1.89 (m, 2H) 2.02/2.14 (s, 3H) 2.70-3.35 (m, 4H) 4.09-4.24 (m, 1H) 4.79-4.96 (m, 1H) 7.27-7.42 (m, J=8.66 Hz, 3H) 7.86 (d, J=7.91 Hz, 2H) 7.91-8.00 (m, 1H) 8.41-8.61 (m, 2H) 8.77 (br. s, 1H) 10.11-10.19 (m, 1H).

Workup

  1. customflushed with argon
  2. additiontreated with toluene (1 mL)
  3. waitfollowed by 4 h at 130° C
  4. additionDioxane (1 mL) was added
  5. stirringthe RM was stirred for an additional 3 days at 130° C
  6. additionThe RM was diluted with dioxane
  7. filtrationfiltered on a pad of Hyflo®
  8. customThe solvent was evaporated off under reduced pressure
  9. customthe crude product was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min)

Sources & evidence

ORD record
ord-20f5ac6dea5f4d0595fe232da50ebb48
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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