Potassium Phosphate, Tribasic → (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(2-methylthiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525652Notes

Reaction equation

HRID 525652 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[S:30][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[S:30][C:29]([CH3:28])=[N:33][CH:32]=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

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 457858292-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazoleHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89908122(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(2-methylthiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (45.4 mg, 0.202 mmol), Pd2(dba)3 (2.463 mg, 2.69 μmol), 2-dichlohexylphosphino-2′-6′-dimethoxybiphenyl (4.42 mg, 10.76 μmol) and K3PO4 (86 mg, 0.403 mmol) were added to a MW vial, which was sealed and evacuated/purged with argon. Dioxane was added and the RM was stirred at 100° C. for 16 h. Additional 2-methylthiasole-5-boronic acid pinacol ester (15.14 mg, 0.067 mmol) and Pd2(dba)3 (2.463 mg, 2.69 μmol) were added and RM was stirred at 100° C. overnight. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 30% for 0.2 min then 30% to 60% in 12 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.35 min, m/z=465.1-466.1 [M+H]+, m/z=463.1-464.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.70 (s, 3H) 3.03-3.09 (m, 1H) 3.25-3.40 (m, 2H) 3.45-3.55 (m, 1H) 4.20-4.27 (m, 1H) 4.88 (d, J=3.18 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.60 (s, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).

Workup

  1. customwas sealed
  2. customevacuated/purged with argon
  3. additionDioxane was added
  4. stirringRM was stirred at 100° C. overnight
  5. filtrationfiltered
  6. customthe filtrate was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by preparative HPLC (Condition 9, 30% for 0.2 min

Sources & evidence

ORD record
ord-e21dbe027d3c4188bd9595e341800797
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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