Potassium Phosphate, Tribasic → methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate

HRID 73751Notes

Reaction equation

HRID 73751 reaction equation
Br[C:2]1[C:3]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[N:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[N:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:3]2[C:2]([C:28]3[N:24]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23][O:18]4)[N:25]=[CH:26][CH:27]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:13]1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 72546088methyl (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate

Product 1

HCID 72546086methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
92 °C

Procedure

A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 9.6, 90 g, 299 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (103.9 g, 373.6 mmol), K3PO4 (126.9 g, 597.7 mmol), Pd(PPh3)2Cl2 (6.29 g, 8.97 mmol) in toluene (900 mL) was stirred at 92° C. and for 16 h. After cooling the mixture to RT, the solution was washed with water (450 mL), 5% NaHCO3 solution (430 mL) and the solvent was evaporated off under reduced pressure to give a residue which was used without further purifications in the next step. HPLC (Condition 7) tR=6.929 min, LC-MS (Condition 8) tR=4.30 min, m/z=373.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 1H), 1.35-1.63 (m, 4H), 1.63-1.86 (m, 3H), 1.89 (br. s, 1H), 2.12-2.39 (m, 1H), 3.11 (br. s, 1H), 3.18-3.48 (m, 4H), 3.78 (s, 4H), 3.88 (d, J=11.54 Hz, 1H), 4.08-4.24 (m, 1H), 4.86 (dd, J=18.20, 2.89 Hz, 1H), 5.02 (d, J=8.28 Hz, 1H), 6.39 (br. s, 1H), 7.58 (d, J=1.25 Hz, 1H), 7.78 (br. s, 1H), 8.69 (t, J=2.01 Hz, 1H).

Workup

  1. temperatureAfter cooling the mixture to RT
  2. washthe solution was washed with water (450 mL), 5% NaHCO3 solution (430 mL)
  3. customthe solvent was evaporated off under reduced pressure
  4. customto give a residue which

Sources & evidence

ORD record
ord-38b1ee1b95a74b3c86c55552d2102f8b
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

Loading…