Sodium Carbonate → (R)-Methyl 6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinate

HRID 924018Notes

Reaction equation

HRID 924018 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].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.[Cl-].[Na+].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:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:3]2[C:2]([C:22]3[CH:23]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:13]1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 72546088methyl (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate

Product 1

HCID 118198944(R)-Methyl 6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinate

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
95 °C

Procedure

(R)-Methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 170.3, 930 mg, 3.1 mmol) and pyrimidin-5-ylboronic acid (765 mg, 6.2 mmol) were dissolved in a solution of DME (5 mL) and EtOH (0.7 mL). A solution of 2 M Na2CO3 (4.63 mL, 9.26 mmol) was added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (260 mg, 0.371 mmol) was added and the RM was stirred at 95° C. in a pressure safe vial for 1.5 h. After cooling at RT, the RM was treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH) a treated with Si-Thiol (1 g) in MeOH to afford the title compound as a grey foamy powder. HPLC (Condition 4) tR=2.95 min, UPLC-MS (Condition 7) m/z=301.1 [M+H]+.

Workup

  1. additionwas added
  2. temperatureAfter cooling at RT
  3. extractionextracted with EtOAc
  4. dry with materialThe combined extracts were dried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give a residue that
  7. customwas purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH)
  8. additiona treated with Si-Thiol (1 g) in MeOH

Sources & evidence

ORD record
ord-af9dbf7ee859437fbec6d1f6adb1d9d7
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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