Sodium Carbonate → 5-(2-Chloro-primidin-4-yl)-2-((S)-3-fluoro-pyrrolidin-1-yl)-nicotinonitrile

HRID 55862Notes

Reaction equation

HRID 55862 reaction equation
[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:8]=2[C:9]#[N:10])[CH2:3]1.BC1C=NC(N2CC[C@H](F)C2)=C(C=1)C#N.[Cl:39][C:40]1[N:45]=[C:44](Cl)[CH:43]=[CH:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.O.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:39][C:40]1[N:45]=[C:44]([C:12]2[CH:13]=[N:14][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]3)=[C:8]([CH:11]=2)[C:9]#[N:10])[CH:43]=[CH:42][N:41]=1

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 775312,4-DichloropyrimidineHCID 903571482-((S)-3-Fluoro-pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrileHCID 178419157HCID 178419157, compound

Product 1

HCID 903695215-(2-Chloro-primidin-4-yl)-2-((S)-3-fluoro-pyrrolidin-1-yl)-nicotinonitrileYield 55%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-((S)-3-Fluoro-pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile and 5-boranyl-2-((S)-3-fluoro-pyrrolidin-1-yl)-nicotinonitrile (7) (2.64 g, ˜9.6 mmol), 2,4-dichloropyrimidine (1.2 g, 9.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol) and Na2CO3 (3.1 g, 28.8 mmol) were dissolved in 1:1 1,4-dioxane-H2O (40 mL) and the mixture was stirred at 120° C. in the microwave (250 W, stirring) for 30 minutes. The mixture was diluted with EtOAc (130 mL) and H2O (40 mL) and the layers separated. The organic phase was washed with saturated brine solution (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (40-63 mesh silica gel, 1:1 isohexane-EtOAc) to provide the title compound as a pale yellow solid (1.6 g, 55%); LCMS, Rt=2.80 min (MeOH-FA method), m/z 304 (MH+).

Workup

  1. customthe layers separated
  2. washThe organic phase was washed with saturated brine solution (50 mL)
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customthe solvent evaporated in vacuo
  6. customThe crude product was purified by column chromatography (40-63 mesh silica gel, 1:1 isohexane-EtOAc)

Sources & evidence

ORD record
ord-f7689369cac64b7fa4a9f547d206a9f9
Source dataset
uspto-grants-2016_09
Patent number
US09433622B2

Reaction notes

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