Cesium fluoride → 2-(((2S,3R)-1-(5-Fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione

HRID 61176Notes

Reaction equation

HRID 61176 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8].[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)CCC>CN(C=O)C.CCOC(C)=O.[Cu]I.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8]

Participants

8

Reactant 3

HCID 25953Cesium fluorideHCID 27632512-(Tributylstannyl)pyrimidineHCID 1177280012-(((2S,3R)-1-(5-Fluoro-2-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione

Product 1

HCID 1177279542-(((2S,3R)-1-(5-Fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dioneYield 56.9%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
105 °C

Procedure

A suspension of the product of Step 228a (537 mg, 1.05 mmol), CsF (322 mg, 2.13 mmol), and CuI (40 mg, 0.210 mmol) in anhydrous DMF (5 mL) was flushed with argon gas for 10 min, then 2-(tributylstannyl)pyrimidine (582 mg, 1.58 mmol) and Pd(PPh3)4 (122 mg, 0.105 mmol) were added at rt. The reaction mixture was then heated to 105° C. under nitrogen for 16 h. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and filtered through a short pad of diatomaceous earth. The filter cake was rinsed with EtOAc (50 mL) and water (50 mL). The layers of the combined filtrate were separated. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a yellow foam (274 mg, 56%): ESI MS (M+H) 459.

Workup

  1. customwas flushed with argon gas for 10 min
  2. temperatureAfter this time, the reaction mixture was cooled to rt
  3. filtrationfiltered through a short pad of diatomaceous earth
  4. washThe filter cake was rinsed with EtOAc (50 mL) and water (50 mL)
  5. customThe layers of the combined filtrate were separated
  6. extractionThe aqueous layer was extracted with EtOAc (3×50 mL)
  7. washThe combined organic layers were washed with 10% aq. LiCl (3×50 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3a9d4ac7f60a47afacd687034bc6e6b8
Source dataset
uspto-grants-2016_09
Patent number
US09440982B2

Reaction notes

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