Cesium carbonate → 5-(3,3-Difluoro-azetidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

HRID 1480142Notes

Reaction equation

HRID 1480142 reaction equation
[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18](Br)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:81][C:82]1([F:86])[CH2:85][NH:84][CH2:83]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([N:84]3[CH2:85][C:82]([F:86])([F:81])[CH2:83]3)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 902039835-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

Product 1

HCID 762837015-(3,3-Difluoro-azetidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amideYield 28%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 78g, 0.05 g, 111 μmol) in dry Toluene (1 ml) under argon atmosphere were added palladium(II) acetate (3.75 mg, 16.7 μmol), BINAP (10.4 mg, 16.7 μmol), cesium carbonate (90.7 mg, 278 μmol) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 15.9 mg, 122 μmol). The reaction mixture was stirred at 120° C. for 45 minutes under microwave radiation. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (14.2 mg, 28%) as a white solid. MS (ESI, m/z): 462.4 (M+H+).

Workup

  1. filtrationThe reaction mixture was filtered through a pad of Celite
  2. concentrationthe filtrate was concentrated in vacuo
  3. dissolutionThe residue was dissolved in ethylacetate
  4. extractionextracted with an 1.0M aqueous solution of sodium bicarbonate
  5. dry with materialThe organic phase was dried over sodium sulfate
  6. customevaporated down to dryness
  7. customThe crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient

Sources & evidence

ORD record
ord-5672effe9e904464a10af4aae96a8909
Source dataset
uspto-grants-2016_08
Patent number
US09409866B2

Reaction notes

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