Sodium Carbonate → HCID 76284223, compound

HRID 1480160Notes

Reaction equation

HRID 1480160 reaction equation
[CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19](Br)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19]([CH:30]3[CH2:32][CH2:31]3)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 2760897Cyclopropylboronic acidHCID 90214962HCID 90214962, compound

Product 1

HCID 76284223HCID 76284223, compound

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 100c, 160 mg, 0.335 mmol) in toluene (4.8 mL) were added cyclopropylboronic acid (43.2 mg, 0.503 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.3 mg, 17 μmol) and 2M aqueous solution sodium carbonate (335 μL, 0.670 mmol). Reaction was stirred at 80° C. for 18 hours. The reaction mixture was diluted with ethylacetate and extracted with water. The organic layer was dried on sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the mixture of epimers (151 mg, 100%). The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 439.7 (M+H+).

Workup

  1. customReaction
  2. extractionextracted with water
  3. customThe organic layer was dried on sodium sulfate
  4. customevaporated down to dryness
  5. customThe crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient
  6. customto yield
  7. additionthe mixture of epimers (151 mg, 100%)
  8. additionThe mixture of epimers
  9. customwas separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane)
  10. customcollected
  11. customisolated as colorless oil

Sources & evidence

ORD record
ord-a3457f210a0a4dea9acba59f6044db87
Source dataset
uspto-grants-2016_08
Patent number
US09409866B2

Reaction notes

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