Dichloromethane → 3-[5-(2-Fluoro-phenyl]-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyrazin-2-ylamide

HRID 1469378Notes

Reaction equation

HRID 1469378 reaction equation
[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:11]1)=[O:9].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(OCC)(=O)C.C1COCC1.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])=[CH:17][N:16]=2)[CH2:11]1)=[O:9]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 27343542-Fluorophenylboronic acidHCID 66710701HCID 66710701, compound

Product 1

HCID 442192113-[5-(2-Fluoro-phenyl]-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyrazin-2-ylamideYield 64.3%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrazin-2-ylamide (Example 6 step 4; 100 mg, 0.285 mmol), 2-fluorophenylboronic acid (Aldrich, 60 mg, 0.428 mmol), potassium carbonate (118 mg, 0.86 mmol) and 1,1-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (23 mg, 10 mole %) in a microwave vial was added THF/H2O (10:1, 3 mL). Nitrogen gas was bubbled through the mixture for 5 mins and the vial sealed and heated at 100° C. in microwave synthesizer for 20 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and filtered through celite (2.5 g IST cartridge). A further 10 mL of ethyl acetate was washed through the celite pad and combined filtrate was washed sequentially with water (25 mL) then sat. sodium chloride solution (25 mL). Mixture was dried over sodium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a crude product, which was purified by flash chromatography, eluting with a gradient of 50 to 100% ethyl acetate in hexane to a afford a gummy solid. which was triturated with diethyl ether, filtered and dried to afford the title compound as colourless solid (67 mg, 64%)

Workup

  1. customNitrogen gas was bubbled through the mixture for 5 mins
  2. customthe vial sealed
  3. customThe cooled reaction mixture
  4. filtrationfiltered through celite (2.5 g IST cartridge)
  5. washA further 10 mL of ethyl acetate was washed through the celite pad
  6. washwas washed sequentially with water (25 mL)
  7. dry with materialMixture was dried over sodium sulphate
  8. filtrationfiltered
  9. customFiltrate solvents were removed in vacuo
  10. customto afford a crude product, which
  11. customwas purified by flash chromatography
  12. washeluting with a gradient of 50 to 100% ethyl acetate in hexane to
  13. customa afford a gummy solid
  14. customwhich was triturated with diethyl ether
  15. filtrationfiltered
  16. customdried

Sources & evidence

ORD record
ord-a7956800552641b99cb855eaaf88d8b1
Source dataset
uspto-grants-2015_04
Patent number
US09006269B2

Reaction notes

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