Nitrogen → HCID 89724208, compound

HRID 624315Notes

Reaction equation

HRID 624315 reaction equation
[C:1](#N)C.[Cl:4][C:5]1[C:6]([F:14])=[C:7](OCI)[CH:8]=[CH:9][CH:10]=1.N#N.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1.[OH2:26]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC(=O)C)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:26][CH3:1])=[C:7]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:6]=1[F:14]

Participants

8

Reactant 5

HCID 947NitrogenHCID 962Water2×HCID 6342AcetonitrileHCID 5226271-Ethynyl-4-fluorobenzeneHCID 89724126HCID 89724126, compound

Product 1

HCID 89724208HCID 89724208, compoundYield 74.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

Acetonitrile (31.5 L; 12.5 vol wrt Int-2) in to the reactor under nitrogen atmosphere at ambient temperature. Charged chlorofluoroiodomethoxybenzene (2.5 kg.) into the reactor with stirring. Charged DM water (12.5 L; 5-5.5 Vol wrt Int-2). Charged TEA (1.6 kg; 1.8 eq wrt Int-2) Purged N2 for NLT 60 min. Charged Oxydiphos (0.24 kg; 5 mol % wrt Int-2), Charged Palladium acetate (49 g; 2.5 mol % wrt Int-2), Charged 4-Fluoro phenylacetylene (1.58 kg; 1.5 eq wrt Int-2) with continuous purging of nitrogen1. Continued N2 Purging for NLT 10 min. Raised the temperature to 70-80° C. Stirred the reaction at 70-80° C. for 5 hrs. Reaction progress was monitored by HPLC. Work Up: After completion of the reaction, cooled the reaction mass to 25-30° C. Charged Ethylacetate (7.75 L; 3-3.5 Vol wrt Int-02), stirred for 5 min. Added DM water (4 L; 1.5-1.6 vol wrt Int-02), stirred for 5 min. Removed and retained bottom aqueous phase for further extraction. Remove and retained top organic phase for further wash. Extract the retained aqueous phase with EtOAc (13.4 L, 5-5.5 Vol wrt Int-02). Combined all organic phases and washed with water (8 L; 3-3.5 Vol). Concentrated the organic phases2 on rotovap at 45° C. completely. Purification: Dissolved crude product in MTBE (25 L; 10-1.5 Vol wrt Int-02) at 45 C. Cooled the mass to ambient temperature. Unloaded the reaction mass, rinse the reactor with MTBE (2.5 L; 1.0-1.5 Vol wrt Int-2). Filtered through celite bed, rinse the container with MTBE (2.5 L; 1.0-1.5 Vol wrt Int-2) and filter the rinse. Washed filter bed with MTBE (5.0 L, 2.0-2.5 Vol wrt Int-2). Concentrated under vacuum at 40° C. to 2-3 Vol stage (wrt Int-2). Charged Methanol (17.53 L; 7.0-7.5 Vol wrt Int-02). Concentrate to 2-3 vol stage3 (wrt Int-2). Cooled to 0° C. Filtered the solid. Washed solid with chilled methanol (0° C.) (12.5 L; 5-5.5 Vol wrt Int-02). Suck dried for 1 hr, and then dried in VTD for 5 hr. at 50-55° C. Wt: 1800 g (74.1% yield). Description (color and appearance): Brown crystalline solid. Purity by HPLC (%): 99%; HPLC RT Time 5.656 min under following conditions: Detector: 210 nm; Injection volume 5.00 μL; Run Time 15 min; Column: YMC UltraHT Pro C18 (50 mm×3.0 mm), 2.0μ; Mobile Phase A—0.05% TFA in MillQ Water; Mobile Phase B—0.05% TFA in Acetonitrile; Flow: 1.0 mL/min; Column Oven—40° C.; Time (min)—0 05 10 12 15; B Conc.—10 90 90 10 10. NMR: (1H NMR, 400 MHz, dmso-d6) δ 7.57 (m, 3H), 7.29 (t, 8.8 Hz, 2H), 7.00 (d, 9.2 Hz, 1H).

Workup

  1. customat ambient temperature
  2. customwith continuous purging of nitrogen1
  3. customfor NLT 10 min
  4. customthe reaction at 70-80° C. for 5 hrs
  5. customReaction progress
  6. customWork Up: After completion of the reaction
  7. temperaturecooled the reaction mass to 25-30° C
  8. customRemoved
  9. extractionfor further extraction
  10. customRemove
  11. extractionExtract the retained aqueous phase with EtOAc (13.4 L, 5-5.5 Vol wrt Int-02)
  12. washwashed with water (8 L; 3-3.5 Vol)
  13. concentrationConcentrated the organic phases2 on rotovap at 45° C. completely
  14. customPurification
  15. dissolutionDissolved crude product in MTBE (25 L; 10-1.5 Vol wrt Int-02) at 45 C
  16. temperatureCooled the mass to ambient temperature
  17. washrinse the reactor with MTBE (2.5 L; 1.0-1.5 Vol wrt Int-2)
  18. filtrationFiltered through celite bed
  19. washrinse the container with MTBE (2.5 L; 1.0-1.5 Vol wrt Int-2)
  20. filtrationfilter the rinse
  21. washWashed
  22. filtrationfilter bed with MTBE (5.0 L, 2.0-2.5 Vol wrt Int-2)
  23. concentrationConcentrated under vacuum at 40° C. to 2-3 Vol stage (wrt Int-2)
  24. concentrationConcentrate to 2-3 vol stage3 (wrt Int-2)
  25. temperatureCooled to 0° C
  26. filtrationFiltered the solid
  27. washWashed solid with chilled methanol (0° C.) (12.5 L; 5-5.5 Vol wrt Int-02)
  28. customSuck dried for 1 hr
  29. customdried in VTD for 5 hr
  30. customat 50-55° C
  31. customHPLC RT Time 5.656 min
  32. customTime 15 min
  33. customColumn Oven—40° C.

Sources & evidence

ORD record
ord-2d31b249420a4d09bc27ae183095f9e1
Source dataset
uspto-grants-2016_04
Patent number
US09303020B2

Reaction notes

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