Trifluoroacetic acid → HCID 89908312, compound

HRID 525731Notes

Reaction equation

HRID 525731 reaction equation
Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:33]1[CH2:36][CH:35]([NH:37]C(=O)OC(C)(C)C)[CH2:34]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.CC(O)C>[NH2:37][CH:35]1[CH2:36][N:33]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:34]1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium Carbonate2×HCID 81531DiisopropylethylamineHCID 15194053-Aminoazetidine, 3-BOC protectedHCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 89908312HCID 89908312, compound

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 70 mg, 0.143 mmol), tert-butyl azetidin-3-ylcarbamate (49.4 mg, 0.287 mmol), DIPEA (0.075 mL, 0.430 mmol) and iPrOH (1 mL) in a sealed vial was stirred at 120° C. for 2 h. The RM was treated with sat. aq. Na2CO3, extracted with EtOAc and the combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 97:3). Fractions containing the desired intermediate were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (1 mL), treated with TFA (0.216 mL, 2.80 mmol) and stirred at RT for 3 h. The RM was treated with sat. aq. Na2CO3, and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 11). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white solid. HPLC (Condition 7) tR=5.545 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=435.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.05 (m, 2H) 3.35-3.35 (m, 2H) 3.53-3.69 (m, 1H) 3.80-3.96 (m, 2H) 6.34-6.45 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.74 (br. s, 1H) 7.87 (d, J=8.99 Hz, 2H) 8.00-8.10 (m, 1H) 8.66-8.78 (m, 1H) 10.24 (br. s, 1H).

Workup

  1. extractionextracted with EtOAc
  2. washthe combined extracts were washed with brine (10 mL)
  3. dry with materialdried over Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a residue which
  6. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 97:3)
  7. additionFractions containing the desired intermediate
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give a residue which
  10. stirringstirred at RT for 3 h
  11. extractionextracted with EtOAc
  12. washThe combined extracts were washed with brine (20 mL)
  13. dry with materialdried over Na2SO4
  14. customthe solvent was evaporated off under reduced pressure
  15. customto give the crude product which
  16. customwas purified by preparative HPLC (Condition 11)
  17. additionFractions containing the product
  18. additiontreated with sat. aq. Na2CO3
  19. customthe MeCN was evaporated off under reduced pressure
  20. customto give an aq. residue which
  21. extractionwas extracted with DCM
  22. dry with materialThe combined extracts were dried over Na2SO4
  23. customthe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record
ord-328b24b6890f4570815bff00a32a0cf5
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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