Methanol → HCID 59632259, compound

HRID 2369097Notes

Reaction equation

HRID 2369097 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:35])[CH3:34])=[N:10]1.O.O.[OH-].[Li+].CO>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:34])[CH3:35])=[N:10]1

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 168937Lithium hydroxide, monohydrateHCID 59632551HCID 59632551, compound

Product 1

HCID 59632259HCID 59632259, compoundYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg of impure material from previous step, 0.35 mmol) in THF (2.0 mL) was added H2O (0.4 mL) followed by lithium hydroxide monohydrate (25.3 mg, 0.6 mmol). After stirring for 1 hour at ambient temperature a biphasic mixture had formed, and LC/MS analysis of the reaction showed no reaction. a small amount of MeOH was added to homogenize the mixture, and the reaction was then heated to 50° C. in an oil bath. After 2 hours stirring at 50° C., LC/MS analysis showed the reaction to be complete. Heating was discontinued, and after stirring at ambient temperature overnight, the reaction was quenched by the addition of 5% aqueous citric acid, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a clear film. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCN/H2O with 0.05% TFA. The major peak from the HPLC was concentrated under reduced pressure to remove most of the solvents, and the resulting acidic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O until the washings were no longer acidic (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (E)-3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoic acid (45.4 mg, 26% yield) as a white powder. 1H NMR (400 MHz CDCl3): δ 821 (1H, s), 7.98 (1H, d, 7.69 (1H, d), 7.45 (1H, t), 7.39 (1H, d), 7.37-7.31 (2H, m), 7.23 (1H, m), 7.15 (1H, m), 7.12-7.07 (2H, m), 7.06 (1H, m), 6.46 (1H, s), 2.45 (3H, s), 1.71 (6H, s). MS(ES): 529 [M+H]+.

Workup

  1. customhad formed
  2. customno reaction
  3. stirringto homogenize the mixture
  4. temperaturethe reaction was then heated to 50° C. in an oil bath
  5. stirringAfter 2 hours stirring at 50° C.
  6. customthe reaction
  7. temperatureHeating
  8. stirringafter stirring at ambient temperature overnight
  9. customthe reaction was quenched by the addition of 5% aqueous citric acid, and EtOAc
  10. customThe layers were separated
  11. extractionthe aqueous was extracted with EtOAc (3×)
  12. washCombined organic extracts were washed with brine
  13. dry with materialdried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure
  16. customto afford a clear film
  17. customThis material was purified by reverse phase preparative HPLC
  18. washeluting with a gradient of MeCN/H2O with 0.05% TFA
  19. concentrationThe major peak from the HPLC was concentrated under reduced pressure
  20. customto remove most of the solvents
  21. extractionthe resulting acidic aqueous was extracted with CH2Cl2 (3×)
  22. washThe combined organic extracts were washed with H2O until the washings
  23. dry with materialdried over Na2SO4
  24. filtrationfiltered
  25. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-18d174d095c14a26b0b06d7110e640a4
Source dataset
uspto-grants-2014_04
Patent number
US08703805B2

Reaction notes

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