Sodium hydride → HCID 59632551, compound

HRID 2369096Notes

Reaction equation

HRID 2369096 reaction equation
[H-].[Na+].COP([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(OC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:44])[CH3:43])=[N:29]1>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:9]/[C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([O:15][CH3:16])=[O:14])=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:43])[CH3:44])=[N:29]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 19744414Methyl 3-[(dimethoxyphosphoryl)methyl]benzoateHCID 59632303HCID 59632303, compound

Product 1

HCID 59632551HCID 59632551, compoundYield 70%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
0 °C

Procedure

To a suspension of NaH (52 mg of a 60% dispersion in mineral oil) in THF (7.5 mL) cooled to 0° C. in an ice bath was added methyl 3-((dimethoxyphosphoryl)methyl)benzoate as a solution in THF (1 mL) followed by a THF (1 mL) rinse of the phosphonate vial and syringe to insure complete transfer. The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 90 minutes at ambient temperature, 4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylbenzaldehyde (0.49 mmol impure from previous step) was added via cannula to the reaction mixture followed by a THF (1 mL) rinse of the flask and cannula after 1 hour-45 minutes at ambient temperature the reaction was quenched by addition of saturated aqueous NH4Cl 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 yellow syrup. The crude product was purified by flash column chromatography eluting with a gradient from 0% to 40% MeCN/CH2Cl2 to afford (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg, 70% yield) of slightly impure product. This material was carried on to the ester hydrolysis without further purification. MS(ES): 521 [M+H]+.

Workup

  1. washrinse of the phosphonate vial and syringe
  2. customThe ice bath was removed
  3. temperatureto warm to ambient temperature
  4. washrinse of the flask and cannula after 1 hour-45 minutes at ambient temperature the reaction
  5. customwas quenched by addition of saturated aqueous NH4Cl and EtOAc
  6. customThe layers were separated
  7. extractionthe aqueous was extracted with EtOAc (3×)
  8. washCombined organic extracts were washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customto afford a yellow syrup
  13. customThe crude product was purified by flash column chromatography
  14. washeluting with a gradient from 0% to 40% MeCN/CH2Cl2

Sources & evidence

ORD record
ord-c61ea3a89cde4ec5b53b86bc69bf0f76
Source dataset
uspto-grants-2014_04
Patent number
US08703805B2

Reaction notes

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