4-Chloro-2-fluorobenzaldehyde → ethyl 4-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate

HRID 869079Notes

Reaction equation

HRID 869079 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14](I)[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]2)=[CH:5][N:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([F:34])[CH:27]=1>C1COCC1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]([OH:31])[C:14]2[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH:16]([CH3:18])[CH3:17])=[C:28]([F:34])[CH:27]=1

Participants

4

Reactant 2

HCID 27249084-Chloro-2-fluorobenzaldehydeHCID 89601334ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-isopropyl-1H-pyrazole-3-carboxylate

Product 1

HCID 89601495ethyl 4-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylateYield 74.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.4, 1.15 g, 2.55 mmol) in 14 ml THF, a solution of 1M isopropylmagnesium chloride lithium chloride complex (2.68 ml, 2.68 mmol) was added at 0° C. and the mixture was stirred for 15 min. Then the solution was cooled down to −78° C. and a solution of 4-chloro-2-fluorobenzaldehyde (405 mg, 2.55 mmol) in 3 ml THF was added. The reaction mixture was stirred for 30 min at temperatures between −78° C. to −20° C. The solution was quenched with 10 ml of 1M NH4Cl solution, washed with brine and extracted 3 times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by chromatography (Silicagel, heptane, heptane/EtOAc 1:4) to give 977 mg (1.901 mmol, 74.5% yield) of the title compound as a white foam. LCMS: (M+H)=479; tR=1.18 min (LC-MS 4). HPLC: tR=5.48 min (HPLC 7). TLC: Rf=0.35 (Heptane/EtOAc 1:2).

Workup

  1. stirringThe reaction mixture was stirred for 30 min at temperatures between −78° C. to −20° C
  2. customThe solution was quenched with 10 ml of 1M NH4Cl solution
  3. washwashed with brine
  4. extractionextracted 3 times with EtOAc
  5. dry with materialThe combined organic phases were dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude product was purified by chromatography (Silicagel, heptane, heptane/EtOAc 1:4)

Sources & evidence

ORD record
ord-a0d387de74154c1a9865208380b52214
Source dataset
uspto-grants-2015_03
Patent number
US08969341B2

Reaction notes

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