Water → [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl]{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol

HRID 72711

Reaction equation

HRID 72711 reaction equation
C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[N:23]1([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[N:23]1([C:27]2[C:32]([CH:33]([C:7]3[CH:8]=[N:9][N:10]([CH3:22])[C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[OH:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1

Participants

6

Reactant 4

HCID 962WaterHCID 710936322-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridineHCID 867125624-(Azetidin-1-yl)-6-chloropyrimidine-5-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 86712563[4-(azetidin-1-yl)-6-chloropyrimidin-5-yl]{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (2.5 M solution in hexanes, 74 μL, 0.185 mmol) was slowly added drop-wise to a −78° C. solution of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C14) (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL). The reaction mixture was allowed to stir at −78° C. for 1 hour, and then a solution of 4-(azetidin-1-yl)-6-chloropyrimidine-5-carbaldehyde (C12) (28.1 mg, 0.142 mmol) in tetrahydrofuran (1 mL) was added. Stirring was continued for 1.5 hours at −78° C., then water was added, and the reaction mixture was removed from the cooling bath. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluent: 94:5:1 dichloromethane/methanol/triethylamine) provided the product. Yield: 40 mg, 0.094 mmol, 67%. LCMS m/z 425.2, 427.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.17-2.26 (m, 2H), 3.72 (s, 3H), 3.89-3.97 (m, 2H), 4.23-4.31 (m, 2H), 6.32 (s, 1H), 7.58 (s, 1H), 7.79 (br d, J=8 Hz, 1H), 7.85 (s, 1H), 7.92 (br dd, J=8, 2 Hz, 1H), 8.58 (br d, J=2 Hz, 1H).

Workup

  1. customto a −78° C.
  2. stirringStirring
  3. waitwas continued for 1.5 hours at −78° C.
  4. customthe reaction mixture was removed from the cooling bath
  5. extractionThe aqueous layer was extracted with ethyl acetate
  6. washthe combined organic layers were washed with saturated aqueous sodium chloride solution
  7. customdried
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification
  11. customprovided the product

Sources & evidence

ORD record
ord-0b14927b242f40229ae465c629ccc93f
Source dataset
uspto-grants-2014_09
Patent number
US08829010B2

Linked notes

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