2-[(R)-4-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester → 2-{(R)-4-[6-(2,4-difluoro-benzyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-piperazin-1-yl}-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester

HRID 1479997Notes

Reaction equation

HRID 1479997 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2].[Br-].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21]([CH2:36][C:35]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=4[F:33])=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 591914582-[(R)-4-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl esterHCID 178505768HCID 178505768, compound2×

Product 1

HCID 591914802-{(R)-4-[6-(2,4-difluoro-benzyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-piperazin-1-yl}-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl esterYield 81.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2-[(R)-4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (229 mg, 0.50 mmol, 1 eq) and THF (1.4 mL) in a microwave vial is added 2,4-difluorobenzylzinc bromide (2.0 mL 0.5 M solution in THF, 2.0 mmol, 4 eq) and tetrakis(triphenylphosphine)palladium (25 mg, 0.03 mmol, 0.05 eq). The vial is sealed and heated in the microwave at 60° C. (high absorption setting) for 25 min. An additional aliquot of 2,4-diflorobenzylzinc bromide (1.0 mL 0.5 M solution in THF, 1.0 mmol, 2 eq) is added and the reaction mixture is heated in the microwave at 100° C. (high absorption setting) for 5 min. The reaction mixture is quenched with water (10 mL) and then extracted with EtOAc (2×25 mL). The combined organic fractions are dried over magnesium sulfate, concentrated and purified by silica gel chromatography (25-75% EtOAc/Heptane) to yield the desired compound (225 mg, 81%).

Workup

  1. customThe vial is sealed
  2. temperaturethe reaction mixture is heated in the microwave at 100° C. (high absorption setting) for 5 min
  3. customThe reaction mixture is quenched with water (10 mL)
  4. extractionextracted with EtOAc (2×25 mL)
  5. dry with materialThe combined organic fractions are dried over magnesium sulfate
  6. concentrationconcentrated
  7. custompurified by silica gel chromatography (25-75% EtOAc/Heptane)

Sources & evidence

ORD record
ord-ab7db89896ca44f289597e29510d3923
Source dataset
uspto-grants-2016_08
Patent number
US09409871B2

Reaction notes

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