Benzene, 1-fluoro-4-(trifluoromethyl)- → 4-(2-Fluoro-5-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 1986932

Reaction equation

HRID 1986932 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])N(OC)C)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])[C:7]2[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]

Participants

7

Reactant 4

HCID 67873Benzene, 1-fluoro-4-(trifluoromethyl)-HCID 11065582tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylateHCID 86586944Isopropanol carbon dioxideHCID 178418339Butyllithium

Product 1

HCID 588175444-(2-Fluoro-5-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl esterYield 48.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

A solution of 4-fluorobenzotrifluoride (25 g, 0.152M) in anhydrous THF (300 ml) was cooled to −60° C. (IPA/CO2 bath) and treated with n-butyl lithium (84 mL of a 2.0M solution in Hexane, 0.168M -1.1 eq) with a maximum rate so not to exceed −60 ° C. The reaction was stirred for 3 hours (temperature maintained) and then treated with a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (51.86 g, 0.190M -1.25 eq, in 130 mL of anhydrous THF) with a maximum rate so as not to exceed −55° C. The mixture was stirred for a further two hours before allowing to warm to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (75 mL) and the THF removed under reduced pressure. The residue was dissolved in ethylacetate (800 mL), washed with 1 N Hydrochloric acid (400 ml), 5%aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively. The organics were dried over MgSO4, filtered and concentrated to give a brown oil, which on triturating in ethyl acetate gave a white solid 27.6 g (48%).

Workup

  1. customto exceed −60 ° C
  2. temperature(temperature maintained)
  3. customto exceed −55° C
  4. stirringThe mixture was stirred for a further two hours
  5. stirringstirred for 0.5 hours
  6. customThe reaction was quenched with saturated ammonium chloride solution (75 mL)
  7. customthe THF removed under reduced pressure
  8. dissolutionThe residue was dissolved in ethylacetate (800 mL)
  9. washwashed with 1 N Hydrochloric acid (400 ml), 5%aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively
  10. dry with materialThe organics were dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customto give a brown oil, which
  14. customon triturating in ethyl acetate

Sources & evidence

ORD record
ord-608d67996efb4ce8a660e71d2acfa4c3
Source dataset
uspto-grants-2009_06
Patent number
US07550469B2

Linked notes

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