Hydrochloric Acid → HCID 22996134, compound

HRID 1167429Notes

Reaction equation

HRID 1167429 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si](C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[C:8]=1[C:24]1([OH:27])[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[NH2:5]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 6397ChlorotrimethylsilaneHCID 740491-Methyl-4-piperidoneHCID 965953,5-DifluoroanilineHCID 178418339Butyllithium2×

Product 1

HCID 22996134HCID 22996134, compoundYield 71.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-74 °C

Procedure

To a stirred solution of 3,5-difluoroaniline (7.0 g, 54 mmol) in anhydrous THF (250 ml) under an atmosphere of nitrogen and cooled to −74° C. was added dropwise nBuLi (1.45M in hexanes, 78.6 ml, 0.114 mol) over a period of 10 minutes. The reaction was allowed to stir at −74° C. for 30 minutes. Chlorotrimethylsilane (12.4 g, 0.114 mol), in anhydrous THF (100 ml) was added dropwise over a period of 10 minutes. The solution was allowed to warm to ambient temperature and then stir for 40 minutes. The reaction was then cooled again to −74° C. and nBuLi (1.45M in hexanes, 43.0 ml, 62.4 mmol) was added dropwise over a period of 10 minutes. After stirring for a further 3.5 hours at −74° C., N-methyl-4-piperidone (7.90 g, 70.5 mmol) in anhydrous THF (50 ml) was added dropwise over a period of 10 minutes. The reaction was allowed to stir to ambient temperature over the weekend. The reaction was acidified with 10% HCl to pH<1 and extracted with diethyl ether. The aqueous phase was separated and treated with 40% NaOH to pH 12 then extracted with diethyl ether and the combined organic phases were washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. The resulting brown oil was triturated with cyclohexane to give the title compound as a pale yellow solid (9.30 g, 71%).

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstir for 40 minutes
  3. temperatureThe reaction was then cooled again to −74° C.
  4. stirringAfter stirring for a further 3.5 hours at −74° C.
  5. stirringto stir to ambient temperature over the weekend
  6. extractionextracted with diethyl ether
  7. customThe aqueous phase was separated
  8. additiontreated with 40% NaOH to pH 12
  9. extractionthen extracted with diethyl ether
  10. washthe combined organic phases were washed with sat NaCl
  11. dry with materialdried over MgSO4
  12. customevaporated under reduced pressure
  13. customThe resulting brown oil was triturated with cyclohexane

Sources & evidence

ORD record
ord-34fb726d6db2462a8f958ed45074bcd9
Source dataset
uspto-grants-2003_09
Patent number
US06617339B1

Reaction notes

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