Trifluoroacetic acid → [(4-Chloro-thiazol-5-yl)methyl]-isobutyl-piperidin-4-yl-amine

HRID 2111933Notes

Reaction equation

HRID 2111933 reaction equation
C([O:5]C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[S:24][CH:23]=[N:22][C:21]=2[Cl:25])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[OH-:5].[NH4+:8].[Cl:25][C:21]1[N:22]=[CH:23][S:24][C:20]=1[CH2:19][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 685750414-{[(4-Chloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester

Product 2

HCID 14923Ammonium HydroxideHCID 57640347[(4-Chloro-thiazol-5-yl)methyl]-isobutyl-piperidin-4-yl-amineYield 178.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Add 4-{[(4-chloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (23.49 g, 60.6 mmol) to dichloromethane (140 mL) and cool to 0° C. Slowly add trifluoroacetic acid (47.0 mL, 610 mmol) and stir for 15 minutes at 0° C. and three hours at room temperature. Cool the reaction to 0° C. and slowly add chilled 2 N NaOH (400 mL). Extract with ethyl acetate (3×200 mL), wash with 2 N NaOH (100 mL) and then with brine (100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 1.2% concentrated ammonium hydroxide/12% ethanol/chloroform then with 2% concentrated ammonium hydroxide/20% ethanol/chloroform to yield 15.59 g (89%) of [(4-chloro-thiazol-5-yl)methyl]-isobutyl-piperidin-4-yl-amine: mass spectrum (ion spray): m/z=288.1 (M+1); 1H NMR (CDCl3): δ=8.63 (s, 1H), 3.80 (s, 2H), 3.17-3.14 (m, 2H), 2.59-2.47 (m, 3H), 2.32 (d, 2H), 1.79-1.65 (m, 4H), 1.50-1.40 (m, 2H), 0.91 (d, 6H).

Workup

  1. temperatureCool
  2. customthe reaction to 0° C.
  3. additionslowly add
  4. extractionExtract with ethyl acetate (3×200 mL)
  5. washwash with 2 N NaOH (100 mL)
  6. dry with materialDry the ethyl acetate over sodium sulfate
  7. filtrationfilter off the sodium sulfate
  8. concentrationConcentrate on a rotary evaporator
  9. custompurify the crude product by flash chromatography on silica gel eluting with 1.2% concentrated ammonium hydroxide/12% ethanol/chloroform

Sources & evidence

ORD record
ord-eeca66eef43a402e91130a408f549b23
Source dataset
uspto-grants-2009_04
Patent number
US07521462B2

Reaction notes

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