Trifluoroacetic acid → 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid tert-butyl ester

HRID 2100662Notes

Reaction equation

HRID 2100662 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:24]([C:34]([F:37])([F:36])[F:35])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])(=[O:48])[CH:46]=[CH2:47].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:50]([O:49][C:45](=[O:48])[CH2:46][CH2:47][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:24]([C:34]([F:37])([F:35])[F:36])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)([CH3:53])([CH3:52])[CH3:51]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 15458tert-Butyl acrylateHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 688120204-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 688156933-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 0.398 mmol) in DCM (2 mL) is added trifluoroacetic acid (TFA) (4 mL). The reaction mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residue obtained is mixed with tert-butyl acrylate (76 mg, 0.6 mmol) and DIEA (193 mg, 1.49 mmol) in MeOH (4 mL) and the mixture is heated in a microwave oven at 90° C. for 30 minutes. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (150:50:1 hexanes/EtOAc/Et3N) to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 2 mL), and the solution is stirred at room temperature for 1 hour. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid. 1H NMR (CD3OD): 1.28-1.85 (10H), 2.88 (t, J=6.2 Hz, 2H), 2.90 (m, 1H), 3.15-3.85 (8H), 3.69 (t, J=6.2 Hz, 2H), 5.42 (s, 2H), 7.38 (br, 1H), 7.57 (d, J=7 Hz, 1H), 7.65 (d, J=7 Hz, 1H), 7.71 (s, 1H), 7.91 (s, 1H), 8.05 (br, 1H); ESI-MS m/z 492.2 (MH+).

Workup

  1. customevaporated to dryness
  2. customThe residue obtained
  3. temperaturethe mixture is heated in a microwave oven at 90° C. for 30 minutes
  4. extractionextracted with EtOAc
  5. washThe combined extracts are washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationAfter concentration
  8. customthe residue is purified by silica gel chromatography (150:50:1 hexanes/EtOAc/Et3N)

Sources & evidence

ORD record
ord-c0209198cd1946f0966ca470afb1eedb
Source dataset
uspto-grants-2009_08
Patent number
US07572811B2

Reaction notes

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