tert-Butyl acrylate → 3-{4-[4-(4-Cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester

HRID 2100657Notes

Reaction equation

HRID 2100657 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O: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]([CH3:34])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[C:49]([O:48][C:44](=[O:47])[CH2:45][CH2:46][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O: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]([CH3:34])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:52])([CH3:51])[CH3:50]

Participants

6

Reactant 3

HCID 15458tert-Butyl acrylateHCID 81531DiisopropylethylamineHCID 688156794-[4-(4-Cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 688137333-{4-[4-(4-Cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (127 mg, 0.27 mmol) in DCM/TFA (1:2 v/v, 3 mL) is stirred for 40 minutes. After concentration, the residue obtained is dissolved in methanol (2 mL). DIEA (130 μL, 1.36 mmol, 5 eq.) and t-butyl acrylate (80 μL, 0.54 mmol, 2 eq.) are added to this solution. The reaction mixture is heated at 90° C. for 30 minutes using microwave irradiation. After concentration, the residue is purified by silica gel chromatography (40% EtOAc in hexanes) to give 3-{4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 3 mL), and the solution is stirred at room temperature for 40 minutes. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 7.41 (d, 2H, J=8 Hz), 7.28 (d, 2H, J=8 Hz), 7.08 (m, 1H), 6.75-6.73 (2H), 5.01 (s, 2H), 3.69 (d, 2H, J=10 Hz), 3.46 (t, 2H, J=7 Hz), 3.18 (m, 2H), 2.95 m, 1H), 2.86 (t, 2H, J=7 Hz), 2.65 (m, 1H), 2.27 (s, 3H), 2.18 (m, 2H), 2.04-1.70 (7H), 1.46-1.30 (5H); MS (ES+): (436.3, M+1)+.

Workup

  1. concentrationAfter concentration
  2. customthe residue obtained
  3. custommicrowave irradiation
  4. concentrationAfter concentration
  5. customthe residue is purified by silica gel chromatography (40% EtOAc in hexanes)

Sources & evidence

ORD record
ord-70d49900a7a94fbab52a0d9d5ef22677
Source dataset
uspto-grants-2009_08
Patent number
US07572811B2

Reaction notes

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