Diisopropylethylamine → N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N-((R)-1-phenyl-ethyl)-benzamide

HRID 385296

Reaction equation

HRID 385296 reaction equation
[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74]>CN(C=O)C>[CH3:71][N:72]([C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74])[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[N:5]3)[CH2:15][CH2:14]2)[CH:17]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2060888(R)-(+)-N-Methyl-1-phenylethylamineHCID 669733373-{1-[2-(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]piperidin-4-yl}-benzoic acidHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium

Product 1

HCID 66973078N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N-((R)-1-phenyl-ethyl)-benzamideYield 41.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (320 mg, 0.80 mmol) in DMF (8 mL) was added diisopropylethylamine (1.01 mL, 4.85 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.41 g, 0.89 mmol) at RT. After stirring for 15 min. at RT, Methyl-((R)-1-phenyl-ethyl)-amine (0.132 g, 0.80 mmol) was added to the reaction mixture. After stirring for 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (20 mL), washed with aq. sat. sodium bicarbonate solution (30 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—((R)-1-phenyl-ethyl)-benzamide (170 mg, 41%). 1H-NMR (400 MHz, d6-DMSO): δ=1.55 (d, 3H), 1.62-1.71 (m, 1H), 1.82-1.89 (m, 2H), 1.99 (s, 3H), 2.22 (s, 3H), 2.54-2.73 (m, 3H), 2.81-2.90 (m, 1H), 3.12-3.21 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 2H), 6.50 (s, 1H), 7.12-7.41 (m, 9H). MS: m/z=513 (M+1)

Workup

  1. stirringAfter stirring for 2 h at RT
  2. customsolvent was evaporated
  3. dissolutionthe resulting brown oil was dissolved in ethylacetate (20 mL)
  4. washwashed with aq. sat. sodium bicarbonate solution (30 mL)
  5. extractionthe aqueous phase was re-extracted with ethylacetate (20 mL)
  6. washThe combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2)

Sources & evidence

ORD record
ord-afb6fd412c4e42238497afe85655f0e8
Source dataset
uspto-grants-2013_02
Patent number
US08367844B2

Linked notes

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