Benzyl Alcohol → (S)-2-(4-benzyloxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 18960Notes

Reaction equation

HRID 18960 reaction equation
[CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:26][CH3:27])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O.O.O.O.O.[Cl-].[Cs+]>C(O)(=O)C>[CH2:27]([O:26][C:24]1[CH2:25][N:21]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[C:22](=[O:28])[CH:23]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1

Participants

7

Reactant 5

HCID 244Benzyl AlcoholHCID 313Hydrochloric AcidHCID 521998p-Toluenesulfonic acid monohydrateHCID 44252903(S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamideHCID 86635227Cesium chloride hexahydrate

Product 1

HCID 44253200(S)-2-(4-benzyloxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideYield 5.4%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 94 mg, 0.24 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) was heated in a sealed tube at 75° C. for 2 h. After that time the reaction mixture was cooled to room temperature, and concentrated. The residue was added to benzyl alcohol (1000 mg, 9.15 mmol), and toluene-4-sulfonic acid hydrate (10 mg), cesium chloride hexahydrate (0.3 g) on silica gel (Sabitha, G.; Reddy, M. N.; Sudhakar, K.; Yadav, J. S.; Letters Org. Chem, 2005, 2, 763-766). The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate and purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-2-(4-benzyloxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (6 mg, 5%): LR-ES-MS m/z calculated for C26H34N4O4 [M]+ 466, observed [M+H]+ 467; 1H NMR (300 MHz, CDCl3) δ ppm 0.77 (br. s., 1H) 1.08 (br. s., 2H) 1.08 (br. s., 6H) 1.32-2.07 (m, 8H) 2.89 (br. s., 1H) 3.79-3.96 (m, 1H) 3.88 (br. s., 2H) 3.98-4.15 (m, 1H) 4.78 (br. s., 1H) 4.92 (br. s., 2H) 5.16 (br. s., 1H) 6.61 (br. s., 1H) 7.08-7.43 (m, 5H) 8.81 (br. s., 1H).

Workup

  1. concentrationconcentrated
  2. concentrationThe reaction mixture was concentrated
  3. dissolutionthe residue was dissolved in dichloromethane
  4. washThe organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution
  5. dry with materialdried over magnesium sulfate
  6. custompurified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0ca9f2fa31c648f98c269d86e001b63a
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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