p-Toluenesulfonic acid monohydrate → (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

HRID 19094Notes

Reaction equation

HRID 19094 reaction equation
CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1

Participants

5

Reactant 2

HCID 521998p-Toluenesulfonic acid monohydrateHCID 66899236HCID 66899236, compound

Product 1

HCID 44253206(S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amideYield 77%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 1.39 mmol) in methanol (13.9 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (40 mg, 0.20 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.49 g, 77%) as an off-white solid: HR-ES-MS m/z calculated for C23H29N4O5F [M+H]+ 461.2195, observed 461.2194; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.32-1.48 (m, 1H), 1.48-1.63 (m, 1H), 1.63-1.82 (m, 1H), 2.29 (s, 3H), 3.17-3.30 (m, 2H), 3.68-3.79 (m, 1H), 3.79-3.91 (m, 1H), 4.07 (dd, J=13.4, 3.8 Hz, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.81-4.89 (m, 2H), 4.92 (d, J=5.4 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 7.08-7.18 (m, 1H), 7.24-7.35 (m, 2H), 7.51 (d, J=2.0 Hz, 1H), 10.75 (s, 1H).

Workup

  1. washwas washed with a saturated aqueous sodium bicarbonate solution (1×150 mL)
  2. dry with materiala saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customPurification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-90e75ec562504c1c879bd788b97f3db7
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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