p-Toluenesulfonic acid monohydrate → HCID 44252460, compound

HRID 19083Notes

Reaction equation

HRID 19083 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]([F: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.C(OCC)(=O)C>[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]([F: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 66899932(S)-2-[4-(2,5-difluoro-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

Product 1

HCID 44252460HCID 44252460, compoundYield 71%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2,5-difluoro-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 (0.35 g, 0.70 mmol) in methanol (7.1 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (20 mg, 0.10 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (000 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, 2-5% methanol/dichloromethane) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.23 g, 71%) as a pale orange solid: HR-ES-MS m/z calculated for C22H26N4O5F2 [M+H]+ 465.1944, observed 465.1943; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.82 (m, 1H), 3.18-3.31 (m, 2H), 3.66-3.79 (m, 1H), 3.84 (dd, J=13.4, 7.5 Hz, 1H), 4.07 (dd, J=13.4, 3.6 Hz, 1H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.86 (dd, J=10.7, 4.7 Hz, 1H), 4.92 (d, J=5.4 Hz, 1H), 5.01 (s, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.15-7.32 (m, 1H), 7.43-7.60 (m, 3H), 10.76 (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, 2-5% methanol/dichloromethane)

Sources & evidence

ORD record
ord-4e86cff2c840444d8d1d8db0ec22e2bf
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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