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

HRID 19317Notes

Reaction equation

HRID 19317 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:40])[CH:15]([N:26]3[CH2:30][C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[CH:28][C:27]3=[O:39])[CH2:16][CH:17]([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[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:40])[CH:15]([N:26]2[CH2:30][C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[CH:28][C:27]2=[O:39])[CH2:16][CH:17]([C:22]([F:23])([F:25])[F:24])[C:18]([F:20])([F:19])[F:21])=[N:9]1

Participants

4

Reactant 2

HCID 521998p-Toluenesulfonic acid monohydrateHCID 866352402-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide

Product 1

HCID 579201722-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amideYield 87.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (32 mg, 0.05 mmol), methanol (2 mL) and p-toluenesulfonic acid hydrate (5 mg, 0.15 mmol) and stirred at 25° C. for 48 h. The mixture was concentrated in vacuo and then taken up in ethyl acetate/methanol and concentrated in vacuo with silica gel (1.5 g). Purification by Biotage flash chromatography (AnaLogix SF15-12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (25 mg, 84%) as a colorless gum: HR-ES-MS m/z calculated for C22H21N4O5ClF6 [M+H]+ 571.1178, observed 571.1177; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20-2.37 (m, 1H), 2.38-2.48 (m, 1H), 3.21-3.32 (m, 2H), 3.71-3.82 (m, 1H), 3.82-3.98 (m, 2H), 4.10 (dd, J=13.6, 4.0 Hz, 1H), 4.29 (d, J=17.9 Hz, 1H), 4.45 (d, J=17.9 Hz, 1H), 4.71 (t, J=5.5 Hz, 1H), 4.89 (s, 1H), 4.89-4.98 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.31-7.42 (m, 1H), 7.43-7.53 (m, 3H), 7.56 (d, J=2.1 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 10.91 (s, 1H).

Workup

  1. customIn a round bottom flask was placed
  2. concentrationThe mixture was concentrated in vacuo
  3. concentrationconcentrated in vacuo with silica gel (1.5 g)
  4. customPurification by Biotage flash chromatography (AnaLogix SF15-12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-ac00a7a95ded4e7bb3c22813b7fa737a
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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