p-Toluenesulfonic acid monohydrate → HCID 44252317, compound

HRID 19058Notes

Reaction equation

HRID 19058 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]=[CH:30][CH:29]=[C:28]([Cl:32])[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>ClCCl.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:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[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 66899479(S)-2-[4-(3-chloro-2-fluoro-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 44252317HCID 44252317, compoundYield 79%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(3-chloro-2-fluoro-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 (0.56 g, 1.08 mmol) in dichloromethane (10 mL) and methanol (10 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (0.04 g, 0.21 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.41 g, 79%) as a light, yellow solid: HR-ES-MS m/z calculated for C22H27N4O5FCl [M+H]+ 481.1649, observed 481.1650; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.39-1.51 (m, 1H), 1.51-1.64 (m, 1H), 1.70-1.81 (m, 1H), 3.22-3.33 (m, 2H), 3.71-3.82 (m, 1H), 3.87 (dd, J=13.6, 7.5 Hz, 1H), 4.09 (dd, J=13.6, 3.8 Hz, 1H), 4.25 (d, J=18.5 Hz, 1H), 4.62 (d, J=18.5 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.88 (dd, J=10.8, 5.0 Hz, 1H), 4.93 (d, J=5.3 Hz, 1H), 5.03 (s, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.5 Hz, 1H), 7.49-7.61 (m, 3H), 10.77 (s, 1H).

Workup

  1. concentrationAt this time, the reaction was concentrated in vacuo
  2. additionThe residue was diluted with dichloromethane (50 mL)
  3. washwas washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL)
  4. dry with materiala saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate
  5. filtrationfiltered
  6. washrinsed with dichloromethane
  7. concentrationconcentrated in vacuo
  8. customPurification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient)

Sources & evidence

ORD record
ord-d0dc8d7ab33141afb37e1c281321a4c4
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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