p-Toluenesulfonic acid monohydrate → HCID 44464553, compound

HRID 2381469Notes

Reaction equation

HRID 2381469 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:36])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])[CH:22]=[N:21]3)[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:36])[CH:15]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[CH:22]=[N:21]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1

Participants

5

Reactant 2

HCID 521998p-Toluenesulfonic acid monohydrateHCID 66892811HCID 66892811, compound

Product 1

HCID 44464553HCID 44464553, compoundYield 77.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (1.21 g, 2.33 mmol) in methanol (23 mL, 0.1 M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (66.3 mg, 0.34 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (200 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and then concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 1-10% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.86 g, 77%) as a white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C22H25N5O5F2 [M+H+] 478.1897 found 478.1896. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.8 Hz, 3H) 0.89 (d, J=6.8 Hz, 3H) 1.38-1.51 (m, 1H) 1.80 (ddd, J=13.6, 9.4, 4.3 Hz, 1H) 2.10-2.26 (m, 1H) 3.21-3.51 (m, 2H) 3.71-3.81 (m, 1H) 3.82-3.92 (m, 1H) 4.09 (dd, J=13.6, 3.9 Hz, 1H) 4.70 (t, J=5.6 Hz, 1H) 4.91-4.96 (m, 1H) 5.52 (dd, J=11.0, 3.9 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).

Workup

  1. washwas washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL)
  2. dry with materialThe organics were dried over magnesium sulfate
  3. filtrationfiltered
  4. washrinsed
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0412c59359ca46418f3bf1c9dc5fb244
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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