p-Toluenesulfonic acid monohydrate → 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 2381474Notes

Reaction equation

HRID 2381474 reaction equation
[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]([OH:18])[CH2:21][OH:20])[N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

4

Reactant 2

HCID 521998p-Toluenesulfonic acid monohydrateHCID 668936033-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide

Product 1

HCID 444666433-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamideYield 84.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (142.4 mg, 0.26 mmol) in methanol (2.6 mL, 0.10M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (7.7 mg, 0.04 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 1-10% methanol/methylene chloride) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (110.3 mg, 84%) as an off-white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C24H27N5O5F2 [M+H+] 504.2053 found 504.2053. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.18 (m, 1H) 1.22-1.76 (m, 8H) 1.88-2.01 (m, 1H) 2.17-2.35 (m, 1H) 3.19-3.32 (m, 2H) 3.70-3.80 (m, 1H) 3.82-3.93 (m, 1H) 4.09 (dd, J=13.3, 4.4 Hz, 1H) 4.70 (t, J=5.5 Hz, 1H) 4.94 (dd, J=5.5, 2.5 Hz, 1H) 5.40-5.51 (m, 1H) 6.03 (d, J=3.0 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=3.0 Hz, 1H) 10.83 (s, 1H).

Workup

  1. concentrationAfter this time, the reaction was concentrated in vacuo

Sources & evidence

ORD record
ord-c184ff8195d44a38b8f1a5a2875fb52f
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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