Cesium carbonate → 2-[4-(2-chloro-3-trifluoromethyl-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

HRID 2381549Notes

Reaction equation

HRID 2381549 reaction equation
[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1[OH:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:41][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:39])[F:40])[C:31]=4[Cl:30])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 27366012-Chloro-3-(trifluoromethyl)phenolHCID 579192872-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide2×

Product 1

HCID 668947062-[4-(2-chloro-3-trifluoromethyl-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

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 2-(4-iodo-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 (Intermediate 94, 51.5 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with 2-chloro-3-trifluoromethyl-phenol (23.6 mg, 0.12 mmol) and cesium carbonate (65.2 mg, 0.20 mmol). The reaction was stirred at 25° C. over 3 nights. At this time, the reaction was warmed to 80° C. overnight. At this time, the reaction was filtered, rinsed with dimethylsulfoxide (1 mL) and then purified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min) to afford 2-[4-(2-chloro-3-trifluoromethyl-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 as a white solid as a mixture of diastereomers (39 mg, 67%); ES+-HRMS m/e calcd for C26H29N5O5F3Cl [M+H+] 584.1882 found 584.1885. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.95 (m, 6H), 1.24 (s, 3H), 1.29, 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 1.99-2.32 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.2 Hz, 1H), 4.04-4.22 (m, 2H), 4.27-4.43 (m, 1H), 5.53 (dd, J=11.2, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.87 (t, J=7.5 Hz, 2H), 8.25 (d, J=2.7 Hz, 1H), 10.85 (s, 1H)

Workup

  1. temperatureAt this time, the reaction was warmed to 80° C. overnight
  2. filtrationAt this time, the reaction was filtered
  3. washrinsed with dimethylsulfoxide (1 mL)
  4. custompurified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min)

Sources & evidence

ORD record
ord-3a19ea09a114434492118e777286bbcd
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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