Sodium Carbonate → 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester

HRID 1972042Notes

Reaction equation

HRID 1972042 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:47]4[CH:48]=[N:49][NH:50][CH:51]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 10340Sodium Carbonate2×HCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole2×HCID 673737524-[5-(3-Bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 673731874-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl esterYield 19%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 80711,2-DimethoxyethaneSolvent2×

Conditions

Temperature
90 °C

Procedure

A mixture of 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 65, 0.2 mmol, 118 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 mmol, 60 mg, 98%), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11.6 mg), 2 N aq. sodium carbonate solution (0.5 mL) and DME (1 mL) was heated at 80° C. for 7 h and at 90° C. for 2 h. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 mmol, 60 mg, 98%), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11.6 mg), 2 N aq. sodium carbonate solution (0.5 mL) and DME (1 mL) were added again and it was heated at 85° C. for 1.5 h. The reaction mixture was partitioned between ethyl acetate (15 mL) and saturated aq. sodium bicarbonate solution (15 mL). The ethyl acetate layer was dried over sodium sulfate. Purification by column chromatography on silica gel using ethyl acetate/hexanes 1:3 to 3:1 gave 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (21.4 mg, 19% yield).

Workup

  1. temperatureit was heated at 85° C. for 1.5 h
  2. customThe reaction mixture was partitioned between ethyl acetate (15 mL) and saturated aq. sodium bicarbonate solution (15 mL)
  3. dry with materialThe ethyl acetate layer was dried over sodium sulfate
  4. customPurification by column chromatography on silica gel

Sources & evidence

ORD record
ord-10e01bd2969b4dec86f0a89e07b23887
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

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