Methanol → 4-[6-Butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester

HRID 402022Notes

Reaction equation

HRID 402022 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].ClCCl.C(N(CC)CC)C.[CH3:49][OH:50].CN([CH:54]=[O:55])C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[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:49]([O:55][CH3:54])=[O:50])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 5

HCID 887MethanolHCID 6228DimethylformamideHCID 6344DichloromethaneHCID 8471TriethylamineHCID 673737524-[5-(3-Bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 673756004-[6-Butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

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, 0.816 mmol, 480 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.163 mmol, 133 mg), 1,1′-bis(diphenylphosphino)ferrocene (0.163 mmol, 90.4 mg), triethyl amine (1.63 mL), MeOH (16.3 mL) and DMF (16.3 mL) was heated at 90° C. under carbon monoxide atmosphere (24 psi) overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aq. sodium bicarbonate solution (200 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×200 mL) and dried over sodium sulfate. Purification by column chromatography on silica gel using 20-50% ethyl acetate in hexanes gave 4-[6-butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester as light yellow, thick oil (428 mg).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aq. sodium bicarbonate solution (200 mL)
  2. washThe ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×200 mL)
  3. dry with materialdried over sodium sulfate
  4. customPurification by column chromatography on silica gel using 20-50% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-671f6cc12d1948d7af774d6f57a4d3c1
Source dataset
uspto-grants-2014_06
Patent number
US08741900B2

Reaction notes

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