Formaldehyde → 5-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester

HRID 1972030Notes

Reaction equation

HRID 1972030 reaction equation
Cl.Cl.[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C=O.O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:40])[CH2:23][CH2:24]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 962WaterHCID 5049666Sodium triacetoxyborohydrideHCID 673727635-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride

Product 1

HCID 584384215-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of 5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride in DCM (6 mL) was added formaldehyde solution in water (37%, 2.26 mmol, 0.168 mL) and 2 drops of acetic acid. Sodium triacetoxyborohydride (3.02 mmol, 674 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate solution (40 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-4.5% MeOH in DCM to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester. This was converted to the title compound using 4 N HCl in dioxane (296 mg). LCMS: m/z 483 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.86-7.93 (2H, m), 7.65-7.71 (1H, m), 7.34-7.38 (1H, m), 5.38-5.55 (1H, m), 4.61-4.65 (1H, m), 3.89 and 3.89 (3H, s), 3.11-3.65 (6H, m), 2.94 (3H, s), 1.16-2.57 (18H, m), 0.83 (3H, dt).

Workup

  1. custompartitioned between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate solution (40 mL)
  2. customThe ethyl acetate layer was separated
  3. dry with materialdried over sodium sulfate
  4. customThe crude product was purified by column chromatography on basic alumina using 0-4.5% MeOH in DCM

Sources & evidence

ORD record
ord-a95d3b84d96141c1b856fed1bf71493a
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

Loading…