Formaldehyde → 3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-1-methyl-piperidin-4-ylmethoxy)-pyridazine

HRID 401957Notes

Reaction equation

HRID 401957 reaction equation
Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][N:31]([CH3:37])[CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 673713573-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride

Product 1

HCID 584384083-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-1-methyl-piperidin-4-ylmethoxy)-pyridazine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.058 mmol, 30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.35 mmol, 75 mg) was added stirred at room temperature for 2 h. Reaction was diluted with DCM (5 mL), DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM—6% (NH3 in MeOH, 2M) in DCM gave 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-1-methyl-piperidin-4-yl methoxy)-pyridazine, which was converted to the title compound by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, salt was washed with anhydrous ether and solid was dried under high vacuum (24 mg). LCMS: m/z 457 [M+1]. 1H NMR (300 MHz, CD3OD): δ 7.86 (1H, s), 7.45 (2H, d), 7.12 (2H, d), 4.68 (2H, d), 4.44-4.50 (1H, m), 3.50-3.62 (2H, m), 3.24-3.39 (2H, m), 3.13 (2H, t), 2.94 (3H, s), 1.74-2.50 (8H, m), 1.20-1.68 (10H, m), 0.82 (3H, t).

Workup

  1. stirringstirred at room temperature for 2 h
  2. customReaction
  3. customwas separated
  4. washwashed with saturated NaHCO3 solution
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM—6% (NH3 in MeOH, 2M) in DCM

Sources & evidence

ORD record
ord-f3d3691d5b4b40b388f1c468edf35f82
Source dataset
uspto-grants-2014_06
Patent number
US08741900B2

Reaction notes

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