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Formaldehyde → 1-{5-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone

HRID 1972018
Notes
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Reaction equation

HRID 1972018 reaction equation
Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O.O.C(Cl)Cl.C(O)(=O)C>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:38])[CH2:32][CH2:31]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 673875181-{5-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone dihydrochloride

Product 1

HCID 584384271-{5-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone
Yield 67.8%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 21908982Water methylene chlorideSolvent

Procedure

To a solution of 1-{5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone dihydrochloride (50 mg, 0.095 mmol) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 0.2 mL), and 0.1 mL of acetic acid. Then sodium triacetoxyborohydride (200 mg) was added. And the mixture was stirred at room temperature for 10 min then condensed. It was then diluted with water/DCM, neutralized with sat NaHCO3 powder, organic layer was separated washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 1-{5-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone (30 mg). This compound was dissolved in DCM (2.0 mL) and 1.0 mL of 4.0 M HCl in dioxane was added. Solvents were evaporated resulting solid was washed with ether and dried to provide the title compound (33 mg). LCMS: m/z 467 [M+1]. 1H NMR (400 MHz, CD3OD) 7.94 (1H, s), 7.83-7.87 (1H, m), 7.68-7.74 (1H, m), 7.39 (1H, t), 5.35-5.43 (1H, m), 4.65-4.71 (1H, m), 3.65 (1H, d), 3.38-3.50 (2H, m), 3.28-3.30 (2H, m), 3.09-3.14 (2H, m), 2.84 (3H, s), 2.67 (3H, s), 2.5 (1H, d), 2.41 (1H, d), 2.24-2.31 (1H, m), 2.05-2.13 (2H, m), 1.80-1.84 (2H, m) 1.64-1.72 (3H, m), 1.51-1.56 (4H, m), 1.28-1.34 (3H, m), 0.83 (3H, t).

Workup

  1. customcondensed
  2. customwas separated
  3. washwashed with water, brine
  4. dry with materialdried (Na2SO4)
  5. customThe solvent was removed in vacuo
  6. customthe residue was purified by column chromatography

Sources & evidence

ORD record
ord-8ff923d6b3d44f15b5cbc436ec06c42d
Source dataset
uspto-grants-2013_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08431575B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes