Formaldehyde → 3-Butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(1-methyl-piperidin-4-yloxy)-pyridazine dihydrochloride

HRID 402039Notes

Reaction equation

HRID 402039 reaction equation
[ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]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)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:45])[CH2:38][CH2:37]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 962WaterHCID 5049666Sodium triacetoxyborohydrideHCID 673716143-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride

Product 1

HCID 673732813-Butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(1-methyl-piperidin-4-yloxy)-pyridazine dihydrochlorideYield 125%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 3-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.0776 mmol, 49.9 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.23 mmol, 0.017 mL), and 1 drop of acetic acid. Sodium triacetoxyborohydride (0.31 mmol, 69.2 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-3% MeOH in DCM, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to provide the title compound (30.1 mg). LCMS: m/z 549 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.24-8.27 (1H, m), 8.04-8.07 (1H, m), 7.90-7.98 (1H, m), 7.78-7.83 (1H, m), 7.37-7.43 (1H, m), 7.27-7.31 (1H, m), 5.37-5.46 (1H, m), 4.59-4.62 (1H, m), 4.38 (2H, t), 3.77 (2H, t), 3.16-3.66 (9H, m), 2.95 (3H, s), 1.25-2.59 (18H, m), 0.82 (3H, t).

Workup

  1. custompartitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 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 0-3% MeOH in DCM
  5. dissolutiondissolved in MeOH
  6. additiontreated with 4 N HCl in dioxane
  7. customThe organic solvents were removed in vacuo
  8. customthe residue was triturated with anhydrous diethyl ether
  9. customThe yellow solid was dried overnight under high vacuum

Sources & evidence

ORD record
ord-1bb5886acbc04da6ad0ebd92c82ea09e
Source dataset
uspto-grants-2014_06
Patent number
US08741900B2

Reaction notes

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