Formaldehyde → (+/-)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-1-methyl-piperidin-4-yloxy)-pyridazine

HRID 2168674Notes

Reaction equation

HRID 2168674 reaction equation
[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 86657796(+/-)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-piperidin-4-yloxy)-pyridazine

Product 1

HCID 86691357(+/-)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-1-methyl-piperidin-4-yloxy)-pyridazine

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a stirred solution of (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-piperidin-4-yloxy)-pyridazine (20 mg, 0.047 mmol) in DCM (4 mL) was added 37% aqueous formaldehyde (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (106 mg, 0.5 mmol). After 2 hrs the mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 2-5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to give (±)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-1-methyl-piperidin-4-yloxy)-pyridazine. The free base was dissolved in DCM, treated with 4.0 M HCl in dioxane and concentrated. The resultant salt was washed with ether and dried to provide the title compound (20 mg). LCMS: m/z 443 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, s), 7.51 (2H, d), 7.14 (2H, d), 5.54-5.60 (1H, m), 5.29 (1H, d), 4.41-4.50 (1H, m), 3.64-3.94 (2H, m), 3.46-3.53 (2H, m), 3.14-3.21 (2H, m), 3.00 (3H, t), 2.40-2.50 (2H, m) 1.96-2.05 (2H, m), 1.77-1.86 (2H, m), 1.23-1.66 (10H, m), 0.82 (3H, t).

Workup

  1. extractionextracted with DCM
  2. dry with materialThe organics were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified by column chromatography

Sources & evidence

ORD record
ord-2e9dc72434ff48208e7cb8a878899c8d
Source dataset
uspto-grants-2015_06
Patent number
US09045461B2

Reaction notes

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