Hydrochloric Acid → HCID 67373322, compound

HRID 1972003Notes

Reaction equation

HRID 1972003 reaction equation
[ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[CH2:4][CH2:5][CH3:6].[CH:38](=O)[CH:39]([CH3:41])[CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([Cl:60])(=O)C.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.C(O)(=O)C.O.CCOC(C)=O.CN(C1C=CN=CC=1)C.CCOCC>[ClH:60].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([N:19]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:20](=[O:22])[CH3:21])[CH:18]=1)[CH2:4][CH2:5][CH3:6]

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 6367Acetyl chlorideHCID 6561IsobutyraldehydeHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 67373992HCID 67373992, compound

Product 1

HCID 67373322HCID 67373322, compoundYield 33.6%

Reagents, catalysts & solvents 5

HCID 176Acetic AcidCatalystHCID 142844-(Dimethylamino)pyridineCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×HCID 22728543Water ethylacetateSolvent

Procedure

To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.2 mmol, 88 mg) in DCM (2.0 mL) was added isobutyraldehyde (0.3 mmol, 28 μL), and 1 drop of acetic acid. Then sodium triacetoxyborohydride (0.6 mmol, 127 mg) was added. The mixture was stirred at room temperature for 1 hour then condensed. The mixture was then diluted with water/EtOAc. The solvent was removed in vacuo and the residue was again dissolved in DCM (2.0 mL) at 0° C., added acetyl chloride (0.4 mmol, 29 μL), DIEA (0.6 mmol, 105 μL) and DMAP (5 mg). And the mixture was stirred at room temperature for 1 hour. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (41 mg). LCMS: m/z 537 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.40-7.43 (1H, m), 7.28-7.35 (2H, m), 7.07 (1H, s), 5.52 (1H, bs), 4.53-4.59 (1H, m), 3.65-3.71 (1H, m), 3.29-3.47 (7H, m), 2.92-2.97 (2H, m), 2.89 (3H, s), 2.18-2.37 (4H, m), 1.99-2.07 (2H, m), 1.84 (3H, s), 1.25-1.83 (9H, m), 1.18-1.26 (2H, m), 0.91-0.95 (6H, m), 0.80 (3H, t).

Workup

  1. customcondensed
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was again dissolved in DCM (2.0 mL) at 0° C.
  4. stirringAnd the mixture was stirred at room temperature for 1 hour
  5. customcondensed in vacuo
  6. customthe residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH)
  7. customto give a colorless sticky solid, which
  8. waitkept at room temperature for 10 min
  9. customcondensed
  10. customtriturated with hexanes

Sources & evidence

ORD record
ord-86191449f9a343da8bd35c6830a87b72
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

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