Hydrochloric Acid → HCID 67387597, compound

HRID 402016Notes

Reaction equation

HRID 402016 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].Br[CH2:39][CH2:40]CC([Cl:44])=O.CCN(C(C)C)C(C)C.[H-].[Na+].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CCOC(C)=O.CCOCC>[ClH:44].[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]2[CH2:40][CH2:39][CH2:21][C:20]2=[O:22])[CH:18]=1)[CH2:4][CH2:5][CH3:6]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 702254-Bromobutyryl chlorideHCID 81531DiisopropylethylamineHCID 67373992HCID 67373992, compound

Product 1

HCID 67387597HCID 67387597, compoundYield 21.6%

Reagents, catalysts & solvents 4

HCID 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 dry DCM (1.0 mL) was added 4-bromobutyryl chloride (0.4 mmol, 47 μL), DIEA (0.4 mmol, 70 μL), and DMAP (10 mg). And the mixture was stirred at room temperature for 1 hour then condensed. It was then diluted with water/EtOAc. The solvent was removed in vacuo and dried under vacuum over night. The residue was dissolved in dry THF (1.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 0.8 mmol, 32 mg) was added and the mixture was heated at 50° C. for 1 hour. It was then poured into ice-water and extracted with ethyl acetate. The organic layers were combined, condensed 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 (25 mg). LCMS: m/z 508 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.56 and 7.67 (1H, s), 7.41-7.48 (1H, m), 7.33-7.37 (1H, m), 7.25-7.31 (1H, m), 5.36-5.55 (1H, m), 4.52-4.58 (1H, m), 3.20-3.70 (8H, m), 3.07-3.13 (2H, m), 2.93 (3H, s), 1.92-2.59 (8H, m), 1.27-1.82 (12H, m), 0.80 (3H, t).

Workup

  1. customcondensed
  2. customThe solvent was removed in vacuo
  3. customdried under vacuum over night
  4. dissolutionThe residue was dissolved in dry THF (1.0 mL) at 0° C.
  5. temperaturethe mixture was heated at 50° C. for 1 hour
  6. extractionextracted with ethyl acetate
  7. customcondensed
  8. customthe residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH)
  9. customto give a colorless sticky solid, which
  10. waitkept at room temperature for 10 min
  11. customcondensed
  12. customtriturated with hexanes

Sources & evidence

ORD record
ord-d96bd734ae8f4ad89fbf181b68d49dec
Source dataset
uspto-grants-2014_06
Patent number
US08741900B2

Reaction notes

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