Hydrochloric Acid → N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

HRID 1910479Notes

Reaction equation

HRID 1910479 reaction equation
[Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][Zn+])#[N:3].Cl[C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[CH:12][CH:11]=1.CCOC(C)=O.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=2)=[CH:12][CH:11]=1)#[N:3]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8857Ethyl AcetateHCID 86687873N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamideHCID 178510995HCID 178510995, compound

Product 1

HCID 86687874N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

Reagents, catalysts & solvents 2

HCID 178418745HCID 178418745, compoundCatalystHCID 962WaterSolvent

Procedure

4-Cyanobutylzinc bromide solution (3.0 equiv., 0.50 mol, 1.0 L) was charged into an argon gas purged 5000 mL 3 neck round bottom flask. Argon(g) purge for 5 minutes followed by the addition of 1117 (1.0 equiv., 0.167 mol, 55.3 g) and NiCl2(dppp) (0.15 equiv., 0.0251 mol, 13.6 g) under a blanket of argon(g). The reaction usually goes to completion after 4 hours (TLC: 1:1 hexanes-ethyl acetate). EtOAc (15 vol., 832 mL) added to deep red solution. Water (15 vol., 832 mL) was added, thick slurry formed. 1N HCl added until slurry breaks to pale blue layer (˜6 vol., 333 mL). Transferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL), dried (MgSO4) and concentrated by rotary evaporation (bath ≦30° C.) to a solid reddish oil. Oil dissolved in dichloromethane (15 vol., 832 mL), silica gel (100 g) was slurried into red solution, this was concentrated by rotary evaporation (bath ≦30° C.) to a solid reddish powder. Loaded onto a bed of silica gel (5 cm×11 cm), flushed with 25% hexanes in ethyl acetate (3 L), combined organics concentrated by rotary evaporation (bath ≦30° C.). Dried under high vacuum to a constant weight to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1118: yield of 58.2 g (92%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.52-7.27 (m, 4H), 3.89 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.61 (m, 2H).

Workup

  1. custompurged 5000 mL 3 neck round bottom flask
  2. customArgon(g) purge for 5 minutes
  3. customThe reaction
  4. customthick slurry formed
  5. washTransferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated by rotary evaporation (bath ≦30° C.) to a solid reddish oil
  8. dissolutionOil dissolved in dichloromethane (15 vol., 832 mL)
  9. concentrationthis was concentrated by rotary evaporation (bath ≦30° C.) to a solid reddish powder
  10. customflushed with 25% hexanes in ethyl acetate (3 L)
  11. concentrationcombined organics concentrated by rotary evaporation (bath ≦30° C.)
  12. customDried under high vacuum to a constant weight

Sources & evidence

ORD record
ord-0323c2f4ec5e437bb7271db1ae7ccc95
Source dataset
uspto-grants-2013_12
Patent number
US08604016B2

Reaction notes

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