Acetic Acid → HCID 66938876, compound

HRID 1716913Notes

Reaction equation

HRID 1716913 reaction equation
[ClH:1].Cl.[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]=1)=[O:7].C=O.[C:29](O)(=O)C.C([BH3-])#N.[Na+]>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:29])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:10]=1)=[O:7]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 66938863HCID 66938863, compound

Product 1

HCID 66938876HCID 66938876, compoundYield 133.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Combine 2-chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 9, 100 mg, 0.240 mmol), methanol (3 mL) and formaldehyde (37% aq., 0.195 mL, 2.39 mmol). Stir at room temperature for 45 min. Cool to 0° C. Add acetic acid (0.412 mL, 7.20 mmol) and sodium cyanoborohydride (26 mg, 0.420 mmol). Stir at room temperature overnight. Concentrate to dryness. Dissolve the residue in a 2/1 mixture of ethyl acetate and hexanes (8 mL) and wash with sodium hydroxide (1N aq., 2×6 mL). Separate the organic layer and dry over magnesium sulfate. Filter and concentrate under reduced pressure. Purify through flash chromatography eluting with a 20/1 mixture of dichloromethane and 2M ammonia in methanol to provide the free base of the title compound (69 mg, 80%). Following a salt formation method similar to Example 1 gives the title compound as a white solid (83 mg, white solid): mass spectrum (free base, ion spray): m/z=358.2 (M+1), 1H NMR (free base, CDCl3): 7.97 (bs, N—H), 7.66 (dd, J=1.7 Hz, 7.5 Hz, 1H), 7.42-7.27 (m, 4H), 7.17 (t, J=8.2 Hz, 1H), 6.82 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.57 (dd, J=2.3 Hz, 8.4 Hz, 1H), 3.59 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.90 (bd, J=11.7 Hz, 2H), 2.78 (s, 3H), 2.26 (s, 3H), 2.05 (td, J=2.3 Hz, 12.0 Hz, 2H), 1.82 (qd, J=3.9 Hz, 12.0 Hz, 2H), 1.70 (bd, J=12.0 Hz, 2H). Analysis calc'd for C20H26Cl3N3O 0.25H2O: C, 55.18; H, 6.14; N, 9.65. Found: C, 55.03; H, 6.11; N, 9.26.

Workup

  1. temperatureCool to 0° C
  2. stirringStir at room temperature overnight
  3. concentrationConcentrate to dryness
  4. dissolutionDissolve the residue
  5. additionin a 2/1 mixture of ethyl acetate and hexanes (8 mL)
  6. washwash with sodium hydroxide (1N aq., 2×6 mL)
  7. customSeparate the organic layer
  8. dry with materialdry over magnesium sulfate
  9. filtrationFilter
  10. concentrationconcentrate under reduced pressure
  11. customPurify through flash chromatography
  12. washeluting with a 20/1 mixture of dichloromethane and 2M ammonia in methanol

Sources & evidence

ORD record
ord-178e529f574c4b92b23d0c5bdaf63d6a
Source dataset
uspto-grants-2010_09
Patent number
US07803813B2

Reaction notes

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