Acetic Acid → HCID 66938762, compound

HRID 1591891Notes

Reaction equation

HRID 1591891 reaction equation
[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)=[O:5].[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:8]=1)=[O:5]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 740491-Methyl-4-piperidoneHCID 5049666Sodium triacetoxyborohydrideHCID 16775466HCID 16775466, compound

Product 1

HCID 66938762HCID 66938762, compoundYield 125.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under an inert atmosphere, stir a mixture of 2-chloro-4-fluoro-N-(3-amino-4-fluorophenyl)benzamide (Preparation 14, 481 mg, 1.7 mmol), 1-methyl-4-piperidone (384 mg, 0.42 mL, 3.4 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g) for 15 min. Add glacial acetic acid (306 mg, 0.3 mL, 5.1 mmol). After 1 hr., add sodium triacetoxyborohydride (900 mg, 4.25 mmol). Allow the reaction to go overnight. Pour the reaction mixture into ethyl acetate (200 mL), and wash once with aqueous NaOH (2N, 30 mL). Separate the organic layer, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure. Further purify the residue by chromatography on silica gel using a 4%–6% gradient of (2M NH3 in methanol) in CH2Cl2 to obtain the free base of the title compound (443 mg, 69% yield). Convert the product to its HCl salt by dissolving it in CH2Cl2 and treating with excess 1.0M HCl in diethyl ether. Add more ether to precipitate the title compound as a white solid: mass spectrum (ion spray): m/z=380.2 (M+1); Analysis calc'd for C19H20ClF2N3O.HCl.H2O: C, 52.54; H, 5.34; N, 9.68. Found: C, 52.93; H, 5.29; N, 9.65; LY 653915: 1H NMR δ (methanol-d4) 7.72(dd, 1H), 7.60(m, 1H), 7.37(dd, 1H), 7.14(m, 3H), 3.74(m, 1H), 3.62(d, 2H), 3.30(dd, 2H), 2.88(s, 3H), 2.36(d, 2H), 1.93(m, 2H)

Workup

  1. customthe reaction
  2. waitto go overnight
  3. washwash once with aqueous NaOH (2N, 30 mL)
  4. customSeparate the organic layer
  5. dry with materialdry over anhydrous sodium sulfate
  6. customremove the solvent under reduced pressure
  7. customFurther purify the residue by chromatography on silica gel using a 4%–6% gradient of (2M NH3 in methanol) in CH2Cl2

Sources & evidence

ORD record
ord-80c032b9837d48a5bc4299587d44892e
Source dataset
uspto-grants-2007_11
Patent number
US07291632B2

Reaction notes

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