Acetic Acid → Entacapone Impurity 9

HRID 132018

Reaction equation

HRID 132018 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=O)C.C(N[N:19](NCC)[C:20](=[O:24])[CH2:21][C:22]#[N:23])C.[C:28](O)(=O)[CH3:29].N1CCC[CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[CH2:33]([N:19]([CH2:28][CH3:29])[C:20](=[O:24])[C:21]([C:22]#[N:23])=[CH:7][C:6]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]([OH:12])=[C:4]([O:3][CH3:1])[CH:5]=1)[CH3:34]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8082PiperidineHCID 5848783-Ethoxy-4-hydroxy-5-nitrobenzaldehyde2×HCID 866114042-cyano-N,N-bis(ethylamino)acetamide

Product 1

HCID 67020297Entacapone Impurity 9Yield 162%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
107.5 °C

Procedure

A flask was charged with 3-methoxy-4-hydroxy-5-nitrobenzaldehyde (25 g, 0.126 mole) (formula 2 where R is methyl) and N,N-diethylaminocyanoacetamide (formula (3)) (22.2 g, 0.158 mole), acetic acid (4.18 g) and piperidine (5.94 g), along with toluene (250 mL) and was heated to a reflux temperature of about 105-110° C. Water was removed azeotrophically for 15 hours. The reaction mixture was concentrated and quenched into dilute hydrochloric acid and chilled water (375 mL), and stirred for 3 hours. The precipitated solid was filtered and dried to provide 36 g (88.95% yield, HPLC purity of 94.2% (including isomer)) of the N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)acrylamide, which was used as such for the next stage.

Workup

  1. customWater was removed azeotrophically for 15 hours
  2. concentrationThe reaction mixture was concentrated
  3. customquenched into dilute hydrochloric acid
  4. temperaturechilled water (375 mL)
  5. filtrationThe precipitated solid was filtered
  6. customdried

Sources & evidence

ORD record
ord-c0c4ef51be6f4c81bd6f0dd9cfc72a5f
Source dataset
uspto-grants-2008_06
Patent number
US07385072B2

Linked notes

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