Acetic Acid → Entacapone Impurity 55

HRID 132017

Reaction equation

HRID 132017 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)[CH3:2].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>O.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][CH2:1][CH3:2])[CH:5]=1)[CH3:34]

Participants

7

Reactant 4

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

Product 1

HCID 69218750Entacapone Impurity 55Yield 172.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A flask was charged with 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (20 g, 0.0947 mole) (formula 2 where R is ethyl) and N,N-diethylaminocyanoacetamide (formula (3)) (14.6 g, 0.1042 mol), acetic acid (3.13 g), and piperidine (4.45 g), along with toluene (200 mL), and was heated to a reflux temperature of about 100-115° C. with continuous removal of water azeotrophically for about 15 hours. After the reaction was complete, the reaction mixture was concentrated to a volume of 20-30 mL, quenched into dilute hydrochloric acid and chilled water (200 mL), and stirred for 60 minutes. The precipitated solid was filtered and dried to provide 30 g (95% yield, HPLC purity of 94% (including isomer)) of N,N-diethyl-2-cyano-3-(-3-ethoxy-4-hydroxy-5-nitrophenyl)acrylamide. The product was used as such directly to the next stage. MR=110.0-117.2° C.

Workup

  1. concentrationthe reaction mixture was concentrated to a volume of 20-30 mL
  2. customquenched into dilute hydrochloric acid
  3. temperaturechilled water (200 mL)
  4. filtrationThe precipitated solid was filtered
  5. customdried

Sources & evidence

ORD record
ord-835738e53b76464a917b4f815a4aaf91
Source dataset
uspto-grants-2008_06
Patent number
US07385072B2

Linked notes

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