4,4'-Oxydibenzoic acid → Propofol

HRID 1183875Notes

Reaction equation

HRID 1183875 reaction equation
[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]=1[O:13]C(C)C)C(O)=O)[CH3:3].O(C1C=CC(C(O)=O)=CC=1)C1C=CC(C(O)=O)=CC=1>CCOCC>[CH:17]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[C:12]=1[OH:13])([CH3:19])[CH3:18]

Participants

4

Reactant 2

HCID 751834,4'-Oxydibenzoic acidHCID 67997425HCID 67997425, compound

Product 1

HCID 4943Propofol

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

The process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), comprises reacting p-hydroxy benzoic acid (Formula II) with an alkylating agent in presence of aq. mineral acid at a temperature in the range of 60-65° C. followed by basification with sodium hydroxide to yield crude 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) including ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V, dimer impurity, 4,4′-oxydibenzoic acid of Formula IV, and the monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI and subsequently (a) washing with toluene at basic pH to remove the ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V; (b) washing with hot water to remove dimer impurity 4,4′-oxydibenzoic acid of Formula IV; (c) washing with methanol-water mixture, to remove monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI, followed by decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III), free from impurities of Formula IV, V and VI, in presence of high boiling solvent and a catalyst at high temperature to yield 2,6-diisopropyl phenol having purity of 99.9% by HPLC. 2,6-diisopropyl phenol thus obtained is substantially free of ether impurity 1,3-di(propan-2-yl)-2-(propan-2-yloxy)benzene of Formula VII and monoalkylated phenol impurity 2-(propan-2-yl) phenol of Formula VIII.

Workup

  1. washthe monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI and subsequently (a) washing with toluene at basic pH
  2. customto remove the ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V
  3. wash(b) washing with hot water
  4. customto remove dimer impurity 4,4′-oxydibenzoic acid of Formula IV
  5. wash(c) washing with methanol-water mixture
  6. customto remove

Sources & evidence

ORD record
ord-4232b7eeb36141debb210cdc11224071
Source dataset
uspto-grants-2014_03
Patent number
US08664452B2

Reaction notes

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