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WO2000034218A1 - Process for purification of 2,6-diisopropyl phenol - Google Patents

Process for purification of 2,6-diisopropyl phenol Download PDF

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Publication number
WO2000034218A1
WO2000034218A1 PCT/KR1999/000737 KR9900737W WO0034218A1 WO 2000034218 A1 WO2000034218 A1 WO 2000034218A1 KR 9900737 W KR9900737 W KR 9900737W WO 0034218 A1 WO0034218 A1 WO 0034218A1
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Prior art keywords
purification
diisopropyl phenol
purity
over
dip
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PCT/KR1999/000737
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French (fr)
Inventor
Jin Kyu Park
Kyung Seok Choi
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Dong Kook Pharmaceutical Co Ltd
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Dong Kook Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/685Processes comprising at least two steps in series
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/70Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
    • C07C37/74Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by distillation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/70Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
    • C07C37/84Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/86Purification; separation; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification

Definitions

  • the present invention relates to a process for the purification of 2,6- diisopropyl phenol and more particularly, to the process for the preparation of 2,6-diisopropyl phenol with extremely high purity expressed by formula (1) by treating with firstly an inorganic acid and secondly a base, extracting with a solvent, and purifying by distillation or crystallization at -20 ⁇ -30 ° C .
  • DIP 2,6-Diisopropyl phenol
  • a DIP 2,6-Diisopropyl phenol expressed by formula (1) is used in anesthesia.
  • US 5,591,311 discloses a purification method of DIP by dissolving the DIP in hydroxide solution followed by heating, neutralizing with an inorganic acid such as sulfuric acid or phosphoric acid, extracting with an organic solvent, and finally purifying by distillation.
  • US 5,175,376 discloses another purification method of DIP by crystallizing at an appropriate temperature with or without using petroleum ether or hexane.
  • US 5,589,598 discloses another purification method of DIP by transformation of the crude DIP into its ester, crystallization and hydrolysis with potassium hydroxide.
  • an object of the present invention is to provide an industrially advantageous method of DIP purification with extremely high purity of 99.99% by using DIP with 90% purity which is synthesized by the method from the present invention.
  • the present invention is characterized in that the raw DIP with over 90% purity is undergoing a series of sequential treatment first with an inorganic acid and second with a base, extraction with a solvent, and purification by distillation or crystallization at -20 ° C to -30 ° C .
  • the present invention is also characterized in that the raw product with over 99% purity is undergoing a series of sequential treatment first with a base and second with an inorganic acid, extraction with a solvent and purification by distillation or crystallization at -20 ° C to -30 ° C .
  • the detailed description of the present invention is given hereunder.
  • the method of the present invention provides DIP with over 99% of purity by carrying the raw product containing 2-isopropyl phenol expressed by formula (2) and 2,4,6-triisopropyl phenol expressed by formula (3).
  • This raw product containing side products, (2) and (3) is prepared by reacting phenol with propylene gas in pH below 1.0 under 250 ⁇ 450 psi at high temperature of 200 - 300 ° C . 1 ⁇ 10 N of an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid was added to the mixture of over 90% purity of DIP containing 2-isopropyl phenol and 2,4,6-triisopropyl phenol.
  • This mixture was stirred for 1 - 3 hours, extracted with an organic solvent and the water was discarded.
  • the organic layer was occasionally washed with water once or twice.
  • the washed organic layer was basified with 1 - ION of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide and aluminum hydroxide to pH 9 - 12.
  • the mixture was stirred for 1 - 3 hours at room temperature.
  • Organic layer was separated from water layer and water residue was removed by extracting with an organic solvent selected from the group consisting of petroleum ether, n-hexane, carbon tetrachloride, chloroform and methylene chloride.
  • the organic layer was dried over Na 2 S0 and then carried out by fractional distillation or crystallized at -20 ° C to -30 ° C to obtain the desired DIP with a purity of 99.99% or above. Further, DIP with a purity of 99% or above dissolved in a base selected from the group consisting of potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide was adjusted to pH 2 - 7 with an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid. Organic layer was separated from water layer and water residue was removed by extracting with an organic solvent selected from the group consisting of petroleum ether and n-hexane. The organic layer was carried out by fractional distillation or crystallized for further purification.
  • Example 1 10£ of 2N hydrochloric acid was added to 10-C of a reactant containing
  • Example 4 To a reactant same as in Example 1 was added 10-C of 2N hydrochloric acid. The mixture was stirred for 1 hour at room temperature. The separated organic layer was basified with 2N sodium hydroxide to pH 9.5, followed by stirring for additional 1 hour. 10£ of petroleum ether was added to the separated organic layer to remove water residue. The organic layer was dried over MgS0 4 and distilled to give 7.951 (86.9%) of DIP with a purity of 99.99% or above.
  • Example 4 To a reactant same as in Example 1 was added 10-C of 2N hydrochloric acid. The mixture was stirred for 1 hour at room temperature. The separated organic layer was basified with 2N sodium hydroxide to pH 9.5, followed by stirring for additional 1 hour. 10£ of petroleum ether was added to the separated organic layer to remove water residue. The organic layer was dried over MgS0 4 and distilled to give 7.951 (86.9%) of DIP with a purity of 99.99% or above.
  • Example 4 To a reactant same as in
  • Example 2 To a reactant same as in Example 1 was added 511 of 5N hydrochloric acid. The mixture was stirred for 1 hour at room temperature. The separated organic layer was basified to pH 10.0 with 2N lithium hydroxide, followed by stirring for additional 1 hour. 10£ of n-hexane was added to the separated organic layer to remove water residue. The organic layer was dried over Na 2 S0 4 and distilled to give 7.65.6 (83.5%) of DIP with a purity of 99.99% or above.
  • a reactant was purified by the procedure of Example 1 except using 2N magnesium hydroxide instead of 2N sodium hydroxide to give 7.45-6 (81.3%) of DIP with a purity of 99.99% or above.
  • a reactant was purified by the procedure of Example 1 except using 2N calcium hydroxide instead of 2N sodium hydroxide to give 5.984J (65.3%) of DIP with a purity of 99.99% or above.
  • Example 9
  • a reactant was purified by the procedure of Example 9 except using 2N potassium hydroxide instead of 2N sodium hydroxide to give 8.7-6 (87%) of DIP with a purity of 99.99% or above.
  • the present invention makes it possible to provide an economically and industrially advantageous method of purifying DIP with extremely high degree of purity unlike conventional methods.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a process for the purification of 2,6-diisopropyl phenol and more particularly, to the process for the preparation of 2,6-diisopropyl phenol with extremely high purity expressed by formula (1) by treating with firstly an inorganic acid and secondly a base, extracting with a solvent and purifying the distillation or crystallization at -20 ∩ -30°C.

Description

PROCESS FOR PURIFICATION OF 2,6-DIISOPROPYL PHENOL
BACKGROUND OF THE INVENITON Field of the Invention
The present invention relates to a process for the purification of 2,6- diisopropyl phenol and more particularly, to the process for the preparation of 2,6-diisopropyl phenol with extremely high purity expressed by formula (1) by treating with firstly an inorganic acid and secondly a base, extracting with a solvent, and purifying by distillation or crystallization at -20 ~ -30 °C .
Figure imgf000003_0001
2,6-Diisopropyl phenol (hereinafter referred to as a DIP) expressed by formula (1) is used in anesthesia. US 5,591,311 discloses a purification method of DIP by dissolving the DIP in hydroxide solution followed by heating, neutralizing with an inorganic acid such as sulfuric acid or phosphoric acid, extracting with an organic solvent, and finally purifying by distillation. US 5,175,376 discloses another purification method of DIP by crystallizing at an appropriate temperature with or without using petroleum ether or hexane. US 5,589,598 discloses another purification method of DIP by transformation of the crude DIP into its ester, crystallization and hydrolysis with potassium hydroxide.
However, the above purification methods necessitate using DIP with a purity of higher than 99.0% as a prerequisite to obtain the desired purity of 99.9%. The major contaminants removed during the purification process are 2- isopropylpheonl expressed by formula (2) and 2,4,6-triisopropyl phenol expressed by formula (3).
Figure imgf000004_0001
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide an industrially advantageous method of DIP purification with extremely high purity of 99.99% by using DIP with 90% purity which is synthesized by the method from the present invention.
Detailed Description of the Invention
The present invention is characterized in that the raw DIP with over 90% purity is undergoing a series of sequential treatment first with an inorganic acid and second with a base, extraction with a solvent, and purification by distillation or crystallization at -20 °C to -30 °C .
The present invention is also characterized in that the raw product with over 99% purity is undergoing a series of sequential treatment first with a base and second with an inorganic acid, extraction with a solvent and purification by distillation or crystallization at -20 °C to -30 °C . The detailed description of the present invention is given hereunder.
The method of the present invention provides DIP with over 99% of purity by carrying the raw product containing 2-isopropyl phenol expressed by formula (2) and 2,4,6-triisopropyl phenol expressed by formula (3). This raw product containing side products, (2) and (3), is prepared by reacting phenol with propylene gas in pH below 1.0 under 250 ~ 450 psi at high temperature of 200 - 300 °C . 1 ~ 10 N of an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid was added to the mixture of over 90% purity of DIP containing 2-isopropyl phenol and 2,4,6-triisopropyl phenol. This mixture was stirred for 1 - 3 hours, extracted with an organic solvent and the water was discarded. The organic layer was occasionally washed with water once or twice. The washed organic layer was basified with 1 - ION of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide and aluminum hydroxide to pH 9 - 12. The mixture was stirred for 1 - 3 hours at room temperature. Organic layer was separated from water layer and water residue was removed by extracting with an organic solvent selected from the group consisting of petroleum ether, n-hexane, carbon tetrachloride, chloroform and methylene chloride. The organic layer was dried over Na2S0 and then carried out by fractional distillation or crystallized at -20 °C to -30 °C to obtain the desired DIP with a purity of 99.99% or above. Further, DIP with a purity of 99% or above dissolved in a base selected from the group consisting of potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide was adjusted to pH 2 - 7 with an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid. Organic layer was separated from water layer and water residue was removed by extracting with an organic solvent selected from the group consisting of petroleum ether and n-hexane. The organic layer was carried out by fractional distillation or crystallized for further purification.
The following examples are intended to be illustrative for the present invention and should not be construed as limiting the scope of this invention defined by the appended claims.
Example 1 10£ of 2N hydrochloric acid was added to 10-C of a reactant containing
91.5% (v/v) of DIP, 2.5% (v/v) of 2-isopropyl phenol, 1% (v/v) of phenol and 5% (v/v) of 2,4,6-triisopropyl phenol and stirred for 1 hour at room temperature. The organic layer separated from the above mixture was then adjusted to pH 10.0 by adding IN Sodium hydroxide. The mixture was stirred for 1 hour at room temperature and again the organic layer was separated out. 10£ of n-hexane was added to the organic layer to remove water residue. The organic layer was dried over Na2S0 and distilled to give 8.2-6 (89.6%) of DIP with a purity of 99.99% or above.
Example 2
After the organic layer obtained from the procedure of Example 1 was dried over Na2S0 , it was crystallized at -25 °C for 1 day to give 6.5£ (71%) of DIP with a purity of 99.99% or above.
Example 3
To a reactant same as in Example 1 was added 10-C of 2N hydrochloric acid. The mixture was stirred for 1 hour at room temperature. The separated organic layer was basified with 2N sodium hydroxide to pH 9.5, followed by stirring for additional 1 hour. 10£ of petroleum ether was added to the separated organic layer to remove water residue. The organic layer was dried over MgS04 and distilled to give 7.951 (86.9%) of DIP with a purity of 99.99% or above. Example 4
After drying DIP obtained from the procedure of Example 3, it was crystallized at -25 °C for 1 day to give 6.20£ (67.8%) of DIP with a purity of 99.99% or above.
Example 5
To a reactant same as in Example 1 was added 511 of 5N hydrochloric acid. The mixture was stirred for 1 hour at room temperature. The separated organic layer was basified to pH 10.0 with 2N lithium hydroxide, followed by stirring for additional 1 hour. 10£ of n-hexane was added to the separated organic layer to remove water residue. The organic layer was dried over Na2S04 and distilled to give 7.65.6 (83.5%) of DIP with a purity of 99.99% or above.
Example 6
After drying DIP obtained from the procedure of Example 5, it was crystallized at -25 °C for 1 day to give 5.75H (62.8%) of DIP with a purity of 99.99% or above.
Example 7
A reactant was purified by the procedure of Example 1 except using 2N magnesium hydroxide instead of 2N sodium hydroxide to give 7.45-6 (81.3%) of DIP with a purity of 99.99% or above.
Example 8
A reactant was purified by the procedure of Example 1 except using 2N calcium hydroxide instead of 2N sodium hydroxide to give 5.984J (65.3%) of DIP with a purity of 99.99% or above. Example 9
10-6 of 99% (v/v) of DIP was adjusted to pH 11.0 by adding 5% of lithium hydroxide. The mixture was stirred for 1 hour at room temperature. The separated organic layer was adjusted to pH 5.0 with 2N hydrochloric acid. 10£ Of n-hexane was added to the separated organic layer to remove water residue. The organic layer was dried over Na2S0 and was crystallized at -25 °C for 1 day to give 8.54 (85%) of DIP with a purity of 99.99% or above.
Example 10
A reactant was purified by the procedure of Example 9 except using 2N potassium hydroxide instead of 2N sodium hydroxide to give 8.7-6 (87%) of DIP with a purity of 99.99% or above.
The present invention makes it possible to provide an economically and industrially advantageous method of purifying DIP with extremely high degree of purity unlike conventional methods.

Claims

CLAIMS What is claimed is:
1. A process for the purification of 2,6-diisopropyl phenol having over 90% purity, wherein a raw 2,6-diisopropyl phenol was treated with firstly an inorganic acid and secondly a bas, extracted with a solvent and purified by distillation or crystallization at a temperature of -20 - -30 °C .
2. The process for the purification of 2,6-diisopropyl phenol having over 90% purity according to claim 1, wherein said inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid in the range of from 1 N to 10 N of concentration.
3. The process for the purification of 2,6-diisopropyl phenol having over 90% purity according to claim 1, wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and aluminum hydroxide in the range of from 1% to 10% of concentration to adjust pH in the range of from 8 to 12.
4. The process for the purification of 2,6-diisopropyl phenol having over 90% purity according to claim 1, wherein said solvent is selected from the group consisting of petroleum ether, n-hexane, carbon tetrachloride, chloroform and methylene chloride.
5. A process for the purification of 2,6-diisopropyl phenol having over 99% purity, wherein a raw 2,6-diisopropyl phenol was treated with firstly a base and secondly an inorganic acid, extracted with a solvent and purified by distillation or crystallization.
6. The process for the purification of 2,6-diisopropyl phenol having over 99% purity according to claim 5, wherein said base is selected from the group consisting of potassium hydroxide, lithium hydroxide, calcium hydroxide and aluminum hydroxide
7. The process for the purification of 2,6-diisopropyl phenol having over 99% purity according to claim 5, wherein said inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid.
8. The process for the purification of 2,6-diisopropyl phenol having over 99% purity according to claim 5, wherein said solvent is selected from the group consisting of petroleum ether and n-hexane.
PCT/KR1999/000737 1998-12-04 1999-12-03 Process for purification of 2,6-diisopropyl phenol Ceased WO2000034218A1 (en)

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KR1998/53200 1998-12-04
KR19980053200 1998-12-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000047871A (en) * 1998-12-04 2000-07-25 강재헌 A process for preparing high purity 2,6-diisopropylphenol
WO2011161687A1 (en) 2010-06-23 2011-12-29 Harman Finochem Limited Process for preparing extra pure 2, 6-diisopropyl phenol
EP2522651A1 (en) 2011-05-12 2012-11-14 Siegfried AG Process for the purification of 2,6-diisopropyl phenol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0511947A1 (en) * 1991-04-30 1992-11-04 Leiras Oy Process for the purification of 2,6-diisopropyl phenol
US5589596A (en) * 1993-04-27 1996-12-31 Sumitomo Chemical Company, Limited Process for producing amines
US5591311A (en) * 1995-10-26 1997-01-07 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
US5696300A (en) * 1994-07-01 1997-12-09 Archimica Spa Propofol purification

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0511947A1 (en) * 1991-04-30 1992-11-04 Leiras Oy Process for the purification of 2,6-diisopropyl phenol
US5589596A (en) * 1993-04-27 1996-12-31 Sumitomo Chemical Company, Limited Process for producing amines
US5696300A (en) * 1994-07-01 1997-12-09 Archimica Spa Propofol purification
US5591311A (en) * 1995-10-26 1997-01-07 Albemarle Corporation Process for purifying a 2,6-dialkylphenol

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000047871A (en) * 1998-12-04 2000-07-25 강재헌 A process for preparing high purity 2,6-diisopropylphenol
WO2011161687A1 (en) 2010-06-23 2011-12-29 Harman Finochem Limited Process for preparing extra pure 2, 6-diisopropyl phenol
US8664452B2 (en) 2010-06-23 2014-03-04 Harman Finochem Limited Process for preparing extra pure 2, 6-diisopropyl phenol
EP2522651A1 (en) 2011-05-12 2012-11-14 Siegfried AG Process for the purification of 2,6-diisopropyl phenol

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