WO2011161687A1 - Process for preparing extra pure 2, 6-diisopropyl phenol - Google Patents

Process for preparing extra pure 2, 6-diisopropyl phenol Download PDF

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Publication number
WO2011161687A1
WO2011161687A1 PCT/IN2010/000527 IN2010000527W WO2011161687A1 WO 2011161687 A1 WO2011161687 A1 WO 2011161687A1 IN 2010000527 W IN2010000527 W IN 2010000527W WO 2011161687 A1 WO2011161687 A1 WO 2011161687A1
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formula
propan
impurity
acid
hydroxy
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PCT/IN2010/000527
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French (fr)
Inventor
Kirti Prakash Jain
Dhananjay Uddhavrao Edaki
Harpreet Singh Minhas
Gurpreet Singh Minhas
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Harman Finochem Limited
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Priority to EP10853576.6A priority Critical patent/EP2516369B1/en
Priority to US13/578,456 priority patent/US8664452B2/en
Publication of WO2011161687A1 publication Critical patent/WO2011161687A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment

Definitions

  • the present invention relates to a process for preparation of highly pure 2,6-diisopropyl phenol suitable for pharmaceutical use.
  • 2, 6-diisopropylphenol is a short-acting, intravenously administered hypnotic agent. It is used as a general anesthetic or as a soporifacient for mechanically ventilated adults, and for procedural sedation.
  • 2, 6-diisopropylphenol has several mechanisms of action, both through potentiation of GABAA receptor activity, thereby slowing the channel-closing time and also acting as a sodium channel blocker. Recent research has also suggested that the endocannabinoid system may contribute significantly to anesthetic action of 2, 6-diisopropylphenol and to its unique properties. 2,6-diisopropylphenol is highly protein-bound in vivo and is metabolized by conjugation in the liver. Its rate of clearance exceeds hepatic blood flow, suggesting an extra-hepatic site of elimination as well.
  • 2,6-diisopropyl phenol is administered intravenously; hence the purity requirement is very high. For most purposes, ideal purity for 2, 6-diisopropylphenol has to be ⁇ more then 99.9%.
  • the commercially available 2, 6-diisopropylphenol is about 97% pure.
  • the said product typically contains unreacted phenol, one or more monoalkylphenols, one or more dialkylphenol isomers other than the desired 2,6- dialkylphenol isomer.
  • Propofol obtained by alkylation of propene with phenol is purified by crystallization as such at a temperature from -20°C to -10°C.
  • said patent discloses purification of Propofol by crystallization from non-polar solvents, such as, petrol ether or hexane. The solvent residues are then removed either by distillation or evaporation and the product itself is recovered as a single fraction in the distillation.
  • non-polar solvents such as, petrol ether or hexane.
  • the solvent residues are then removed either by distillation or evaporation and the product itself is recovered as a single fraction in the distillation.
  • such a procedure is not well suited for use in a large scale commercial operation.
  • US 5264085 describe a method of continuously separating components of a hydrous phenol mixture containing methanol by distillation. The method involves recovering methanol from the top of a single distillation column, dragging water containing phenols as a side stream from the recovery section of the distillation column and the dehydrated phenols as a bottom product.
  • US5705039 discloses a process for the purification of impure 2,6-diisopropylphenol which comprises: a) subjecting the impure 2,6-diisopropylphenol to a first continuous distillation in a single distillation column in an inert environment to produce (i) a first overhead distillate of impurities boiling below the boiling point of 2,6-diisopropylphenol at the prevailing pressure and (ii) first column bottoms enriched in 2,6-diisopropylphenol; .
  • US559131 1 describes the process of purification of 2,6-diisopropylphenol which involves washing the mixture with aqueous alkali metal hydroxide solution in an inert atmosphere and separating the aqueous and organic phases, washing the resulting organic phase with water, and then subjecting the water-washed organic phase to distillation in an inert environment to recover purified diisopropylphenol(DIP).
  • US5589598 describes a process for the purification of 2,6-diisopropylphenol (Propofol) by transformation of the crude propofol into its ester with a carboxylic or sulphonic acid, followed by crystallization and hydrolysis.
  • Propofol is generally prepared from phenol and propene by Friedel-Crafts-alkylatiOn, whereby in the reaction, besides the desired product, small amounts of other isomers and phenol derivatives are formed thus affecting the purity of the product.
  • the major contaminants being 2,4- and 2,5-diisopropyl phenol, 2,4,6-triisopropyl phenol, and 1 - isppropoxy-2,4-diisopropylbenzene having small differences in their boiling points.
  • the present invention discloses economical process for preparation of highly pure 2, 6-diisopropylphenol.
  • p-hydroxy benzoic acid is reacted with an alkylating agent in presence of acidic and/or dehydrating medium at 60-65°C followed by basification to obtain 4-hydroxy-3,5-diisopropyI benzoic acid of Formula III.
  • 4-hydroxy-3,5-diisopropyl benzoic acid prior to decarboxylation stage inhibit impurities development at Propofol formation.
  • 4-hydroxy-3,5-diisopropyl benzoic acid of Formula III substantially free from impurities of Formula IV, V and VI is then subjected to decarboxylation in presence of high boiling solvent and alkali metal hydroxide as a catalyst in inert atmosphere, at high temperature to yield 2, 6-diisopropylphenol (Propofol). Formation of major contaminants of Propofol i.e.
  • Propofol thus formed is further extracted using hydrocarbons solvents like toluene, xylene etc and then washing the organic layer with aqueous sodium bicarbonate and finally with water.
  • the solvent is removed under reduced pressure and the residue is distilled off under high vacuum to give extra pure 2,6-disopropyl phenol free of the impurities described above.
  • Propofol prepared by the above method is highly pure and overcomes the drawbacks associated with impurity generation thus enabling its use in pharmaceutical compositions.
  • the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) of the present invention and a pharmaceutically acceptable excipients(s)/ carrier(s).
  • the pharmaceutical composition of the invention may be a solid form, a liquid suspension or an injectable composition.
  • the present invention relates to a process for the preparation of highly pure 2,6- diisopropylphenol of formula I employing alkylation of p-hydroxy benzoic acid to form dialkylated p-hydroxy benzoic acid followed by decarboxylation.
  • the process of the present invention comprises Friedel Craft's alkylation of p-hydroxybenzoic acid of Formula II in presence of acidic and/or dehydrating substance followed by basification with sodium hydroxide to produce 4- hydroxy-3, 5-diisopropyl benzoic acid of Formula III.
  • the alkylating agent can be selected from isopropyl alcohol, isopropyl halide, preferably isopropyl alcohol and the acidic and/or dehydrating substance is selected from aqueous mineral acid; preferably 85-95% w/w aqueous sulfuric acid.
  • the reaction is carried out at the temperature in the range of 60-65°C.
  • the solvent that can be used for washings is selected from water, lower alcohols, hydrocarbons either alone or in combination thereof.
  • the ether impurity of Formula V is removed by washing of aqueous reaction mass_at basic pH using toluene, while the dimer impurity of Formula IV is removed by repetitive hot water washing , whereas the monoalkylated impurity of Formula VI is ' removed by methanol-water purification.
  • 4-hydroxy-3, 5-diisopropyl benzoic acid of- Formula III thus obtained is 99.85% pure. All the remaining impurities are below 0.05%. It is advantageous to carry out the purification of 4-hydroxy-3, 5-diisopropyl benzoic acid of Formula III prior to decarboxylation stage as it inhibits impurities development at Propofol formationE.g. ether impurity l,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.
  • 4-hydroxy-3, 5-diisopropyl benzoic acid of Formula III, substantially free from impurities mentioned above is subjected to decarboxylation in presence of high boiling solvent and alkali metal hydroxide as a catalyst in an inert atmosphere to yield 2, 6-diisopropylphenol (Propofol). Formation of major contaminants of Propofol i.e.
  • Propofol thus formed is further extracted using hydrocarbon solvents like toluene, xylene etc and then washing the organic layer with aqueous sodium bicarbonate and finally with water. After removal of solvent, the residue is distilled off under high vacuum to give extra pure 2,6-diisopropyl phenol having purity of 99.90% and free from ether impurity l,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.
  • the catalyst used during decarboxylation is selected from alkali metal hydroxide such as sodium or potassium hydroxide.
  • the temperature for the reaction is in the range of 120- 160°C.
  • the high boiling point solvents used are preferably the solvents having boiling point above 130°C, and are selected from ethylene glycol, dimethylformamide or dimethylacetamide.
  • Propofol thus prepared by the above process is highly pure, overcomes the drawbacks associated with impurity generation and is suitable for pharmaceutical use.
  • the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) of the present invention and a pharmaceutically acceptable excipients(s)/ carrier(s).
  • the pharmaceutical composition of the invention may be a solid form, a liquid suspension or an injectable composition.
  • the active ingredient(s) and excipient(s)/ carrier(s) can be formulated into compositions and dosage forms according to methods known in the art.
  • the ⁇ therapeutically effective amount' as described above means and includes the amount required to treat/alleviate the severity of symptoms associated with this ailments as decided by the persons of ordinary skill in the art.
  • Precipitated solid was washed twice, each time with 250ml of hot water and dried to obtain crude product. Crude solid was dissolved in 350 ml of methanol and treated with activated carbon, filtered and added into 1000ml chilled water at about 10- 15°C. The precipitate was filtered off and washed twice with 200ml of water each time. After drying under vacuum at 70-75°C up to a constant weight, 4-hydroxy-3,5- diisopropyl benzoic acid was obtained.
  • the process for the preparation of highly pure 2,6-diisopropyl phenol 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)benzolc 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
  • the invention further relates to pharmaceutical composition
  • pharmaceutical composition comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) prepared by process as claimed in claim 1 along with pharmaceutically acceptable excipients(s)/ carrier(s).
  • Propofol highly pure 2,6-diisopropyl phenol

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Abstract

Disclosed herein is a process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), which comprises reacting p-hydroxy benzoic acid (Formula II) with an alkylating agent in presence of aq. mineral acid followed by basification and subsequent washings to yield 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) free of dimer impurity, 4, 4'-oxydibenzoic acid of Formula IV, ether impurity 3,5-di(propan-2-yl)-4- (propan-2-yloxy)benzoic acid of Formula V and the monoalkylated impurity 4-hydroxy- 3-(propan-2-yl) benzoic acid of Formula VI; and decarboxylating 4- hydroxy-3,5- diisopropylbenzoic acid (Formula III) in presence of high boiling solvent and sodium hydroxide as a catalyst at high temperature to yield 2, 6-diisopropyl phenol 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. Propofol prepared by the process of the present invention is suitable for pharmaceutical use.

Description

PROCESS FOR PREPARING EXTRA PURE 2,
6-DIISOPROPYL PHENOL
Field of Invention:
The present invention relates to a process for preparation of highly pure 2,6-diisopropyl phenol suitable for pharmaceutical use.
Background of Invention:
2, 6-diisopropylphenol, commonly known as "Propofol", is a short-acting, intravenously administered hypnotic agent. It is used as a general anesthetic or as a soporifacient for mechanically ventilated adults, and for procedural sedation.
2, 6-diisopropylphenol has several mechanisms of action, both through potentiation of GABAA receptor activity, thereby slowing the channel-closing time and also acting as a sodium channel blocker. Recent research has also suggested that the endocannabinoid system may contribute significantly to anesthetic action of 2, 6-diisopropylphenol and to its unique properties. 2,6-diisopropylphenol is highly protein-bound in vivo and is metabolized by conjugation in the liver. Its rate of clearance exceeds hepatic blood flow, suggesting an extra-hepatic site of elimination as well.
Generally, 2,6-diisopropyl phenol is administered intravenously; hence the purity requirement is very high. For most purposes, ideal purity for 2, 6-diisopropylphenol has to be^more then 99.9%. The commercially available 2, 6-diisopropylphenol is about 97% pure. The said product typically contains unreacted phenol, one or more monoalkylphenols, one or more dialkylphenol isomers other than the desired 2,6- dialkylphenol isomer.
A myriad of patents/patent applications have been filed across globe for preparation and purification of 2, 6-diisopropylphenol, namely US5696300, , US4275248, US3029276, WO2005033279, CN1197055, WO200034218, EP169359, US3367981 , US3271314, US3766276, SU170505, US2831898, US2207753, GB 1318100, US4391998, US4774368, US5589598 and US6362234. EP051 1947 discloses purification of 2, 6-diisopropylphenol (Propofol). Accordingly, Propofol obtained by alkylation of propene with phenol is purified by crystallization as such at a temperature from -20°C to -10°C. In an alternate method, said patent discloses purification of Propofol by crystallization from non-polar solvents, such as, petrol ether or hexane. The solvent residues are then removed either by distillation or evaporation and the product itself is recovered as a single fraction in the distillation. However, such a procedure is not well suited for use in a large scale commercial operation.
US 5264085 describe a method of continuously separating components of a hydrous phenol mixture containing methanol by distillation. The method involves recovering methanol from the top of a single distillation column, dragging water containing phenols as a side stream from the recovery section of the distillation column and the dehydrated phenols as a bottom product.
US5705039 discloses a process for the purification of impure 2,6-diisopropylphenol which comprises: a) subjecting the impure 2,6-diisopropylphenol to a first continuous distillation in a single distillation column in an inert environment to produce (i) a first overhead distillate of impurities boiling below the boiling point of 2,6-diisopropylphenol at the prevailing pressure and (ii) first column bottoms enriched in 2,6-diisopropylphenol; . b) collecting, cooling and storing the first column bottoms while continuously maintaining them in an inert environment; c) discontinuing the first continuous distillation; and d) subjecting said first column bottoms to a second continuous distillation in an inert environment in the same single distillation column to produce a second overhead distillate composed of purified 2,6-diisopropylphenol.the process is however tedious and not economically viable.
US559131 1 describes the process of purification of 2,6-diisopropylphenol which involves washing the mixture with aqueous alkali metal hydroxide solution in an inert atmosphere and separating the aqueous and organic phases, washing the resulting organic phase with water, and then subjecting the water-washed organic phase to distillation in an inert environment to recover purified diisopropylphenol(DIP). US5589598 describes a process for the purification of 2,6-diisopropylphenol (Propofol) by transformation of the crude propofol into its ester with a carboxylic or sulphonic acid, followed by crystallization and hydrolysis.
Propofol is generally prepared from phenol and propene by Friedel-Crafts-alkylatiOn, whereby in the reaction, besides the desired product, small amounts of other isomers and phenol derivatives are formed thus affecting the purity of the product. The major contaminants being 2,4- and 2,5-diisopropyl phenol, 2,4,6-triisopropyl phenol, and 1 - isppropoxy-2,4-diisopropylbenzene having small differences in their boiling points.
In view of the above drawbacks in the preparation of Propofol there remains a need to develop a process for the preparation of 2,6-diisopropylphenol (Propofol) with high purity suitable for pharmaceutical use and which is simple, economical for large scale manufacturing.
Summary of Invention:
Accordingly, the present invention discloses economical process for preparation of highly pure 2, 6-diisopropylphenol.
In an aspect of the reaction, p-hydroxy benzoic acid is reacted with an alkylating agent in presence of acidic and/or dehydrating medium at 60-65°C followed by basification to obtain 4-hydroxy-3,5-diisopropyI benzoic acid of Formula III.
Besides the desired product, significant amounts of contaminants are also formed such as ether impurit 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 which are removed by simple washings with solvent mixtures.
Purification of 4-hydroxy-3,5-diisopropyl benzoic acid prior to decarboxylation stage inhibit impurities development at Propofol formation. In another aspect, 4-hydroxy-3,5-diisopropyl benzoic acid of Formula III substantially free from impurities of Formula IV, V and VI, is then subjected to decarboxylation in presence of high boiling solvent and alkali metal hydroxide as a catalyst in inert atmosphere, at high temperature to yield 2, 6-diisopropylphenol (Propofol). Formation of major contaminants of Propofol i.e. ether impurity l,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 are avoided.
The Propofol thus formed is further extracted using hydrocarbons solvents like toluene, xylene etc and then washing the organic layer with aqueous sodium bicarbonate and finally with water. The solvent is removed under reduced pressure and the residue is distilled off under high vacuum to give extra pure 2,6-disopropyl phenol free of the impurities described above.
Propofol prepared by the above method is highly pure and overcomes the drawbacks associated with impurity generation thus enabling its use in pharmaceutical compositions.
Accordingly in an aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) of the present invention and a pharmaceutically acceptable excipients(s)/ carrier(s). Further, the pharmaceutical composition of the invention may be a solid form, a liquid suspension or an injectable composition.
Description of Invention:
TheJnvention will now be, described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.
The present invention relates to a process for the preparation of highly pure 2,6- diisopropylphenol of formula I employing alkylation of p-hydroxy benzoic acid to form dialkylated p-hydroxy benzoic acid followed by decarboxylation.
Figure imgf000006_0001
Formula I
In an embodiment, the process of the present invention comprises Friedel Craft's alkylation of p-hydroxybenzoic acid of Formula II in presence of acidic and/or dehydrating substance followed by basification with sodium hydroxide to produce 4- hydroxy-3, 5-diisopropyl benzoic acid of Formula III.
Figure imgf000006_0002
Formula II Formula III
The alkylating agent can be selected from isopropyl alcohol, isopropyl halide, preferably isopropyl alcohol and the acidic and/or dehydrating substance is selected from aqueous mineral acid; preferably 85-95% w/w aqueous sulfuric acid. The reaction is carried out at the temperature in the range of 60-65°C.
Further, . besides the desired product i.e. 4-hydroxy-3, 5-diisopropyl benzoic acid of Formula III, other contaminants are also formed such as ether impurity 3,5-di(propan-2- yl)-4-(propan-2-yloxy)benzoic acid of Formula V(0.2-0.5%), dimer impurity, 4,4'- oxydibenzoic acid of Formula IV(2-10%) and the monoalkylated impurity 4-hydroxy-3- (propan-2-yl) benzoic acid of Formula VI (0.5-1.05%) which are removed by washings with solvent mixture.
The solvent that can be used for washings is selected from water, lower alcohols, hydrocarbons either alone or in combination thereof.
Figure imgf000007_0001
Formula VI Formula VIII
Accordingly, the ether impurity of Formula V is removed by washing of aqueous reaction mass_at basic pH using toluene, while the dimer impurity of Formula IV is removed by repetitive hot water washing , whereas the monoalkylated impurity of Formula VI is ' removed by methanol-water purification. 4-hydroxy-3, 5-diisopropyl benzoic acid of- Formula III thus obtained is 99.85% pure. All the remaining impurities are below 0.05%. It is advantageous to carry out the purification of 4-hydroxy-3, 5-diisopropyl benzoic acid of Formula III prior to decarboxylation stage as it inhibits impurities development at Propofol formationE.g. ether impurity l,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.
The alkylation of p-hydroxybenzoic acid rather than phenol itself in presence of acidic and/or dehydrating agent controls exhaustive alkylation and excessive formation of isomeric byproducts like 2,4 diisopropyl phenol and 2, 4, 6 triisopropyl phenols which are difficult to eliminate completely due to small differences in their boiling points. Further, p-hydroxybenzoic acid being an inexpensive commercially available reagent makes the invention more economic for manufacture of 2,6-diisopropylphenol.
In another embodiment, 4-hydroxy-3, 5-diisopropyl benzoic acid of Formula III, substantially free from impurities mentioned above is subjected to decarboxylation in presence of high boiling solvent and alkali metal hydroxide as a catalyst in an inert atmosphere to yield 2, 6-diisopropylphenol (Propofol). Formation of major contaminants of Propofol i.e. ether impurity l,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 are avoided by using 4-hydroxy-3,5-diisopropyl benzoic acid substantially free from impurities of Formula III, IV and V. High boiling solvent facilitates to attain the desired temperature for decarboxylation. The inert environment in the reaction helps in reducing the impurity level at initial stage.
The Propofol thus formed is further extracted using hydrocarbon solvents like toluene, xylene etc and then washing the organic layer with aqueous sodium bicarbonate and finally with water. After removal of solvent, the residue is distilled off under high vacuum to give extra pure 2,6-diisopropyl phenol having purity of 99.90% and free from ether impurity l,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.
The catalyst used during decarboxylation is selected from alkali metal hydroxide such as sodium or potassium hydroxide. The temperature for the reaction is in the range of 120- 160°C.
The high boiling point solvents used are preferably the solvents having boiling point above 130°C, and are selected from ethylene glycol, dimethylformamide or dimethylacetamide.
Propofol thus prepared by the above process is highly pure, overcomes the drawbacks associated with impurity generation and is suitable for pharmaceutical use.
Accordingly in an embodiment, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) of the present invention and a pharmaceutically acceptable excipients(s)/ carrier(s). Further, the pharmaceutical composition of the invention may be a solid form, a liquid suspension or an injectable composition. The active ingredient(s) and excipient(s)/ carrier(s) can be formulated into compositions and dosage forms according to methods known in the art.
The ^therapeutically effective amount' as described above means and includes the amount required to treat/alleviate the severity of symptoms associated with this ailments as decided by the persons of ordinary skill in the art.
Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Example 1:
360 ml sulphuric acid was added slowly to 25 ml chilled water at 10 - 15°C to a round bottom flask supplied with a mechanical stirrer. To this stirred mass was charged p- hydroxy benzoic acid lOOg (0.72M) lot wise followed by Isopropyl alcohol 130g (2.16M) at a temperature below 15°C. The reaction mass was finally heated to 60 - 65°C for 4 hrs. After reaction completion the reaction mass was quenched in caustic solution and washed two times with toluene (400 ml).The aqueous layer obtained was acidified using aq. HC1 solution. Precipitated solid was washed twice, each time with 250ml of hot water and dried to obtain crude product. Crude solid was dissolved in 350 ml of methanol and treated with activated carbon, filtered and added into 1000ml chilled water at about 10- 15°C. The precipitate was filtered off and washed twice with 200ml of water each time. After drying under vacuum at 70-75°C up to a constant weight, 4-hydroxy-3,5- diisopropyl benzoic acid was obtained.
120g (74.6 %) yield,
M.P. 147°C,
Purity by HPLC 99.85 %. Example 2:
To the solution of 4-hydroxy-3,5-diisopropyl benzoic acid lOOg (0.45 M) (example 1) in ethylene glycol (150 ml) was added sodium hydroxide pallets 41.5g (1.03M) and heated to 140- 145 °C under inert atmosphere. After 7 hrs of continued heating at 140-145°C, the react4on mass was cooled to room temperature and diluted with 5 times water. The pH of the mass was then adjusted to 1-2 using concentrated Hydrochloric acid, reaction mixtiire was stirred for one hour and extracted three times with 200 ml toluene, combined toluene layers were washed twice with 5 % aq. sodium bicarbonate solution (50 ml) and finally with water (200 ml), solvent was removed under reduced pressure and a dark brown colored residue which remained was distilled under high vacuum condition (0.2 mm/Hg) to yield 75g ( 93.5%) of 2,6- diisopropyl phenol collected as a colourless to pale yellow oily liquid, HPLC Purity 99.93 %.
The process as substantially described hereinabove is summarized below:
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)benzolc 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- diis propylbenzoic 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 l ,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.
The invention further relates to pharmaceutical composition comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) prepared by process as claimed in claim 1 along with pharmaceutically acceptable excipients(s)/ carrier(s).

Claims

We Claim,
1. A process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), comprising:
(a) 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) along with impurities such as 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,
i. washing the crude mixture with toluene at basic pH to remove the said ether impurity 3, 5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V; ii. washing with hot water to remove the said dimer impurity 4, 4'- oxydibenzoic acid of Formula IV;
Hi. washing with methanol-water mixture to remove the said monoalkylated impurity 4-hydrbxy-3-(propan-2-yl) benzoic acid of Formula VI, and
(b) decarboxylating the substantially pure 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) of step (a) in presence of high boiling solvent and a catalyst at high temperature to yield 2, 6-diisopropyl phenol free of ether impurity l ,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.
2. The process as claimed in claim 1(a), wherein aq. mineral acid solution is 85-95% w/w aqueous sulfuric acid.
3. The process as claimed in claim 1(b), wherein high boiling solvent is selected from ethylene glycol, dimethylformamide and dimethylacetamide.
4. The process as claimed in claim 1(b), wherein the catalyst is selected from alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The process as claimed in any of the preceding claims, wherein purity of 2, 6- diisopropylphenol produced is above 99.9 % by HPLC.
A pharmaceutical composition comprising a therapeutically effective amount of highly pure 2,6-diisopropyl phenol (Propofol) prepared by process as claimed in claim 1 along with pharmaceutically acceptable excipients(s)/carrier(s).
PCT/IN2010/000527 2010-06-23 2010-08-10 Process for preparing extra pure 2, 6-diisopropyl phenol WO2011161687A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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EP2801563A1 (en) * 2013-05-06 2014-11-12 LANXESS Deutschland GmbH Decarboxylation of 6-methylsalicylic acid
CN106565424A (en) * 2016-11-05 2017-04-19 广东嘉博制药有限公司 Preparation method for high-purity propofol
WO2021191832A1 (en) 2020-03-26 2021-09-30 Fresenius Kabi Oncology Ltd. Process for the preparation of propofol
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Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU170505A1 (en) В. А. Камбулова METHOD FOR PRODUCING ALKYLPHENOLS
US2207753A (en) 1937-06-10 1940-07-16 Clarence H Macomber Di-alkyl phenols
US2831898A (en) 1954-04-29 1958-04-22 Ethyl Corp Phenol alkylation process
US3029276A (en) 1958-06-25 1962-04-10 Bayer Ag Process for the production of 3, 5-disubstituted-4-hydroxy benzoic acids and their esters
US3271314A (en) 1958-12-04 1966-09-06 Ethyl Corp 2, 6-diisopropylphenol
US3367981A (en) 1963-05-10 1968-02-06 Ethyl Corp Phenol alkylation process
GB1318100A (en) 1970-08-08 1973-05-23 Ciba Geigy Uk Ltd Preparation of bisphenols
US3766276A (en) 1970-03-16 1973-10-16 Ethyl Corp Phenol alkylation process
SU443019A1 (en) 1973-01-05 1974-09-15 Предприятие П/Я Г-4740 The method of obtaining 2,6-diisopropylphenol
US4275248A (en) 1979-06-25 1981-06-23 Uop Inc. Preparation of 2,4,6-triisopropylphenol
US4391998A (en) 1981-10-21 1983-07-05 Mobil Oil Corporation Production of para-isopropylphenol
EP0169359A1 (en) 1984-07-05 1986-01-29 Mitsubishi Kasei Corporation Process for producing orthoalkylphenols
US4774368A (en) 1987-05-21 1988-09-27 Ethyl Corporation Process for making meta-alkyl phenols
EP0511947A1 (en) 1991-04-30 1992-11-04 Leiras Oy Process for the purification of 2,6-diisopropyl phenol
US5264085A (en) 1991-08-28 1993-11-23 Mitsubishi Petrochemical Company, Ltd. Method of separating components of phenols mixture by distillation
US5589598A (en) 1994-09-28 1996-12-31 Zambon Group S.P.A. Process of purification of 2,6-diisopropylphenol
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
US5705039A (en) 1995-10-13 1998-01-06 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
CN1197055A (en) 1998-05-13 1998-10-28 临湘市氨基化学品厂 2,6-isopropyl-phenol preparing method
WO2000034218A1 (en) 1998-12-04 2000-06-15 Dong Kook Pharmaceutical Co., Ltd. Process for purification of 2,6-diisopropyl phenol
WO2001087289A2 (en) * 2000-05-19 2001-11-22 Astrazeneca Ab Propofol for treatment of sepsis
US6362234B1 (en) 2000-08-15 2002-03-26 Vyrex Corporation Water-soluble prodrugs of propofol for treatment of migrane
WO2005033279A2 (en) 2003-09-29 2005-04-14 University Of Virginia Patent Foundation Discovery of novel soluble crystalline anesthetics

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2389065A (en) 1941-09-24 1945-11-13 Hoffmann La Roche Process for the manufacture of nicotinic acid
US2459597A (en) 1945-05-16 1949-01-18 Gulf Research Development Co Di-alkylated mono-hydroxy phenol
US4474368A (en) 1982-12-17 1984-10-02 Burroughs Corporation Oscillating finger sheet item detac apparatus
US5395752A (en) 1993-03-19 1995-03-07 Ciba Corning Diagnostics Corp. Long emission wavelength chemiluminescent compounds and their use in test assays
US5323812A (en) * 1993-10-05 1994-06-28 Snap-Tite, Inc. Pressure-locked coupling

Patent Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU170505A1 (en) В. А. Камбулова METHOD FOR PRODUCING ALKYLPHENOLS
US2207753A (en) 1937-06-10 1940-07-16 Clarence H Macomber Di-alkyl phenols
US2831898A (en) 1954-04-29 1958-04-22 Ethyl Corp Phenol alkylation process
US3029276A (en) 1958-06-25 1962-04-10 Bayer Ag Process for the production of 3, 5-disubstituted-4-hydroxy benzoic acids and their esters
US3271314A (en) 1958-12-04 1966-09-06 Ethyl Corp 2, 6-diisopropylphenol
US3367981A (en) 1963-05-10 1968-02-06 Ethyl Corp Phenol alkylation process
US3766276A (en) 1970-03-16 1973-10-16 Ethyl Corp Phenol alkylation process
GB1318100A (en) 1970-08-08 1973-05-23 Ciba Geigy Uk Ltd Preparation of bisphenols
SU443019A1 (en) 1973-01-05 1974-09-15 Предприятие П/Я Г-4740 The method of obtaining 2,6-diisopropylphenol
US4275248A (en) 1979-06-25 1981-06-23 Uop Inc. Preparation of 2,4,6-triisopropylphenol
US4391998A (en) 1981-10-21 1983-07-05 Mobil Oil Corporation Production of para-isopropylphenol
EP0169359A1 (en) 1984-07-05 1986-01-29 Mitsubishi Kasei Corporation Process for producing orthoalkylphenols
US4774368A (en) 1987-05-21 1988-09-27 Ethyl Corporation Process for making meta-alkyl phenols
EP0511947A1 (en) 1991-04-30 1992-11-04 Leiras Oy Process for the purification of 2,6-diisopropyl phenol
US5264085A (en) 1991-08-28 1993-11-23 Mitsubishi Petrochemical Company, Ltd. Method of separating components of phenols mixture by distillation
US5696300A (en) 1994-07-01 1997-12-09 Archimica Spa Propofol purification
US5589598A (en) 1994-09-28 1996-12-31 Zambon Group S.P.A. Process of purification of 2,6-diisopropylphenol
US5705039A (en) 1995-10-13 1998-01-06 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
US5591311A (en) 1995-10-26 1997-01-07 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
CN1197055A (en) 1998-05-13 1998-10-28 临湘市氨基化学品厂 2,6-isopropyl-phenol preparing method
WO2000034218A1 (en) 1998-12-04 2000-06-15 Dong Kook Pharmaceutical Co., Ltd. Process for purification of 2,6-diisopropyl phenol
WO2001087289A2 (en) * 2000-05-19 2001-11-22 Astrazeneca Ab Propofol for treatment of sepsis
US6362234B1 (en) 2000-08-15 2002-03-26 Vyrex Corporation Water-soluble prodrugs of propofol for treatment of migrane
WO2005033279A2 (en) 2003-09-29 2005-04-14 University Of Virginia Patent Foundation Discovery of novel soluble crystalline anesthetics

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731265A (en) * 2012-06-12 2012-10-17 四川百利药业有限责任公司 Preparation method of high-purity propofol
EP2801563A1 (en) * 2013-05-06 2014-11-12 LANXESS Deutschland GmbH Decarboxylation of 6-methylsalicylic acid
WO2014180834A1 (en) * 2013-05-06 2014-11-13 Lanxess Deutschland Gmbh Decarboxylation of 6-methylsalicylic acid
CN106565424A (en) * 2016-11-05 2017-04-19 广东嘉博制药有限公司 Preparation method for high-purity propofol
CN106565424B (en) * 2016-11-05 2020-05-19 广东嘉博制药有限公司 Preparation method of high-purity propofol
WO2021191832A1 (en) 2020-03-26 2021-09-30 Fresenius Kabi Oncology Ltd. Process for the preparation of propofol
WO2023111488A1 (en) 2021-12-17 2023-06-22 Pcas Process for producing propofol
FR3130797A1 (en) 2021-12-17 2023-06-23 Pcas METHOD FOR THE PREPARATION OF PROPOFOL
RU2822829C2 (en) * 2022-07-14 2024-07-15 Алексей Георгиевич Александров Method of producing propofol active pharmaceutical substance

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US8664452B2 (en) 2014-03-04

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