Description:DESCRIPTION

FIELD OF INVENTION
The present invention relates to an environmentally sustainable process for the preparation of highly pure 2,6-diisopropyl phenol (Propofol) utilizing a reusable catalyst, which minimizes pollution and waste generation.

BACKGROUND OF THE INVENTION
2,6-Diisopropylphenol, commonly known as Propofol, is a short-acting, intravenously administered anesthetic agent widely used for general anesthesia and sedation. Given its intravenous application, exceptionally high purity (≥99.9%) is required. However, existing processes for synthesizing and purifying 2,6-diisopropylphenol are often resource-intensive, generate significant harmful waste, and have a high environmental impact due to the use of non-recoverable catalysts and harmful solvents.

USSR Patent application SU443019A1 describe a process of reacting p-hydroxybenzoic acid with Isopropyl alcohol in presence of Sulfuric acid to get technical grade 3,5-Disiopropyl-4-hydroxybenzoic acid which is then reacted with Triethylamine followed by high vacuum distillation to get 99.6% pure 2,6-Diisopropylphenol as depicted in Scheme-1.
This patent uses excess Triethyl amine for decarboxylation step which is toxic and is an irritant. Likewise, it is a volatile organic compound (VOC) and can contribute to air pollution rendering a negative impact on environment. The process also does not meet the purity required by pharmacopoeia. In this process the isolated intermediate is having less Purity.

Scheme-1
U.S. Pat. No. 8,664,452 describes a process of preparing propofol by reacting p-hydroxybenzoic acid with Isopropyl alcohol in presence of Sulfuric acid to provide crude 3,5-Disiopropyl-4-hydroxybenzoic acid which is quenched in aqueous caustic solution and washed with toluene to obtain a pure product which is then reacted with Sodium Hydroxide in Ethylene Glycol followed by high vacuum distillation to get 99.93% pure 2,6-Diisopropylphenol as depicted in US 8664452 as depicted in Scheme-2. The patent necessitates a large quantity of caustic soda, leading to increased effluent generation. Furthermore, the process employs toluene for extraction, adding to solvent load and environmental impact. Still, further, the necessity for an inert atmosphere and multiple washing and distillation steps may increase operational complexity and costs as Reaction mass is quenched in Caustic solution to neutralize the Sulfuric acid used in the reaction requires a lot of volume of water and due to exothermicity, lot of cooling is required leading to increase in volume of reaction mass.
Scheme-2
Russian Patent No. 2822829C2 discloses a process of reacting p-hydroxybenzoic acid with Isopropyl alcohol in presence of Sulfuric acid to get technical grade 3,5-Disiopropyl-4-hydroxybenzoic acid which is then reacted with Sodium Hydroxide in Ethylene Glycol followed by high vacuum distillation to get pure propofol as shown in Scheme-3. While the patent presents an improved process for propofol purification, it involves multiple steps, including solvent handling, alkaline treatments, and steam distillation, which may increase operational complexity and require specialized equipment. Further, the use of solvents and alkali solutions necessitates proper waste management to mitigate environmental impact.

Scheme-3
European Patent EP0511947 discloses a method for 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. While the process improves purity and is highly effective for achieving pharmaceutical-grade propofol, there are several drawbacks. The purification process relies heavily on maintaining precise temperatures between -25°C and +18°C. Achieving and maintaining these low temperatures can be energy-intensive, requiring specialized equipment such as cooling systems, which could increase operational costs. In the examples provided, the yield of purified propofol is 60% from the raw material. Although the purity is very high (>99.9%), the relatively low yield could be a concern for large-scale manufacturing, as it means a substantial amount of the raw material is not recovered as usable product. In Example 2, the process uses non-polar aliphatic solvents (e.g., hexane or petrol ether) for dissolving the raw propofol and washing the crystals. These solvents are volatile and can pose environmental and safety hazards if not handled properly. Additionally, the need to remove solvent residues adds extra steps to the process, increasing the time, complexity, and cost. The crystallization process at temperatures as low as -20°C requires significant cooling energy, which can make the process more energy-intensive, especially when scaling up to industrial levels. While the process is effective on a small scale (as demonstrated in the examples), scaling it up may present challenges. For example, achieving the same level of cooling, uniformity in crystallization, and solvent recovery on a larger scale might require significant modifications to the process or equipment. The process involves the reaction of Phenol with Propene gas in one of the steps, which is not well suited for use in a large-scale commercial operation and requires dedicated equipment.
U.S. Pat. No. 5,591,311 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). The drawback of the process is it involves multiple steps, such as washing the impure DIP mixture with aqueous alkali or alkaline earth metal hydroxide, followed by water washes and distillation. Maintaining an inert atmosphere during both the washing and distillation steps adds operational complexity and additional cost due to the need for nitrogen or another inert gas. The washing steps require temperatures ranging from 50°C to 100°C. This introduces a potential risk of thermal degradation or the formation of undesired by-products if the temperature is not carefully controlled. The final purification of the organic phase involves distillation in an inert atmosphere, which requires high capital investment in distillation equipment.
U.S. Pat. No. 5,589,598 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. This patent adds an additional step to convert propofol to ester and then purify and convert it back to Propofol, which increases the step and, therefore, cost. The process involves a significant number of organic solvents (e.g., methylene chloride, isopropanol, methanol, sec-butanol, dimethylsulfoxide), handling and disposal of which raise environmental and safety concerns, as many of them are hazardous and require proper disposal or recovery methods. This makes the process less environmentally friendly and could increase operational costs due to solvent management. The process results in a lower yield of propofol, which does not make the process commercially viable. After multiple steps, large quantities of solvents are involved, especially in the crystallization and washing steps. This means that significant investment in solvent recovery systems would be required for a sustainable and cost-effective process. Without efficient recovery, the process could generate a considerable amount of solvent waste, adding both environmental and financial burdens. Moreover, handling by-products and achieving high yields from low-purity starting material are challenges that may impact the feasibility of scaling the process for industrial use.
To address these issues, there is a need for a more sustainable and economically viable process that meets the stringent purity requirements for pharmaceutical-grade Propofol while minimizing environmental impact.

SUMMARY OF THE INVENTION
A first aspect of the present invention relates to an environmentally friendly process for the preparation of substantially pure and high-yielding propofol comprising alkylating p-hydroxy benzoic acid with isopropyl alcohol in the presence of an acid to obtain crude 4-hydroxy-3,5 di-isopropyl benzoic acid, which is followed by purification of crude 4-hydroxy-3,5 di-isopropyl benzoic acid to obtain purified 4-hydroxy-3,5 di-isopropyl benzoic acid. The purified 4-hydroxy-3,5 di-isopropyl benzoic acid is decarboxylated in C1-C5 alcoholic solvent, with a recoverable and reusable catalyst recovered in at least 95% yield, to obtain crude propofol. The decarboxylation step is carried out in the absence of sodium hydroxide. The final step involves the purification of crude propofol to obtain substantially pure and high-yielding propofol.

DETAILED DESCRIPTION OF THE INVENTION

This present invention relates to an environmentally friendly process for the preparation of substantially pure and high-yielding propofol through the alkylation of p-hydroxybenzoic acid to form 3,5-diisopropyl-4-hydroxybenzoic acid, followed by decarboxylation. The process employs hydrotalcite, a layered double hydroxide, as a reusable catalyst during the decarboxylation step, significantly reducing catalyst waste and associated environmental hazards.
In one embodiment, p-hydroxybenzoic acid is alkylated with an isopropylating agent in the presence of sulfuric acid, an acidic medium, at a controlled temperature range (60–65°C) to produce a technical-grade intermediate. This intermediate is subsequently purified and subjected to decarboxylation with hydrotalcite at 170–180°C, resulting in high-purity Propofol.
The hydrotalcite catalyst used here is recoverable and reusable, enhancing process sustainability. Additionally, the reaction employs high-boiling-point, environmentally friendly solvents such as ethylene glycol, further contributing to the process's green profile. After synthesis, Propofol is purified through solvent extraction and fractional distillation, yielding a highly pure product suitable for pharmaceutical applications.
The alkylation of p-hydroxy benzoic acid to obtain 4-hydroxy-3,5 di-isopropyl benzoic acid may be carried out with a suitable alkylating agent. Suitable alkylating agent may be selected from Isopropyl alcohol, Isopropyl chloride, Isopropyl bromide, Isopropyl tosylate, Isopropyl acetate. It is preferable to use an alkylating agent such as isopropyl alcohol in the present process.
The alkylation of p-hydroxy benzoic acid to obtain substantially pure 4-hydroxy-3,5 di-isopropyl benzoic acid may be carried out in the presence of a suitable acid. Suitable acid may be selected from Sulphuric acid, Hydrochloric Acid, Phosphoric Acid, Tetrafluoroboric Acid, Methanesulfonic Acid, Trifluoromethanesulfonic Acid, Acetic Acid, Benzenesulfonic Acid, p-Toluenesulfonic Acid, Boric Acid, Citric Acid, Formic Acid, Chlorosulfonic Acid, Hydrofluoric Acid. It is preferable to use an acid such as Sulphuric acid in the present process.
The addition of sulfuric acid to water for the said alkylation reaction may be carried out at a temperature between 5 to 20°C, more preferably between 10 to 20°C, most preferably between 10 to 15°C.

The said alkylation reaction may be carried out at a temperature between 50 to 80°C, more preferably between 60 to 70°C, most preferably between 60 to 65°C.
The said alkylation reaction may be heated for a period between 2 to 5 hours, more preferably 2 to 4 hours, most preferably between 3 to 4 hours.
The crude solid 4-hydroxy-3,5di-isopropyl benzoic acid may be subjected to purification by charcoalisation with activated charcoal, celite to remove impurities. It is preferable to use activated charcoal for purification of 4-hydroxy-3,5 di-isopropyl benzoic acid.
The substantially pure 4-hydroxy-3,5di-isopropyl benzoic acid is free from the dimer, ether, and monoalkylated impurities ensuring a purer intermediate and minimizing downstream purification requirements.
The substantially pure 4-hydroxy-3,5di-isopropyl benzoic acid is at least 99.5% pure. More preferably it is at least 99.7% pure and most preferably it is at least 99.9% pure.
The decarboxylation of 4-hydroxy-3,5di-isopropyl benzoic acid to obtain crude propofol may be carried out in ethylene glycol.
The decarboxylation of 4-hydroxy-3,5di-isopropyl benzoic acid to obtain crude propofol may be carried in presence of a recoverable and reusable layered double hydroxide catalyst such as hydrotalcite, zeolites such as ZSM-5, Mordenite. It is preferable to use hydrotalcite as a catalyst to obtain propofol.
The decarboxylation of 4-hydroxy-3,5di-isopropyl benzoic acid to obtain crude propofol may be carried out at a temperature between 150 to 180°C, more preferably between 155 to 175°C, most preferably between 160 to 170°C.
The decarboxylation of 4-hydroxy-3,5di-isopropyl benzoic acid to obtain crude propofol may be carried out for a period between 6 to 10 hours, more preferably 7 to 9 hours, most preferably between 7 to 8 hours.
The crude propofol may be purified using solvent extraction followed by fractional distillation. The solvents for solvent extraction of crude propofol may be selected from toluene, Cyclohexane it is preferable to use toluene as the solvent. The fractional distillation may be carried out under high vacuum conditions (5mm/Hg) at a temperature of between 108 to 115 °C.

The two step process is as depicted in Scheme-4

Scheme – 4
Example – 1 – Preparation of 4-hydroxy-3,5 di-isopropyl benzoic acid
A solution of 648 gm of sulfuric acid was added slowly to 25 mL chilled water (10-15°C) in a round bottom flask equipped with a mechanical stirrer. To this mixture, 100 gm of p-hydroxybenzoic acid (0.72 M) was charged gradually, followed by the addition of 100 gm of isopropyl alcohol (1.66 M) at temperatures below 20°C. The reaction mixture was then heated to 60-65°C and maintained for 3-4 hours. Upon completion, the mixture was cooled to room temperature and quenched with water. The resulting solid was filtered, washed with 1 litre of water twice, and dried to obtain a crude product. The crude solid was dissolved in a mixture of 500 mL of water and 60 gm of sodium hydroxide (NaOH). The solution was treated with activated carbon and stirred for 30 minutes. The mixture was filtered through Hyflobed, and the filtrate was precipitated by the addition of hydrochloric acid (HCl). The precipitate was washed with 3 litres of water and dried to give the crude 4-hydroxy-3,5 di-isopropyl benzoic acid. The 4-hydroxy-3,5 di-isopropyl benzoic acid was dried at 90-100◦C till a constant weight was obtained 125gm (78.1%)
Melting Point - 146◦C
Purity by HPLC - 99.80%

Example 1a - Preparation of 4-hydroxy-3,5 di-isopropyl benzoic acid
360 ml of sulfuric acid was slowly added to chilled water at 10-15°C in a round-bottom flask equipped with a mechanical stirrer. To this stirred mixture, 100 g of p-hydroxybenzoic acid was added in portions, followed by 100 g of isopropyl alcohol, keeping the temperature below 20°C. The reaction mixture was then heated to 60-65°C for 3-4 hours. After completion, the reaction mixture was cooled to room temperature and then quenched in water at room temperature. The precipitated solid was cooled and filtered, then washed twice with water and dried to obtain the crude product. The crude solid was dissolved in aqueous NaOH and treated with activated carbon. It was stirred for 30 minutes and then filtered through Hyflobed. The filtrate was precipitated by adding aqueous HCl solution. The precipitated solid was washed with water and dried to obtain the crude product. The crude product was dissolved in acetone and treated with activated carbon. It was stirred for 30 minutes and filtered through Hyflobed, then precipitated by adding aqueous HCl solution.
After drying HAO 90-100◦C up to a constant wt 4-hydroxy-3,5 di-isopropyl benzoic acid was obtained 125gm (78.1%)
Melting Point - 144◦C
Purity by HPLC – 99.93%

Example 2 – Preparation of Propofol using hydrotalcite catalyst
To the solution of 4-hydroxy-3,5-di-isopropyl benzoic acid, 100 gm (0.45M) (example 1) in ethylene glycol (200ml) was added Hydrotalcite (15gm) and heated slowly 160-170◦C. Under atmosphere after 8-9 hrs of continued heating at 160-170◦C. Check the TLC. The RM was cooled at room temperature and diluted with 5 times water. The reaction mass is filtered to recover Hydrotalcite. The reaction mixture was then extracted two times 250ml toluene. The combined toluene layer was washed with water (200ml). The separated toluene layer was distilled under a vacuum to obtain dark brown coloured Crude Propofol, which was fractionally distilled under high vacuum conditions (5mm/Hg) to yield 76gm (95%) of 2,6-di-isopropyl phenol collected as a colourless liquid.
Boiling Point - 254◦C
Purity by HPLC - 99.94%

Example 2a: Preparation of Propofol using hydrotalcite catalyst
To a solution of 100 g of 4-hydroxy-3,5-di-isopropylbenzoic acid (Example 1) in 200 ml of ethylene glycol, 15 g of Hydrotalcite was added, and the mixture was heated slowly to 160-170°C under an inert atmosphere. After 8 hours of continuous heating at 160-170°C, TLC was checked. The reaction mixture was then cooled to room temperature and diluted with five times the volume of water. The pH of the mixture was adjusted to 1-2 using concentrated hydrochloric acid. The reaction mixture was stirred for one hour and then extracted twice with cyclohexane. The combined cyclohexane layers were washed with caustic lye solution. The aqueous layer was transferred to another round-bottom flask, and caustic lye (NaOH + H2O) was added. The mixture was filtered, and the catalyst was recovered. The yield of recovered Hydrotalcite was 95%, and it was reusable. The cyclohexane layer was subjected to distillation to obtain a dark brown-colored crude product, which was distilled under high vacuum (5 mm Hg) through a packed column, yielding 76 g (95%) of 2,6-di-isopropylphenol as a colorless liquid.
Boiling Point - 254◦C
Purity by HPLC – 99.94%

Example – 2c - Preparation of Propofol using Hydrotalcite catalyst
To a solution of 100 g (0.45M) of 4-hydroxy-3,5-di-isopropylbenzoic acid (Example 1) in 200 ml of ethylene glycol, 15 g of Hydrotalcite was added, and the mixture was heated slowly to 160-170°C under an inert atmosphere. After 8-9 hours of continuous heating at 160-170°C, TLC was checked. The reaction mixture was then cooled to room temperature and diluted with five times the volume of water. The pH of the reaction mass was adjusted to 1-2 using dilute HCl. The reaction mixture was then extracted twice with 250 ml of toluene. The obtained aqueous layer was then neutralized with sodium hydroxide to precipitate Hydrotalcite, which, after drying, could be reused in the next experiment. The combined toluene layers were washed with 200 ml of water. The separated toluene layer was distilled under vacuum to obtain a dark brown-colored crude product, which was then fractionally distilled under high vacuum conditions (5 mm Hg) to yield 76 g (95%) of 2,6-di-isopropylphenol as a colorless liquid.
Boiling Point - 254◦C
Purity by HPLC - 99.90%

Example 2d - Preparation of Propofol using imidazole catalyst
To the solution of 4-hydroxy-3,5-di-isopropyl benzoic acid (example 1) in ethylene glycol was added Imidazole and heated slowly 150-160◦C. Under atmosphere after 8-9 hrs of continue heating at 150-160◦C. Check the TLC the RM was cooled at room temperature and dilute with 5 times water. The pH of mass was the adjust 1-2 using concentrated hydrochloric acid. Reaction mixture was stirred for one hour and extract two-time toluene. Combined toluene layer was washed with caustic lye solution. Toluene layer solvent was removed under reduced pressure and a dark brown coloured residue which remained was distilled under high vacuum condition (5mm/Hg) to yield 76gm (95%) of 2,6-di-isopropyl phenol collected as a colourless liquid.
Purity by HPLC – 99.94%
Boiling Point - 254◦C , Purity by HPLC – 99.93%
Table-1: Different proportions of use of catalyst in Step-2 of the process
Catalyst and its Qty. Batch size Observation Catalyst recovery
Hydrotalcite :- 4 gm 100 gm Reaction time:-12hrs Recovered
Hydrotalcite:- 7.5 gm 100 gm Reaction Time:-10 hrs Recovered
Hydrotalcite :-20 gm 100 gm Reaction Time:-6 hrs Recovered
Imidazole + Hydrotalcite:-2 gm+ 2 gm 100 gm Reaction Time:-5 hrs Recovery of catalyst is not possible
Imidazole :- 10 gm 100 gm Reaction Time:- 4 hrs Recovered

Table-2: List of impurities as per European Pharmacopeia (EP) HPLC method in purified Propofol
S. No. HPLC Impurities Relative retention time (as per pharmacopeia) Limit Peak % area
1. A-2,4-bis(1-methylethyl) phenol 3.0 0.1% -
2. B-(1-methylethyl)-6 (methylethyl)phenol 0.7 0.1% -
3. C-2-(1-methylethyl) phenol 3.4 0.1% -
4. D-2,5-diisopropyl phenol 2.5 0.1% -
5. E-3,3,5,5-tetrakis (1methyl ethyl) biphenyl-4,4-diol 4.0 0.01% -
6. F-3-(1-methylethyl) phenol 5.8 0.1% -
7. G-2-(1-methylethoxy)-1,3-bis(1-methylethyl) benzene 0.5 0.2% 0.03%
8. H-4-(1-methylethyl) phenol 6.4 0.1% -
9. I-oxydibenzene 0.6 0.05% 0.03%
10. P-1-methylethyl-4-hydroxy -3,5-bis(1-methylethyl) benzoate 2.9 0.1% -
11. N-4-hydroxy-3,5-bis (1methylethyl) benzoic acid 2.3 0.1% -
12. Unknown impurity - 0.05% 0.03%

Table-3: List of impurities as per EP GC method in purified Propofol
S. No. GC Impurities Relative retention time (as per pharmacopeia) Limit Peak % area
1 J- 2,6-bis(1-methylethyl)benzene-1,4-dione 1.01 0.05% BDL
2 K-1-(1-methylethoxy)-2-(1-methylethyl)benzene 0.76 0.05% BDL
3 L-2,2-dimethyl-4-(1-methylethyl)-1,3-benzodioxole 0.81 0.05% BDL
4 O-2-(1-methylethyl)-6-propylphenol 1.03 0.05% BDL
5 Total Unknown Impurities -- 0.10% 0.03%

, Claims:We Claim
1. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol, comprising the steps of:
a. Alkylation of p-hydroxy benzoic acid with an alkylating agent in the presence of an acid to obtain crude 4-hydroxy-3,5 di-isopropyl benzoic acid;
b. Purification of crude 4-hydroxy-3,5 di-isopropyl benzoic acid to obtain substantially pure 4-hydroxy-3,5 di-isopropyl benzoic acid;
c. Decarboxylation of purified 4-hydroxy-3,5 di-isopropyl benzoic acid in C1-C5 alcoholic solvent, with a recoverable and reusable catalyst, to obtain crude propofol; and
d. Purification of crude propofol to obtain substantially pure and high yielding propofol.
2. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the alkylating agent of step(a) is selected from Isopropyl alcohol, Isopropyl chloride, Isopropyl bromide, Isopropyl tosylate and Isopropyl acetate.
3. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the acid is selected from Sulphuric acid, Hydrochloric Acid, Phosphoric Acid, Tetrafluoroboric Acid, Methanesulfonic Acid, Trifluoromethanesulfonic Acid, Acetic Acid, Benzenesulfonic Acid, p-Toluenesulfonic Acid, Boric Acid, Citric Acid, Formic Acid, Chlorosulfonic Acid, Hydrofluoric Acid.
4. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the purification of step (b) is carried out using activated charcoal or celite.
5. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the substantially pure 4-hydroxy-3,5 di-isopropyl benzoic acid obtained is free from dimer, ether, and monoalkylated impurities.
6. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the recoverable and reusable catalyst used in decarboxylation step (c) is selected from hydrotalcite, imidazole, ZSM-5, Mordenite or a combination thereof.
7. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the yield of recovery of the recoverable and reusable catalyst used in decarboxylation step (c) is atleast 95%.
8. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the decarboxylation step (c) of purified 4-hydroxy-3,5 di-isopropyl benzoic acid is carried out in the absence of sodium hydroxide.
9. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the catalyst of step (c) is recovered by filtration of reaction mass obtained after completion of the decarboxylation step.
10. An environmentally friendly process for the preparation of substantially pure and high-yielding propofol as claimed in claim 1, wherein the catalyst of step (c) is recovered by filtration of acidified reaction mass neutralized with a base after completion of the decarboxylation step.