PROCEDURE FOR PREPARING PROPOFOL

Abstract

This disclosure relates to a process for preparing 2,6-diisopropyl phenol. The process includes a step of decarboxylating 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts in an aqueous medium under pressure.

Description

Title of the invention: METHOD FOR PREPARING PROPOFOL FIELD OF INVENTION

[0001] The invention relates to a method for preparing propofol. STATE OF THE ART

[0002] Propofol is a rapid-acting, short-acting general anesthetic. It was developed in the 1970s by Glenn. It is administered intravenously. Therefore, for its pharmaceutical use, its degree of purity must be very high (typically > 99.7%). Numerous methods for preparing and purifying this compound have been proposed.

[0003] For example, it can be prepared from phenol and propene by Friedel-Crafts alkylation. However, the yields are not high, and the operating conditions involve high pressures and high temperatures. Moreover, this synthetic route leads to numerous impurities, particularly due to the reactivity of phenol not only at ortho positions on the hydroxyl group, but also at para positions on the hydroxyl group and on the hydroxyl group itself. These impurities have similar boiling points and are therefore difficult to remove.

[0004] To overcome this lack of selectivity during alkylation, it has been proposed to prepare propofol by alkylation of a phenol substituted with a para group followed by removal of the para group from the phenol. The starting substrate can be 4-chlorophenol or 4-hydroxybenzoic acid. In particular, in the latter case, in a first step the acid 4-Hydroxybenzoic acid is alkylated at positions 3 and 5 to obtain 4-hydroxy-3,5-diisopropylbenzoic acid, which is then decarboxylated in the second step. This synthetic route is described in particular in patent SU443019, in the patent applications WO 2011 / 161687, WO 2013 / 035103, IN1420 / MUM / 2012, CN106588576 and WO 2021 / 191832 or in the article by Pramanik et al., “Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances” Org. Process Res. Dev. 2014,18, 152-156 or the article by Mougeot et al., “Continuous flow synthesis of propofol” Molécules 2021, 26, 7183.

[0005] In SU443019, alkylation takes place in the presence of sulfuric acid, water, and isopropyl alcohol. 4-Hydroxy-3,5-Diisopropylbenzoic acid is isolated by precipitation in the reaction medium and rinsing with water. Decarboxylation takes place in the sorted thylamine to 120-140°C for 1 hour. This process leaves behind many impurities that are difficult to remove.

[0006] In WO 2011 / 161687, the number of impurities is reduced by purifying the intermediate product, 4-hydroxy-3,5-diisopropylbenzoic acid, by acid-base washing, washing with water or a water / methanol mixture, and / or recrystallization in a water / methanol mixture. The second decarboxylation step takes place in the presence of alkali metal hydroxide in a high-boiling-point solvent at high temperature (140-145°C). The high-boiling-point solvent may be ethylene glycol, dimethylformamide, or dimethylacetamide.

[0007] In WO 2013 / 035103, Friedel-Crafts alkylation takes place in the presence of an acid followed by acid-base washing, precipitation in acidic medium, washing with water and recrystallization in a methanol / water mixture to obtain 4-hydroxy-3,5-diisopropylbenzoic acid. Decarboxylation takes place in the presence of a catalyst in a high boiling point organic solvent at high temperature (140-145°C).

[0008] In IN1420 / MUM / 2012 and the article by Pramanik et al., 4-Hydroxybenzoic acid is alkylated in the presence of acid. 4-Hydroxy-3,5-Diisopropylbenzoic acid is extracted in toluene, precipitated in an alcohol / water mixture, and rinsed with a nonpolar solvent. The decarboxylation step takes place in 2-ethoxyethanol in the presence of alkali metal hydroxide at a temperature between 120 and 160°C.

[0009] In CN106588576, the Friedel-Crafts alkylation takes place in the presence of a solid acid under ultrasound and without solvent. 4-Hydroxy-3,5-Diisopropylbenzoic acid is obtained by filtration and precipitation. The decarboxylation step is catalyzed by an enzyme in a buffered aqueous medium for 1 to 6 days.

[0010] In WO2021 / 191832, 4-hydroxybenzoic acid is alkylated in the presence of acid according to the article by Pramanik et al. to obtain 4-hydroxy-3,5-diisopropylbenzoic acid. The latter is carboxylated in the presence of a heterocyclic base, in particular imidazole, and with or without solvent. This process also leads to the production of numerous organic waste products.

[0011] In the article by Mougeot et al., the alkylation and decarboxylation steps each take place in continuous flow. The Friedel-Crafts alkylation is carried out in the presence of acid and isopropanol. The decarboxylation takes place in the presence of an organic base in various organic solvents, in particular 2-butoxyethanol.

[0012] The processes described require multiple steps of isolation and purification of the intermediate and the product, long reaction times or the use of flammable solvents.

[0013] Thus, a need remains for the provision of an efficient, simple process, more environmentally friendly and economically competitive for preparing propofol on an industrial scale.

[0014] SUMMARY

[0015] The invention relates to a process for preparing 2,6-diisopropyl phenol comprising a step of decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts in an aqueous medium under pressure.

[0016] Other aspects of the invention are as described below and in the claims. DETAILED DESCRIPTION

[0017] The inventors have developed a process that meets the stated requirements. The process for preparing 2,6-diisopropylphenol or 2,6-bis(propan-2-yl)phenol, commonly referred to as propofol, proposed by the inventors includes a step of decarboxylation of the acid 4-Hydroxy-3,5-diisopropylbenzoic acid (also known as 4-hydroxy-3,5-di(propan-2-yl)benzoic acid) or one of its salts in an aqueous medium under pressure.

[0018] Propofol is thus manufactured by limiting the use of toxic solvents (such as 2-ethoxyethanol, ethylene glycol, dimethylformamide or dimethylacetamide) or the use of toxic organic bases (such as triethylamine or imidazole) and by reducing the emission of organic and / or toxic waste.

[0019] According to the proposed process, it is also not necessary to evaporate toxic high-boiling-point organic solvents generally used in known prior art processes during the decarboxylation step.

[0020] Furthermore, the isolation and purification of propofol are simplified. Indeed, at the end of the decarboxylation step, the propofol is separated directly by decantation from the aqueous reaction medium followed by distillation. Extraction is not necessary.

[0021] The reaction time of the decarboxylation step is reduced, in particular when the reaction takes place in continuous flow.

[0022] Furthermore, in continuous flow, propofol is obtained with a degree of purity of up to 98% even before purification. The degrees of purity presented here are determined by high-performance liquid chromatography (HPLC) according to a method of the European Pharmacopoeia.

[0023] Decarboxylation of 4-hydroxy-3,5-diisovirovylbenzoic acid or one of its salts

[0024] The decarboxylation step of 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts takes place in an aqueous medium under pressure.

[0025] The term “under pressure” refers to a pressure greater than atmospheric pressure. normal spherical, i.e. greater than 0.1MPa.

[0026] The 4-hydroxy-3,5-diisopropylbenzoic acid useful in the process of the present invention may be in the form of salts, such as a monosalt or a disalt. Examples of salts include, but are not limited to, salts of alkali metals (e.g., lithium, sodium, potassium, and cesium salts), salts of alkaline earth metals (e.g., calcium, barium, strontium, and magnesium salts), or ammonium salts derived from ammonia or a primary, secondary, or tertiary organic amine having from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, and piperidine. The 4-hydroxy-3,5-diisopropylbenzoic acid salt is preferably a monosalt or disalt of alkali metals.Thus, in certain embodiments, the 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts useful in the process of the present invention is 4-hydroxy-3,5-diisopropylbenzoic acid or a mono-salt or di-salt of alkali metals.

[0027] The aqueous medium typically consists exclusively of water. However, small amounts of organic solvent may be present in the aqueous medium. Thus, in some embodiments, the aqueous medium may comprise, in addition to water, up to 10% by volume of organic solvent, in particular up to 5% by volume of organic solvent.

[0028] The reaction can take place in the presence of a base, preferably a mineral one.

[0029] In particular, the base may be a hydroxide, a carbonate, an alkoxide or the Tripotassium phosphate. It may be a hydroxide, carbonate, or alkoxide of alkali metals or alkaline earth metals. Preferably, the base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal alkoxide, or tripotassium phosphate (K3PO4). Even more preferably, the base is an alkali metal hydroxide.

[0030] More particularly, the base is LiOH, NaOH, KOH, tBuOK or K3PO4, preferably sodium hydroxide.

[0031] The amount of base typically varies from 0.1 to 3 molar equivalents relative to the amount of 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts, preferably from 0.5 to 2.5 equivalents, more preferably from 1.0 to 2.5 equivalents.

[0032] Typically, the decarboxylation step is carried out in the absence of enzyme.

[0033] In particular, the decarboxylation step is carried out in less than 18 hours, plus particularly between 5 minutes and 6 PM.

[0034] The decarboxylation step can take place in batch or in continuous flow.

[0035] It can therefore be implemented in an autoclave.

[0036] When the decarboxylation step takes place in a batch, preferably, the pressure of the medium The reaction pressure of the decarboxylation step varies from 0.2 MPa to 1.2 MPa, preferably from 0.25 MPa to 1.0 MPa. Thus, the decarboxylation step is preferably carried out at a pressure varying from 0.2 MPa to 1.2 MPa, preferably from 0.25 MPa to 1.0 MPa.

[0037] When the decarboxylation step takes place in batch, in particular, the decarboxylation step takes place at a temperature ranging from 120°C to 200°C, preferably from 125°C to 190°C, more preferably from 135°C to 180°C.

[0038] When the decarboxylation step takes place in a batch, in particular, the decarboxylation step takes place for a duration ranging from 30 minutes to 18 hours, preferably from 1 hour to 3 p.m.

[0039] When the decarboxylation step takes place in continuous flow, the pressure of the reaction medium for the decarboxylation step typically varies from 1.0 MPa to 2.5 MPa, preferably from 1.5 MPa to 2.0 MPa. Thus, the decarboxylation step is preferably carried out at a pressure ranging from 1.0 MPa to 2.5 MPa, preferably from 1.5 MPa to 2.0 MPa.

[0040] When the decarboxylation step takes place in continuous flow, the decarboxylation step generally takes place at a temperature ranging from 160°C to 220°C, preferably from 170°C to 210°C, more preferably from 190°C to 210°C.

[0041] In particular, when the decarboxylation step takes place in continuous flow, the temperature and pressure are adapted so that the reaction medium is always in liquid phase.

[0042] Typically, in a continuous flow process, an aqueous solution of 4-hydroxy-3,5-diisopropylbenzoic acid in a basic medium is prepared, or an aqueous solution of the salt of 4-hydroxy-3,5-diisopropylbenzoic acid is prepared. The resulting aqueous solution is introduced into a continuous reactor. The continuous reactor is, in particular, thermostated to the required temperature. The aqueous solution is introduced into the continuous reactor at the required pressure. The residence time typically varies from 30 seconds to 20 minutes, preferably from 45 seconds to 15 minutes.

[0043] The 4-hydroxy-3,5-diisopropylbenzoic acid useful in the context of the present invention can be prepared according to methods described in the prior art, in particular in the article by Pramanik et al. (“Commercial Manufacturing of Propofol: Shn-plifying the Isolation Process and Control on Related Substances” Org. Process Res. Dev. 2014,18, 152-156).

[0044] In particular, 4-hydroxy-3,5-diisopropylbenzoic acid can be prepared from 4-hydroxybenzoic acid.

[0045] 4-Hydroxybenzoic acid can thus be alkylated in the presence of isopropanol and an acid to give 4-hydroxy-3,5-diisopropylbenzoic acid.

[0046] The acid is preferably a mineral acid. It can be selected from the group consisting of hydrochloric acid, perchloric acid and sulfuric acid, in particular the acid is sulfuric acid.

[0047] The molar amount of acid added generally varies from 8 to 16 equivalents relative to the molar amount of 4-hydroxybenzoic acid, preferably from 10 to 15 equivalents.

[0048] Preferably, the acid is in the form of an acidic aqueous solution, in particular aqueous sulfuric acid. Aqueous sulfuric acid is typically at a concentration of 85 to 98% by weight, preferably 89% to 98% by weight.

[0049] The molar amount of isopropanol typically varies from 2.0 to 3.5 equivalents relative to the molar amount of 4-hydroxybenzoic acid, preferably from 2.2 to 3.0 equivalents.

[0050] Alkylation is typically carried out at a temperature ranging from 40°C to 70°C, preferably from 50°C to 65°C.

[0051] The reaction medium during the alkylation step is typically heated for 3 to 24 hours, preferably for 4 to 16 hours.

[0052] Following the alkylation step, the crude reaction product is treated in order to isolate 4-hydroxy-3,5-diisopropylbenzoic acid and possibly to purify it.

[0053] The treatment may include the following steps, in particular as described in the article by Pramanik et al. cited above:

[0054] a) Addition of an aqueous solution and an organic solvent to the crude reaction mixture obtained at the end of the alkylation step,

[0055] b) Separation of the organic phase containing the acid 4-hydroxy-3,5-diisopropylbenzoic acid,

[0056] c) Optionally, concentration of the organic phase,

[0057] d) Optionally precipitation or recrystallization of the acid 4-hydroxy-3,5-diisopropylbenzoic acid.

[0058] The aqueous solution added in step a) can be water.

[0059] The organic solvent added in step a) can be toluene, dichloromethane, the cyclohexane, heptane or ethyl acetate. Preferably, the organic solvent added in step a) is toluene.

[0060] In step d), the precipitation of 4-hydroxy-3,5-diisopropylbenzoic acid can take place by dissolving it in an organic solvent and then adding water. The organic solvent used for precipitation can be an alcohol or an alkane, for example methanol, ethanol, cyclohexane, or heptane.

[0061] During step d), the recrystallization of 4-hydroxy-3,5-diisopropylbenzoic acid can be carried out in a solvent such as an alkane, in particular heptane.

[0062] The 4-hydroxy-3,5-diisopropylbenzoic acid obtained can be directly subjected to the decarboxylation step. Alternatively, the acid The 4-hydroxy-3,5-diisopropylbenzoic acid obtained can be pre-treated with a basic aqueous phase, in particular an aqueous phase with a pH greater than 9.5. The aqueous phase containing the salt obtained can be directly subjected to the decarboxylation step or the salt obtained can be isolated. Isolation and purification

[0063] Following the decarboxylation step, propofol can be isolated and purified using techniques well known to those skilled in the art. Thus, the process of the present invention may include a step of isolating and purifying propofol. Propofol is present in the organic phase formed at the end of the decarboxylation reaction.

[0064] The organic phase can thus be separated from the aqueous phase to isolate the propofol. Propofol is advantageously obtained with a degree of purity greater than or equal to 97%, preferably greater than or equal to 98%.

[0065] The resulting propofol can then be purified by distillation. The degree of purity obtained after distillation is then 99.9%.

[0066] The following examples are given for illustrative purposes only. They should in no way be considered as limiting the present invention. EXAMPLES

[0067] Example 1: Preparation of propofol by batch decarboxylation in pressurized water

[0068] 4-Hydroxy-3,5-Diisopropylbenzoic acid (10 g, 45 mmol, 1 equiv) is suspended in water (22 mL) and stirred at room temperature. A 20% w / v aqueous NaOH solution (2 equiv, 28 mL) is slowly added while maintaining a temperature of 20°C, and the reaction mixture is stirred for 30 min. The reaction mixture is transferred to a 100 mL autoclave and heated for 2 h at the desired temperature indicated in Table 1. The reaction mixture is then cooled to room temperature, and the organic phase is decanted. The conversion is then analyzed by HPLC and reported in Table 1.

[0069] [Tables 1] Test Temperature (°C) Pressure (bar) Conversion (%) 1 180 9 99.7 2 160 6 99.7 3 140 3 79

[0070] Example 2: Preparation of propofol by decarboxylation in pressurized water in batch

[0071] 4-Hydroxy-3,5-Diisopropylbenzoic acid (10 g, 45 mmol, 1 equiv) is suspended in water (50 mL) and stirred at room temperature. A base (2 equiv) is added while maintaining the temperature at 20°C, and the reaction mixture is stirred for 30 min. The reaction mixture is transferred to a 100 mL autoclave and heated for 2 h at 160°C. The reaction mixture is then cooled to room temperature, and the organic phase is decanted. The conversion is then analyzed by HPLC and reported in Table 2.

[0072] [Tables2] Test Base Conversion (%) 1 KOH 99.8 2 LiOH.H2O 99 3 k2co3 >99.9 4 Na2CO3 >99.9 5 K3PO4 >99.9 6 tBuOK 97

[0073] Example 3:

[0074] 4-Hydroxy-3,5-Diisopropylbenzoic acid (35.6 g, 160.2 mmol, 1 equiv) is suspended in water (70 mL) and stirred at room temperature. A 20% w / v aqueous NaOH solution (100 mL, 320.3 mmol, 2 equiv) is slowly poured while maintaining a temperature of 20°C. The reaction mixture is stirred for 30 min and then placed in a 250 mL autoclave. The reaction mixture is heated to 140°C for 8 h. The reaction mixture is cooled to 60°C and then transferred to a dropping funnel, and the organic phase is subsequently separated from the aqueous phase. Crude propofol is obtained with a yield of 85% and an HPLC purity of 97.2%.

[0075] Example 4: Preparation of propofol by decarboxylation in water in continuous flow

[0076] 4-Hydroxy-3,5-Diisopropylbenzoic acid (10 g, 45 mmol, 1 equiv) is suspended in water (22 mL) and stirred at room temperature. A 20% w / v aqueous NaOH solution (20%, 28 mL) is slowly poured in while maintaining the temperature at 20°C. The reaction mixture is stirred for 30 min, then filtered. The resulting solution is then injected into a continuous chemistry setup comprising a Hastelloy® C276 alloy tubular reactor with an internal diameter of 1.5 mm and a volume of 5 mL, equipped with a double jacket and temperature-controlled by a cryothermostat (HUBER Ministat 230). The Hastelloy® C276 alloy reactor is The reactor is preheated to the desired temperature, and the internal pressure is set to 18 bar using a pressure regulator. The reaction medium is injected using a piston metering pump (Eldex Optos) at pressure P (see Table 3). The residence time in the reactor (tsej - see Table 3) is controlled by the pump flow rate. Samples are taken from the system outlet after tsej (at least 3 x tsej - see Table 3) and analyzed by HPLC (conversion and % Propofol: %PFL - see Table 3).

[0077] [Tables3] T (°C) tséj (min) Flow rate (mL / min) Tprépèv (min) Pressure P (PSI) Conversion (%) %PFL 180 5 1 18 264 34% 30.48% 180 10 0.5 30 268 45% 39.40% 190 5 1 15 264 47% 40.23% 190 10 0.5 30 271 93% 90.34% 200 5 1 15 274 92% 88.62% 200 10 0.5 30 274 ​​98% 93.73%

Claims

Demands

1. Process for preparing 2,6-diisopropyl phenol comprising a step of decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts in an aqueous medium which may comprise, in addition to water, up to 10% by volume of organic solvent under pressure, the pressure being greater than 0.1 MPa.

2. A process according to claim 1, characterized in that the decarboxylation step is carried out in the presence of a base, preferably a mineral base, more preferably an alkali metal hydroxide.

3. A process according to the preceding claim, characterized in that the base is present in an amount ranging from 0.1 to 3 molar equivalents relative to the amount of 4-hydroxy-3,5-diisopropylbenzoic acid or one of its salts, preferably from 0.5 to 2.5 equivalents.

4. A process according to any one of the preceding claims, characterized in that the decarboxylation step is carried out in batches.

5. A process according to claim 4, characterized in that the decarboxylation step is carried out at a pressure ranging from 0.2 MPa to 1.2 MPa, preferably from 0.25 MPa to 1.0 MPa.

6. A process according to any one of claims 4 or 5, characterized in that the decarboxylation step is carried out at a temperature ranging from 120°C to 200°C, preferably from 125°C to 190°C.

7. A process according to any one of claims 1 to 3, characterized in that the decarboxylation step is carried out in continuous flow.

8. A process according to claim 7, characterized in that the decarboxylation step is carried out at a pressure ranging from 1.0 MPa to 2.5 MPa, preferably from 1.5 MPa to 2.0 MPa.

9. A process according to any one of claims 7 or 8, characterized in that the decarboxylation step is carried out at a temperature ranging from 160°C to 220°C, preferably from 170°C to 210°C.