Preparation method of tricaprylyl glycerol

Abstract

The present invention relates to a process for the preparation and purification of glycerol - tri - (3 - hydroxybutyrate) of formula (I) and its optically active isomers, in particular the enantiomer (R,R,R).

Description

[0001] Technical field of the invention

[0002] The present invention relates to a method for preparing and purifying glycerol tri-(3-hydroxybutyrate), wherein glycerol tri-(3-hydroxybutyrate) is used in a diet with specific nutritional requirements, such as a ketogenic diet.

[0003] Background art of the invention

[0004] Glycerol tri-(3-hydroxybutyrate) having the following structural formula (I),

[0005]

[0006] In particular, the enantiomer of formula (Ia) having all three (R)-configured stereocenters,

[0007]

[0008] is used in a ketogenic diet (KD), wherein the ketogenic diet is a nutritional regimen consisting of a high fat content and a low carbohydrate content. A high fat but low carbohydrate diet results in ketosis, in which the body obtains energy in the form of ketone products from fat. This type of diet has been used to treat various diseases, such as for treating intractable epilepsy in infants (E. Van der Louw et al., Eur. J. Paediatr. Neurol. 2016 20, 798 - 809).

[0009] Patent application WO 95 / 09144 describes a method for obtaining glycerol tri-(3-hydroxybutyrate) of formula (I), which method first esterifies glycerol of formula (II) with tert-butyl acetoacetate of formula (III), and then hydrogenates the intermediate of formula (IV) in the presence of a Raney nickel catalyst.

[0010]

[0011] Although the condensation of glycerol of formula (II) and acetoacetate of formula (III) maintains a good yield, the hydrogenation under a Raney nickel catalyst requires a pressure of 1000 psi, thus about 70 bar, which is a very high pressure, especially from the perspective of industrial scale production. In addition, patent application WO 95 / 09144 describes that it is necessary to remove residual nickel in the product through an ion exchange resin to purify the desired product.

[0012] U.S. Patent 5,693,850 is derived from the above-mentioned patent application WO 95 / 09144 and thus describes a method for preparing water-soluble glycerides which are used as parenteral nutrients. Specifically, the method provides for reacting glycerol or protected glycerol with acetoacetate or an acetoacetate precursor at a temperature of 0 °C to 180 °C to produce acetoacetyl glycerol. The acetoacetyl glycerol is reduced in the presence of hydrogen and a hydrogenation catalyst at a temperature reaching 25 °C to 140 °C. This reduction is generally carried out at a hydrogen pressure of 13.8 bar (200 psi) to 689.5 bar (10,000 psi), with a preferred value of 34.5 bar (500 psi) to 68.9 bar (1000 psi). In particular, the use of Raney nickel as a catalyst requires a pressure of 68.9 bar (1000 psi). In particular, the latter pressure value is very high, especially from the perspective of industrial-scale production. In addition, as described in this patent, a hydrogen pressure below 13.8 bar (200 psi) is ineffective, especially when using Raney nickel as a catalyst, and requires a very long reaction time and / or a higher temperature.

[0013] Patent application JP.03-083950 describes a method for obtaining an optically active compound of formula (Ia) through a series of reactions. This reaction first protects methyl 3-(R)-hydroxybutyrate of formula (V) such as with THP, and then undergoes hydrolysis to obtain the acid of formula (VI). The carboxylic acid is then activated by treatment with CDI, and then esterified with glycerol of formula (II) to obtain a protected intermediate of formula (VII). The tetrahydropyran protecting group of the compound of formula (VII) is deprotected in an acidic environment, ultimately producing the optically active product of formula (Ia):

[0014]

[0015] The method described in JP.03-083950 is a long-range method and results in a low yield of the desired product. Further, the product of formula (Ia) is purified by chromatography to obtain a pure compound.

[0016] At room temperature, both the compound of formula (I) and its optically active isomer (Ia) exist in the form of oils, as is the case for all short-chain fatty acid triglycerides known to those skilled in the art. Since it is impossible to purify these compounds by crystallization and since silica chromatography is to be avoided on an industrial scale, it is also very complex to purify the compounds of formula (I) and formula (Ia) to obtain a product with a suitable purity of higher than 99% expressed as A% measured by HPLC, and no different method has been reported in the literature to achieve such a purity so far.

[0017] Accordingly, there is a need for an alternative, simpler and more advantageous method for preparing glycerol tri-(3-hydroxybutyrate) of formula (I) and its optically active isomers of formula (Ia) having all three stereocenters in the (R) configuration. This novel method should in particular provide fewer synthetic steps, avoid the excessive use of protecting groups and improve the atom economy of the method. The method should also be economical and safe for humans and the environment, using mild reaction conditions and providing the desired compound in high yield and high chemical and stereochemical purity.

[0018] Summary of the Invention

[0019] The present invention relates to a method for preparing a compound of formula (I)

[0020]

[0021] The compound is either as a single enantiomer or as a mixture of isomers, and the method comprises subjecting a compound of formula (IV) to a hydrogenation reaction in the presence of a ruthenium-based catalyst

[0022]

[0023] Another object of the present invention is a method for purifying a compound of formula (I) as defined above, comprising:

[0024] a. washing the aqueous solution of the compound of formula (I) one or more times with an organic solvent S1 as defined herein, wherein the aqueous solution typically contains 0% - 5% w / w of NaCl;

[0025] b. increasing the NaCl concentration of the aqueous solution of the compound of formula (I) in step (a) to greater than 5% w / w;

[0026] c. extracting the aqueous solution of the compound of formula (I) in step (b) one or more times with a solvent S2 as defined herein, and

[0027] d. concentrating the solution of the compound of formula (I) in solvent S2 to obtain the compound of formula (I) as a clear oil.

[0028] The organic solvent S1 is typically an organic solvent selected from the group consisting of cyclic ethers or acyclic ethers or non-polar aprotic solvents.

[0029] The organic solvent S2 is typically an organic solvent selected from the group consisting of polar aprotic solvents; chlorinated solvents; esters; or straight-chain or branched C 3 -C 7 ketones.

[0030] Detailed Description of the Invention

[0031] The present invention relates to a method for preparing a compound of formula (I).

[0032]

[0033] The compound is a single enantiomer or a mixture of isomers, and the method comprises subjecting a compound of formula (IV) to a hydrogenation reaction in the presence of a ruthenium-based catalyst.

[0034]

[0035] The hydrogenation of the compound of formula (IV) can be carried out by catalytic hydrogenation in the presence of a homogeneous or heterogeneous Ru-based metal catalyst.

[0036] When the metal catalyst is heterogeneous, it is preferably deposited on an inert support such as carbon, barium hydroxide, alumina, calcium carbonate; preferably carbon. The concentration of the metal on the support can vary between about 1% - 30%, preferably between about 5% - 20%.

[0037] In some embodiments, the hydrogen pressure employed can vary between about 1 bar and about 50 bar, preferably between 2 bar and 40 bar, for example 3 bar, 4 bar, 5 bar, 6 bar, 7 bar, 8 bar, 9 bar, 10 bar, 15 bar, 20 bar, 25 bar, 30 bar or 35 bar.

[0038] In some embodiments, the hydrogen pressure used can vary between about 1 bar and about 50 bar, particularly between about 1 bar and about 40 bar, particularly between about 1 bar and about 30 bar, particularly between about 1 bar and about 20 bar, more particularly between about 1 bar and about 13 bar, even more particularly between about 1 bar and about 10 bar.

[0039] The molar amount of the catalyst used relative to the compound of formula (IV) is about 0.1% - 10%, preferably about 0.5% - 5%.

[0040] The hydrogenation reaction can be carried out in the presence of an organic solvent, such as selected from: polar aprotic solvents, usually dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide; cyclic or acyclic ethers, usually tetrahydrofuran or dioxane or methyl tert-butyl ether; chlorinated solvents, usually dichloromethane; non-polar aprotic solvents, usually toluene or hexane; polar protic solvents, such as straight-chain or branched C 1 -C 6Alcohols, especially methanol, ethanol, isopropanol or butanol; esters, such as ethyl acetate, isopropyl acetate, butyl acetate; carboxylic acids, such as acetic acid or propionic acid; or water; or a mixture of two or more of said solvents, preferably a mixture of 2 or 3 solvents.

[0041] Preferably, the reaction can be carried out in C 1 -C 6 alcohol (such as ethanol or isopropanol), an ester solvent (such as ethyl acetate) or a mixture of an ester solvent (such as ethyl acetate) and water.

[0042] The hydrogenation reaction can be carried out at a temperature between about 0 °C and the reflux temperature of the solvent; preferably at a temperature between about 25 °C and the reflux temperature.

[0043] The hydrogenation reaction of the compound of formula (IV) can also be carried out by a hydrogen transfer reaction, in which a homogeneous or heterogeneous metal catalyst (for example, the catalyst as defined above, and in the same molar amount) and a hydrogen donor are used. The hydrogen donor is preferably selected from cyclohexene; cyclohexadiene; methylcyclohexene; limonene; dipentene; mentene; hydrazine; hypophosphorous acid or its derivatives, such as sodium hypophosphite; indoline; ascorbic acid; formic acid or its sodium or ammonium salts; and secondary alcohols, such as isopropanol.

[0044] The molar ratio between the hydrogen donor and the compound of formula (IV) can be about 1.5 to 50, preferably about 1.5 to 10.

[0045] The hydrogen transfer reduction reaction can be carried out in the presence of an organic solvent, which is preferably selected from one of the solvents described above.

[0046] In a preferred aspect of the present invention, the catalyst is heterogeneous, and more preferably Ru / C.

[0047] In another preferred aspect of the present invention, the catalyst is homogeneous, and more preferably a ruthenium complex having a monophosphine or diphosphine ligand (which is well known in the chemistry of enantioselective hydrogenation), such as the homogeneous catalyst Ru((R)-BINAP)Cl 2 .

[0048] According to a preferred aspect of the present invention, using the homogeneous catalyst Ru((R)-BINAP)Cl 2 hydrogenation of the compound of formula (IV) gives the compound of formula (Ia)

[0049]

[0050] All three stereocenters of the compound of formula (Ia) are of configuration (R).

[0051] Accordingly, in another aspect, the present invention provides an advantageous process for preparing a compound of formula (Ia) as defined herein.

[0052]

[0053] The process comprises subjecting a compound of formula (IV) to a hydrogenation reaction in the presence of the homogeneous catalyst Ru((R)-BINAP)Cl 2 in the presence of the homogeneous catalyst Ru((R)-BINAP)Cl

[0054]

[0055] In embodiments using the homogeneous catalyst Ru((R)-BINAP)Cl 2 the hydrogen pressure for the hydrogenation reaction can be from about 1 bar to about 50 bar, in particular from 2 bar to 45 bar, more particularly from 2 bar to 40 bar.

[0056] In other embodiments using the homogeneous catalyst Ru((R)-BINAP)Cl 2 the hydrogen pressure for the hydrogenation reaction can be from about 1 bar to about 150 bar, for example 10 bar, 20 bar, 30 bar, 35 bar, 40 bar, 50 bar, 60 bar, 70 bar, 80 bar, 90 bar, 100 bar, 120 bar or 140 bar.

[0057] In other embodiments using the homogeneous catalyst Ru((R)-BINAP)Cl 2 the hydrogen pressure for the hydrogenation reaction can be from about 20 bar to about 100 bar, in particular from about 25 bar to about 100 bar, in particular from about 30 bar to about 100 bar, in particular from about 35 bar to about 100 bar, in particular from about 40 bar to about 100 bar, in particular from about 45 bar to about 100 bar, in particular from about 50 bar to about 100 bar, more particularly from about 55 bar to about 100 bar, even more particularly from about 60 bar to about 100 bar. Possible examples are 20 bar, 25 bar, 30 bar, 35 bar, 40 bar, 45 bar, 50 bar, 55 bar, 60 bar, 65 bar, 70 bar, 75 bar, 80 bar, 85 bar, 90 bar, 100 bar.

[0058] The compounds of formula (IV) are known compounds and can be prepared, for example, from glycerol of formula (II)

[0059]

[0060] with tert-butyl acetoacetate of formula (III)

[0061]

[0062] obtained by the esterification reaction.

[0063] The compounds of formula (II) and formula (III) are commercially available.

[0064] At the end of the hydrogenation, liquid glycerol tri(-3-hydroxybutyrate) of formula (I) and its enantiomer of formula (Ia) are obtained by evaporation of the solvent, and the purity of this liquid measured by HPLC is always higher than 90% but lower than 99%.

[0065] Surprisingly, it has been found that, unlike common lipophilic and water-insoluble triglycerides (such as the compound of formula (IV)), glycerol tri(-3-hydroxybutyrate) of formula (I) and its enantiomer of formula (Ia) have amphiphilic properties, which enable them to be soluble in water, as well as in their aqueous salt solutions and organic solvents under specific experimental conditions.

[0066] The present invention also relates to a method for purifying a compound of formula (I) or formula (Ia), comprising:

[0067] a. washing the aqueous solution of the compound of formula (I) or formula (Ia) one or more times with an organic solvent S1 as defined herein, wherein the aqueous solution contains 0% to 5% w / w, preferably 1% to 5% w / w of NaCl;

[0068] b. increasing the NaCl concentration of the aqueous solution of the compound of formula (I) or (Ia) in step (a) to greater than 5% w / w, preferably at least 10% w / w, more preferably at least 15% w / w;

[0069] c. extracting the aqueous solution of the compound of formula (I) or formula (Ia) in step (b) one or more times with an organic solvent S2 as defined herein; and

[0070] d. concentrating the solution of the compound of formula (I) or formula (Ia) in the organic solvent S2 to obtain a transparent oily compound of formula (I) or formula (Ia) with a purity usually greater than 99% measured by HPLC.

[0071] The solvent S1 is an organic solvent selected, for example, from the following: cyclic or acyclic ethers, usually diethyl ether or methyl tert-butyl ether, usually methyl tert-butyl ether; non-polar aprotic solvents, usually toluene.

[0072] The solvent S2 is an organic solvent selected, for example, from the following: polar aprotic solvents, usually acetonitrile; chlorinated solvents, usually dichloromethane; esters, such as ethyl acetate, isopropyl acetate, butyl acetate, preferably ethyl acetate; straight-chain or branched C3 -C 7 Ketones, such as methyl ethyl ketone, methyl isobutyl ketone.

[0073] The washing of the compound of formula (I) or (Ia) with solvent S1 or extraction with solvent S2 can be carried out at a temperature of about 0 °C to about 60 °C; preferably at a temperature of about 25 °C to about 60 °C, for example at a temperature of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C or 55 °C.

[0074] The solution of the compound of formula (I) or (Ia) in solvent S2 can be dehydrated by drying. The drying can be carried out with a dehydrating agent, such as sodium sulfate (Na 2 SO 4 ), magnesium sulfate (MgSO 4 ), or anhydrous calcium chloride (CaCl 2 ), preferably sodium sulfate (Na 2 SO 4 ).

[0075] Without resorting to chromatographic purification techniques, a transparent oily compound of formula (I) or (Ia) with a purity greater than 99% as measured by HPLC has never been obtained.

[0076] The present invention also relates to a method for purifying a compound of formula (I) or (Ia) having a purity greater than 99% as measured by HPLC without resorting to purification techniques of the chromatographic type, for example without chromatographic purification on an ion exchange resin or a normal or reverse stationary phase.

[0077] According to step (c) of the purification process, the compound of formula (I) or (Ia) is extracted from an aqueous solution in an organic solvent, which also allows the content of all heavy metals and ruthenium (especially in the compound of formula (I) or (Ia)) to be much lower than the limits provided by the ICH guidelines, which could only be achieved previously by chromatographic purification using an ion exchange resin.

[0078] Therefore, the present invention also relates to a compound of formula (I) or (Ia) having a heavy metal content of less than 0.5 ppm obtained according to the process and purification method of the present invention.

[0079] The following examples further illustrate the present invention:

[0080] Example 1 - Synthesis of Triacetylglycerol of Formula (IV)

[0081] In an inert atmosphere, glycerol (150 g, 1.69 mol) and tert-butyl acetoacetate (1350 g, 8.55 mol) were added to a 3000 ml flask, and the mixture was heated at 95 °C - 100 °C for 2.5 hours. Then the reaction mixture was concentrated under reduced pressure of 200 - 250 mbar and an internal temperature of 80 °C - 90 °C, and toluene was added to the reaction mixture in portions, a total of 1.5 liters. Then the residue after distillation was cooled at 0 - 10 °C, diluted with cold isopropanol (-10 °C, 2.5 liters), the phases were separated, and the alcohol phase was discarded to obtain a crude oil (620 g), which was washed repeatedly with cold isopropanol until the product (400 g) was obtained. Its HPLC purity (200 nm) expressed as A% was 98.6%, the content of glycerol diacetoacetate was less than 0.3%, and the yield was 70%.

[0082] 1 H-NMR(CDCl 3 , 300 MHz) δ: 11.8*(s, 1H); 5.34(m, 1H); 4.99*(s, 1H); 4.32(m, 4H); 3.49(s, 6H); 2.25(s, 9H); 1.96*(s, 3H). *Keto-enol tautomerism.

[0083] HPLC-MS: 345 (M / z + 1)

[0084] Example 2 - Synthesis of glycerol - tri(-3-hydroxybutyrate) of formula (I)

[0085] At room temperature, a solution of triacetylglycerol (100 g, 0.29 mol) of formula (IV) in ethyl acetate (500 ml) and 5% ruthenium on carbon (30 g) with a water content of approximately 50% were charged into a 1000 ml autoclave. The autoclave was inerted with nitrogen, evacuated, and then pressurized with hydrogen at 4.5 - 5 bar and stirred at 1000 rpm for 6 - 8 hours. The reaction was monitored by HPLC analysis. When the reaction was complete, the reactor was inerted, the catalyst was filtered off using perlite, and washed with ethyl acetate (100 ml). The solution was concentrated to a residue under reduced pressure and at a temperature of 30°C - 35°C. The crude product was dissolved in water (350 ml), treated with decolorizing carbon (2.5 g), maintained with stirring for 2 hours, then filtered through perlite and washed with water (150 ml). Sodium chloride (25 g) and methyl tert-butyl ether (140 ml) were added to the aqueous phase. The two phases were maintained at a temperature of 45°C - 50°C with vigorous stirring for 30 minutes, separated, and the organic phase was discarded. More sodium chloride (50 g) and ethyl acetate (400 ml) were added to the aqueous phase. These phases were maintained at 45°C - 50°C with stirring for 30 minutes, and the phases were separated. The aqueous phase was further extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and concentrated to a residue under reduced pressure and at a temperature of 30°C - 35°C. The washing and extraction procedures were repeated three times to obtain 72 g of the compound of formula (I) as a colorless oil. The HPLC purity (200 nm) expressed as A% was 99.3%, and the yield was 71%.

[0086] 1 H-NMR(CDCl 3 , 300 MHz) δ: 5.32 (m, 1H); 4.44 - 4.10 (m, 7H); 2.76 (s, 3H); 2.52 - 2.35 (m, 6H); 1.21 (d, 9H).

[0087] HPLC-MS: 351 (M / z + 1)

[0088] Example 3 - Synthesis of glycerol - tri - (3 - R) - hydroxybutyrate of formula (Ia)

[0089] At room temperature, a solution of triacetylglycerol (150 g, 0.43 mol) and the catalyst Ru((R)-BINAP)Cl 2A solution of [[ID=]], (0.69 g, 0.87 mmol) in ethanol (500 ml) was charged into a 1000 ml autoclave. The autoclave was inerted with nitrogen, heated at 40 °C - 45 °C, evacuated, and then pressurized with hydrogen at 35 bar and 1600 rpm for 6 - 8 hours. The disappearance of the starting product was verified by HPLC analysis. The autoclave was unloaded and the solution was filtered through perlite and carbon plates. The solution filtered into a residue was concentrated at a temperature of 45 °C - 50 °C and under reduced pressure. The product was dissolved in water (500 ml), decolorizing carbon (3.75 g) was added, and it was kept under vigorous stirring at room temperature for 2 hours. The crude solution was filtered through a perlite plate, washed with water (225 ml), and the aqueous solution was used for the purification step.

[0090] 1 H-NMR(CDCl 3 , 300 MHz) δ: 5.32 (m, 1H); 4.44 - 4.10 (m, 7H); 2.76 (s, 3H); 2.52 - 2.35 (m, 6H); 1.21 (d, 9H).

[0091] HPLC-MS: 351 (M / z + 1).

[0092] Example 4 - Purification of Glycerol-Tris-(3-(R)-hydroxybutyric acid) Ester of Formula (Ia)

[0093] Sodium chloride (36 g) was added to the solution obtained in Example 3, heated at a temperature of 45 °C - 50 °C, the aqueous phase was washed with toluene (2 x 225 ml), and then with methyl tert-butyl ether (2 x 200 ml). Sodium chloride (180 g) was added to the aqueous solution, the product was extracted with ethyl acetate (2 x 200 ml), the recombined organic phase was dehydrated with sodium sulfate, filtered through perlite, and concentrated to a residue at a temperature of 45 °C - 50 °C and under reduced pressure. 120 g of glycerol-tris-(3-(R)-hydroxybutyric acid) ester of formula (Ia) was obtained, with an HPLC purity (200 nm) of 99.1% expressed as A%, and a yield of 79%. Optical rotation power (C = 1, 15 methanol) = -22.0°.

Claims

1. A method for preparing a compound of formula (I) The compound is a single enantiomer or a mixture of isomers, The method comprises subjecting a compound of formula (IV) to a hydrogenation reaction in the presence of a ruthenium-based catalyst wherein, The hydrogen pressure of the hydrogenation reaction varies between 1 bar and 10 bar, and the ruthenium-based catalyst is ruthenium on carbon; Among them, the hydrogenation reaction is carried out in the presence of an organic solvent, and the organic solvent is selected from: polar aprotic solvents, and the polar aprotic solvents are selected from dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide; cyclic ethers or acyclic ethers, and the cyclic ethers or acyclic ethers are selected from tetrahydrofuran or dioxane or methyl tert-butyl ether; chlorinated solvents, and the chlorinated solvents are selected from dichloromethane; non-polar aprotic solvents, and the non-polar aprotic solvents are selected from toluene or hexane; polar protic solvents, and the polar protic solvents are selected from straight-chain or branched C 1 -C 6 alcohols; esters, and the esters are selected from ethyl acetate, isopropyl acetate, butyl acetate; carboxylic acids, and the carboxylic acids are selected from acetic acid or propionic acid; or a mixture of two or more of the above solvents.

2. The method according to claim 1, wherein the hydrogenation reaction is carried out at a temperature from 0 °C to the reflux temperature of the solvent.

3. The method according to claim 1, wherein the compound of formula (I) as defined in claim 1 is purified by a method comprising the following steps: a. washing the aqueous solution of the compound of formula (I) one or more times with an organic solvent S1, wherein the aqueous solution contains 0%-5% w / w of NaCl; b. increasing the NaCl concentration of the aqueous solution of the compound of formula (I) in step (a) to greater than 5% w / w; c. extracting the aqueous solution of the compound of formula (I) in step (b) one or more times with an organic solvent S2, and d. concentrating the solution of the compound of formula (I) in the organic solvent S2 to obtain the compound of formula (I), wherein the solvent S1 is an organic solvent selected from the following: cyclic or acyclic ethers or non-polar aprotic solvents, and wherein the solvent S2 is an organic solvent selected from the following: polar aprotic solvents; chlorinated solvents; esters; or straight-chain or branched C 3 -C 7 ketones.

4. The method according to claim 3, wherein the purification process does not include purification by chromatography.

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