HK1205096B - Method for the preparation of triglycerides of medium-chain length fatty acids - Google Patents

Description

Process for the preparation of triglycerides of medium-chain length fatty acids

Technical Field

A process for the preparation of glycerides of medium chain length monocarboxylic fatty acids (triglycerides) consists of the reaction of precursor free fatty acids with glycerol in the presence of a catalyst under partial vacuum. The process of the present invention enables the formation of triglycerides without solvent. The process preferably uses a metal catalyst such as an oxide or chloride of tungsten, molybdenum, calcium, zinc, chromium or magnesium. The process of the invention enables the preparation of the final triglycerides in high yield and high purity (> 99.5%). The process of the invention is particularly convenient for large scale production of triglycerides of medium chain length fatty acids.

Background

Triglycerides of medium-chain length fatty acids (known as medium-chain triglycerides or MCTs) can be synthesized by esterifying glycerol with fatty acids of C8 (caprylic acid) or C10 (capric acid) carbon chain lengths. MCTs are generally commercially available as mixtures of glycerides of C8 and C10 fatty acids, in which small amounts (1% each) of glycerides of C6 (caproic acid) and C12 (lauric acid or lauric acid) are present.

MCT and its component medium-chain fatty acids are nontoxic substances used in food and pharmaceutical industries. For example, Trul K.A. et al (Food and Chemical society 38:79-98,2000) claim that MCT has been used in an increasing number of Food and nutritional applications. In addition, Roach, R.R, (Cereal chem.73(2):197-98,1996) reported that glyceryl tricaprate (triglyceride of C10), which is usually mixed with glyceryl tricaprylate (triglyceride of C8), is used as an antifoaming and antistatic agent for plastics, a lubricant, a water treatment agent, and a mold release agent for baked products and candies. MCTs are also used primarily as emulsifiers in various human and veterinary pharmaceutical preparations and cosmetics. Us patent 7,745,488 describes the use of medium chain fatty acids or metal salts or triglycerides or MCT as hematopoiesis-inducing agents. There are several toxicological studies that support the safety of MCT. For example, the safety of human dietary consumption of MCT (up to 1g/kg) has been confirmed in several clinical trials. Indeed, according to part 170 of the U.S. federal regulations (CFR), the U.S. Food and Drug Administration (FDA) has granted fatty acid triglycerides a GRAS (generally recognized as safe) status for use as food ingredients. In addition, a review of the literature on the use of triglycerides, such as tricaprin or tricaprylin, in cosmetics supports the safety of these compounds (International journal of society 2001, (20), 61-94). Similarly, the cosmetic ingredient examination (CIR) panel concluded that tricaprin and tricaprylin were safe for use in cosmetics and the practice of the invention at concentrations (Elder, R.L. et al, J.Environ.Pathol.Toxicol.4:105-120, 1980). U.S. patent 4,602,040 describes another use of MCT as a pharmaceutical excipient. Recently, MCT has been used to formulate existing drugs to enhance palatability and stability (Pharmaceutical Development and Technology,2003, vol.8, (1),111-115) or to improve drug distribution/solubility. Indeed, the use of triglycerides for the formulation of poorly water-soluble drugs has been investigated by different methods including nano-ions, micelles and emulsions. For example, the oral bioavailability of the slightly water soluble drug anethol trithione is enhanced by the use of MCT sub-microemulsion formulations (Si-Fei, H et al, International Journal of pharmaceuticals 2009,379(1), 18-24). In addition, the antitumor efficacy and absorption of paclitaxel, a poorly water-soluble cancer drug, have been improved by using MCT as a carrier (Hong, J.W. et al, mol.cancer ther.2007,6(12) 3239-47; U.S. patent application 2006/0104999).

As is generally known in the art, MCT is obtained by reacting glycerol with medium-chain length fatty acids in the presence of an acid and at elevated temperature (140-260 ℃) or at 70-90 ℃ using an enzyme such as a lipase. The low purity of the triglycerides obtained by these known techniques makes it necessary to carry out decolourisation and chromatographic purification/distillation, which makes large scale synthesis difficult. Generally, the yields and purities obtained by these known techniques do not exceed 75% due to incomplete esterification and product loss during workup and purification.

There is a need to improve the yield of MCT synthesis. In view of large-scale production, it is also desirable to simplify the production process thereof.

Summary of The Invention

One aspect of the present invention relates to a process for the preparation of triglycerides of medium chain length fatty acids comprising the steps of:

a) mixing glycerol with 3 molar equivalents or an excess of the medium-chain length fatty acids, wherein each medium-chain length fatty acid contains a chain of 6 to 12 carbons;

b) reacting the mixture of step (a) with a divalent or trivalent metal cation catalyst; and

c) heating at 160 ℃ or higher under partial vacuum for a time sufficient to form triglycerides. The temperature is preferably from about 160 ℃ to about 180 ℃, and preferably from about 170 ℃ to about 175 ℃, and more preferably about 175 ℃. The period of time is preferably between 8 hours and 24 hours, and more preferably about 22 hours.

Since glycerol has 3 reactive sites for attachment of medium-chain length fatty acids, 1 stoichiometric equivalent of medium-chain length fatty acids means 3 molar equivalents, or three medium-chain length fatty acid molecules are present for one glycerol molecule. An excess of medium chain length fatty acids means that there are more than three medium chain length fatty acid molecules, or more than 3 molar equivalents, for one glycerol molecule. In a preferred embodiment, glycerol is mixed with more than 3 equivalents of medium chain length fatty acids. In another preferred embodiment, glycerol is mixed with at least 4 molar equivalents of medium chain length fatty acids.

In a preferred embodiment, the partial vacuum is from about 1mm Hg to about 20mm Hg, and preferably from about 5mm Hg to about 15mm Hg, and more preferably about 10mm Hg.

In a preferred embodiment, the metal salt catalyst is tungsten oxide, tungsten chloride, tungsten carbonyl, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, zinc oxide, zinc chloride, magnesium oxide, magnesium chloride, molybdenum oxide, molybdenum chloride, chromium oxide, or chromium chloride. Preferred catalysts include tungsten oxide, tungsten chloride, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, zinc oxide, zinc chloride, magnesium oxide, magnesium chloride, molybdenum oxide, molybdenum chloride, chromium oxide, and chromium chloride. The most preferred catalyst is calcium oxide. Another most preferred catalyst is tungsten oxide. Yet another most preferred catalyst is zinc oxide. The amount of catalyst is preferably from about 0.5% to about 2.5% (w/w), more preferably from about 1% to about 2% (w/w).

In a preferred embodiment, each medium-chain length fatty acid contains a chain of 6 carbons, 8 carbons, 10 carbons, or 12 carbons.

In a preferred embodiment, the medium chain length fatty acids comprise a mixture of fatty acids having a chain of 8 carbons and fatty acids having a chain of 10 carbons.

In embodiments where the medium-chain length fatty acid contains chains of 8 to 12 carbons, the process further comprises recovery steps comprising the steps of:

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding hot alcohol to form an alcohol solution, wherein the temperature of the hot alcohol varies from about 60 ℃ to the alcohol boiling temperature, preferably about 80 ℃;

g) filtering the alcohol solution to obtain a filtered solution; and

h) the filtered solution is maintained at a temperature of between about 0 ℃ to about 20 ℃, preferably about 0 ℃ to about 5 ℃ for a time sufficient to crystallize the triglycerides formed, preferably for a period of at least 1 hour and more preferably for a period of about 2 hours.

It is believed that removing the partial vacuum means restoring the solution to normal or ambient atmospheric pressure.

In a preferred embodiment of the invention, the hot alcohol is ethanol or isopropanol. In another preferred embodiment, the hot alcohol is ethanol and its temperature is about 80 ℃. The volume of hot alcohol is preferably the volume necessary to dissolve the triglycerides formed.

The step of filtering the alcoholic solution before cooling and crystallization allows to remove solid impurities that may be present.

In a preferred embodiment, the process further comprises the further step of adding cold alcohol to the filtered solution before maintaining the cold temperature during which crystallization occurs. The temperature of the cold alcohol is preferably from about 0 ℃ to about 5 ℃, and more preferably about 0 ℃. The addition of cold alcohol helps to cool the triglyceride and crystallize it.

In a preferred embodiment, the cold alcohol is the same type of alcohol as the hot alcohol. The cold alcohol volume is preferably the volume available for cooling the triglyceride.

Medium chain length fatty acids having 6 to 7 carbons are volatile fatty acids and therefore the recovery step needs to be adapted to this feature. In embodiments where the medium-chain length fatty acids contain chains of 6 to 7 carbons, the process further comprises recovery steps comprising the steps of:

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding an organic solvent for dissolving the triglyceride to form an organic solution;

g) adding an aqueous sodium hydroxide solution to the organic solution; the aqueous solution is preferably 1-2% NaOH;

h) recovering the organic solution and discarding the aqueous solution;

i) treating the organic solution with a desiccant;

j) filtering the organic solution through silica gel;

k) treating the organic solution with a desiccant; and

l) evaporating the organic solvent.

In a preferred embodiment of the present invention, the organic solvent is hexane, dichloromethane, ethyl acetate or ether. The volume of organic solvent is preferably the volume necessary to dissolve all the triglycerides formed by the reaction. Filtration through silica gel allows for rapid purification of the triglyceride. The silicone gel is preferably in the form of a pad (i.e., a silicone gel pad). The step of washing with aqueous sodium hydroxide solution enables the removal of unreacted fatty acids. The step of treating with a desiccant is a treatment well known in the chemical art, which includes the steps of adding a desiccant to a solution and removing the desiccant by filtration. The amount of desiccant is preferably the amount necessary to capture all water molecules remaining in the organic solution. In a preferred embodiment of the invention, the drying agent is magnesium sulfate or sodium sulfate.

In a preferred embodiment of the invention, the catalyst is calcium oxide, tungsten oxide or zinc oxide; and the yield of the produced triglyceride is 75 to 95%.

In a preferred embodiment of the invention, the process produces triglycerides in a yield of 75% to 95% and a purity of at least 99% or 99.5%, wherein the process comprises the steps of:

a) mixing glycerol with at least 3 molar equivalents of the medium-chain length fatty acids, wherein each medium-chain length fatty acid contains a chain of 8 to 12 carbons;

b) reacting the mixture of step (a) with calcium oxide, tungsten oxide or zinc oxide;

c) heating at a temperature of about 175 ℃ under a partial vacuum of about 10mm Hg for a period of about 22 hours such that triglycerides are formed;

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding hot alcohol at a temperature of about 80 ℃ to form an alcohol solution;

g) filtering the alcohol solution to obtain a filtered solution; and

h) the filtered solution is maintained at a temperature between about 0 ℃ and about 5 ℃ for a period of about 2 hours.

In a preferred embodiment of the invention, the process produces triglycerides in a yield of 75% to 95% and a purity of at least 99% or 99.5%, wherein the process comprises the steps of:

a) mixing glycerol with at least 3 molar equivalents of the medium-chain length fatty acids, wherein each medium-chain length fatty acid contains a chain of 6 to 7 carbons;

b) reacting the mixture of step (a) with calcium oxide, tungsten oxide or zinc oxide;

c) heating at a temperature of about 175 ℃ under a partial vacuum of about 10mm Hg for a period of about 22 hours such that triglycerides are formed;

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding an organic solvent for dissolving the triglyceride to form an organic solution;

g) adding 1-2% NaOH aqueous solution;

h) recovering the organic solution and discarding the aqueous solution;

i) treating the organic solution with a desiccant;

j) filtering the organic solution through silica gel;

k) treating the organic solution with a desiccant; and

l) evaporating the organic solvent.

The invention also relates to triglycerides of medium-chain length fatty acids prepared by the process of the invention.

In a preferred embodiment of the invention, the triglycerides of medium-chain length fatty acids prepared by the process of the invention have a purity of at least 99%, and more preferably, the triglycerides have a purity of at least 99.5%.

The invention also relates to a pharmaceutical formulation comprising the triglycerides of medium-chain length fatty acids of the invention as excipients. The triglycerides can be recognized as having different characteristics, including their ability to improve the solubility of poorly water-soluble active ingredients. The concentration of the triglyceride in the pharmaceutical formulation may vary between about 50% to about 90% (w/w), preferably between about 70% and about 80% (w/w), and most preferably about 80% (w/w).

In a preferred embodiment of the invention, the pharmaceutical formulation further comprises from about 25% to about 75% (w/w) ethyl decanoate and from about 2.5% to about 10% (w/w) ethanol.

In a preferred embodiment of the invention, the pharmaceutical formulation further comprises an active ingredient dissolved therein. Advantageously, the water solubility of the active ingredient is less than about 1mg/100 ml. Examples of active ingredients that may advantageously benefit from the formulation of the present invention are paclitaxel, gemcitabine, cyclophosphamide, doxorubicin and 5-fluorouracil.

One aspect of the present invention relates to a pharmaceutical composition comprising the triglyceride of medium-chain length fatty acids of the present invention as an active ingredient. In the pharmaceutical composition, the triglyceride is preferably in a therapeutically effective amount. It is known that triglycerides of medium-chain length fatty acids have a variety of therapeutic effects and therefore their therapeutically active amount can vary depending on the desired therapeutic effect. The concentration of triglycerides in the pharmaceutical composition may preferably vary between 50% and 100% (W/W).

In a thirteenth preferred embodiment of the present invention, the pharmaceutical composition further comprises a second active ingredient. The second active ingredient may or may not benefit from its synergistic effect with the combination of triglycerides. The second active ingredient may be paclitaxel, gemcitabine, cyclophosphamide, doxorubicin or 5-fluorouracil.

Detailed Description

The present invention provides an improved process for the synthesis of triglycerides of medium-chain length fatty acids (i.e., chain lengths of 6 to 12 carbon atoms). Glycerol is reacted with an excess of free fatty acids, preferably at least 3 molar equivalents, and more preferably 4 molar equivalents. The desired chain length of the free fatty acids is advantageously selected from C6 to C12. According to the invention, the reaction of glycerol with free fatty acids is carried out in the presence of a catalyst and in the absence of a solvent. The reaction is carried out under partial vacuum and at a temperature varying between 160-180 c (preferably 175 c) to produce a triglyceride product. The partial vacuum contemplated by the present invention is a low vacuum, which can be achieved in the laboratory with basic equipment in which the pressure is below atmospheric and above 1mm Hg or 1 Torr. The process advantageously enables the synthesis of triglycerides without solvent. The combination of catalyst, partial vacuum and heat provides the ideal conditions for esterifying glycerol with medium chain length fatty acids such that all medium chain length fatty acids react with the hydroxyl groups of glycerol. Thus, when an excess of medium chain length fatty acids is present with glycerol under the conditions of the present invention, all or almost all of the hydroxyl groups of the glycerol are esterified by the medium chain length fatty acids.

The catalyst of the present invention is a metal salt catalyst. This metal salt may be an oxide or chloride of one of the following metals: tungsten, calcium, magnesium, zinc, molybdenum or chromium. Preferred catalysts are tungsten oxide and calcium oxide. Preferred triglycerides prepared by the process of the present invention are triglycerides of caprylic (C8 fatty acids) and capric (C10 fatty acids).

Although the compounds of the present invention are limited to those products that are triesters of medium-chain length fatty acids and glycerol, it will be appreciated by those skilled in the art that certain structural modifications outside the scope of the claims of the present invention are still clearly within the scope of the present invention. For example, medium chain length fatty acid diglycerides can be prepared by the present invention by replacing glycerol with serinol, and thus, two molecules of medium chain length fatty acids are linked to two hydroxyl groups of serinol via esterification, which constitutes one obvious example. Similarly, medium-chain length fatty acid diglycerides and monoglycerides (wherein two and one molecules of medium-chain length fatty acids, respectively, are esterified to glycerol) provide another obvious example. Additionally, one skilled in the art will appreciate that medium chain length fatty acid sources of various carbon chain lengths may be used. Thus, commercially available mixtures of medium chain triglycerides (e.g., mixtures of glycerides of C8 and C10 fatty acids in various ratios) also constitute additional obvious examples. Finally, in another aspect of the invention and in order to solubilize otherwise insoluble drugs, medium chain length triglycerides may be used as delivery vehicles or excipients. In addition, ethyl decanoate and ethanol can be used as co-solvents.

Preferably, the triglycerides synthesized by the process of the present invention are recovered by crystallization from cold alcohol and/or precipitation. The cold alcohol may be ethanol or isopropanol.

The problem currently exists in finding a convenient large scale preparation process that will provide triglycerides of medium chain length fatty acids in high yield, high purity and at a reasonable cost. It has been surprisingly found that when glycerol is mixed with medium chain fatty acids and heated in the presence of metal oxides or chlorides under partial vacuum, a triglyceride product is obtained in high yield and purity after precipitation by ethanol. This high yield and purity overcomes the difficulties associated with large scale purification by column chromatography/distillation. Purification is achieved by dissolving the crude product in an alcohol, followed by cooling the alcohol, preferably in an ice bath, to precipitate a pure triglyceride product, as shown in the examples below.

Triglycerides of medium-chain length fatty acids refer to those triglycerides of monocarboxylic fatty acids with carbon chain lengths of 6 to 12 carbons, including C6 (caproic acid), C8 (caprylic acid), C10 (capric acid) and C12 (lauric acid ). Although chain lengths of even number of carbon atoms constitute a preferred embodiment of the present invention, triglycerides of carboxylic acids of odd number of carbon atom chain lengths of glycerol can also be prepared in high product yield and purity. Chains of odd number of carbon atoms include 7 (heptanoic acid), 9 (nonanoic acid) and 11 (undecanoic acid). According to a preferred embodiment, the triglycerides of medium-chain fatty acids are tricaprates (tricaprans) and tricaprylates (tricaprylin). The reaction temperature is preferably 160 ℃ under a partial vacuum of 10mmHg and more preferably 175 ℃ under the same vacuum. The latter condition completely removes the by-product water formed during the reaction, thereby accelerating the formation of the triglyceride product. Temperatures below 160 ℃ may be less desirable because they reduce the reaction rate and result in a reduced yield of triglyceride product relative to the free fatty acid and glycerol reactants. The crude product is preferably dissolved in cold ethanol, filtered and then crystallized by cold ethanol. Yields of 75% to 95% can be achieved by appropriate choice of reactant ratios, reaction temperature and length.

The triglycerides of the present invention can be formulated by methods known to those skilled in the art using pharmaceutically acceptable carriers (Merck Index, Merck & co., Rahway, NJ). These compositions include, but are not limited to, solids, liquids, oils, emulsions, gels, aerosols, inhalants, capsules, pills, patches, and suppositories.

The triglycerides of the present invention also have physical properties different from those of common fats, such as lower viscosity, solubility in alcohol, non-greasy feel on the skin, and are therefore particularly useful in the pharmaceutical and cosmetic and toiletry industries. However, tricaprin and trilaurin can be used in solid compositions due to their relatively high melting points, in contrast to the mixed triglycerides or caprylic triglyceride described above.

The following examples are provided to illustrate the present invention, but are not intended to limit the scope thereof. These embodiments can be summarized by the following equations:

all HPLC chromatograms and mass spectra were recorded on an HP1100LC-MS Agilent instrument using an analytical Zorbax SB-phenyl chromatographic column with a gradient of 15-99% acetonitrile-water (eluent) containing 0.01% trifluoroacetic acid over a period of 8 minutes at a flow rate of 2 ml/min. An ELSD detector was used to analyze triglycerides.

Example 1: tricaprin (capric acid: n ═ 8)

To a 250mL flask containing glycerol (5.0g,54.3mmol) and equipped with a condenser was added decanoic acid (37.4g,217.2mmol) andcalcium oxide (45.4mg,0.8 mmol). The mixture was heated at 175 ℃ under partial vacuum (1 torr, waterjet vacuum) for 22 hours. The water temperature in the condenser was about 35 ℃ in order to maintain a gentle reflux of decanoic acid and to speed up the removal of water under vacuum. The reaction was cooled to room temperature and the residue was dissolved in hot ethanol (95%, 400 mL). The solution was treated with charcoal, filtered through glass fiber and cooled in an ice bath at 0-5 ℃ for 2 hours. Tricaprin crystallizes as a white solid, which is filtered and washed with cold ethanol (95%, 40 mL). Yield of the product: 27.5g (91%); mp29-31 ℃;¹H NMR(400MHz,CDCl₃):δ5.22-5.29(m,1H),4.29(dd,J＝11.9,J＝4.3,2H),4.14(dd,J＝11.9,J＝6.1,2H),2.26-2.34(m,6H),1.54-1.65(m,6H),1.18-1.36(m,36H),0.87(t,J＝7.0,9H)。¹³C NMR(101MHz,CDCl₃):δ73.54,173.13,69.07,62.32,34.44,34.27,32.09,29.67,29.65,29.51,29.50,29.34,29.30,25.13,25.08,22.90,14.33；MS(ES)m/z578(M+Na⁺)；HPLC:5.6min。

example 2: trilaurin (lauric acid: n ═ 10)

The triglyceride of lauric acid was prepared as described in example 1 by using 15g of lauric acid (74.9mmol), 1.7g of glycerol (18.7mmol) and 15.7mg of calcium oxide (0.28 mmol). Yield of the product: 9g (78%); mp is 45-47 deg.C;¹H NMR(400MHz,CDCl₃):δ5.25-5.28(m,1H),4.29(dd,J＝11.7,J＝4.3,2H),4.14(dd,J＝11.9,J＝6.1,2H),2.28-2.34(m,6H),1.55-1.66(m,6H),1.20-1.36(m,48H),0.87(t,J＝7.0,9H)。¹³C(101MHz,CDCl₃):δ？173.55,173.14,69.07,62.33,34.45,34.29,32.15,29.86,29.73,29.71,29.58,29.53,29.50,29.35,29.31,25.10,22.92,14.36；HPLC:6.5min。

example 3: tricaprylin (caprylic acid: n ═ 6)

Triglycerides of octanoic acid were prepared as described in example 1 by using 11g of octanoic acid (74.9mmol), 1.7g of glycerol (18.7mmol) and 15.7 gmg of calcium oxide (0.28 mmol). Since tricaprylin is a liquid, the crude product was filtered with ethyl acetate/hexane (5-10%) on silica gel instead of glass fiber. This gave the pure product as a colorless oil. Yield: 8g (89%);¹H NMR(400MHz,CDCl₃):δ5.25-5.28(m,1H),4.29(dd,J＝11.9,J＝4.3,2H),4.14(dd,J＝11.9,J＝6.1,2H),2.28-2.34(m,6H),1.56-1.66(m,6H),1.20-1.36(m,24H),0.87(t,J＝7.0,9H)。¹³C(101MHz,CDCl₃):δ173.56,173.14,69.07,62.33,34.45,34.28,31.89,31.88,29.28,29.24,29.16,29.14,25.13,25.08,22.83,14.30；HPLC:4.5min。

example 4: trihexanoic acid ester (hexanoic acid: n ═ 4)

The procedure described in example 1 was slightly modified since the trihexanoic acid ester was a volatile compound. The procedure detailed in example 4 is applicable to a process for the preparation of triglycerides from volatile medium chain length fatty acids, such as fatty acids having a chain of 6 to 7 carbons. To a 250mL flask containing glycerol (1.73g,18.7mmol), equipped with a condenser and a Dean-Stark trap charged with hexanoic acid, was added hexanoic acid (8.7g,74.9mmol) and calcium oxide (15.7mg,0.3 mmol). The mixture was heated at 175 ℃ under vacuum overnight (22 hours, 10 mmHg). The mixture was cooled and dissolved in ethyl acetate. The solution was washed with 10% sodium hydroxide, brine (NaCl), treated with magnesium sulfate-charcoal to remove water and filtered on glass fibers. The filtrate was concentrated to give a yellow oil, which was dissolved in hexane and poured onto 10X 10cm²And (5) placing the silica gel pad. The compound was eluted with 10% ethyl acetate/hexanes. The pure fractions were combined and concentrated to give a colorless oil. Yield: 5.8g, 80%;¹H NMR(400MHz,CDCl₃):δ5.23-5.29(m,1H),4.29(dd,J＝11.9,J＝4.3,2H),4.14(dd,J＝11.9,J＝6.1,2H),2.27-2.34(m,6H),1.56-1.66(m,6H),1.22-1.37(m,12H),0.89(t,J＝7.0,9H)。¹³C(101MHz,CDCl₃):δ173.56,173.14,69.07,62.32,34.39,34.23,31.45,31.41,24.78,24.75,22.51,14.12；HPLC:3.8min.

example 5: yields of triglycerides of medium-chain length fatty acids obtained with different metal catalysts.

Glycerol trihexanoate, glycerol trioctanoate, glycerol tricaprate and glycerol trilaurate were synthesized according to the procedures described in examples 1-4, except that: the calcium oxide catalyst was replaced with magnesium, zinc, tungsten, molybdenum and chromium salts.

Table 1: yields of triglycerides of medium-chain length fatty acids obtained with different catalysts.

All changes and substitutions that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

From the foregoing, it will be apparent to those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are to be considered in all respects only as illustrative and not restrictive, since the scope of legal protection afforded the invention will be indicated by the appended claims rather than by the description herein.

Claims (24)

1. A process for the preparation of triglycerides of medium-chain length fatty acids comprising the steps of:

a) mixing glycerol with 3 molar equivalents or an excess of the medium-chain length fatty acids, wherein each of the medium-chain length fatty acids contains a chain of 6 to 12 carbons;

b) reacting the mixture of step (a) with a divalent or trivalent metal cation catalyst; and

c) heating at a temperature of 160 ℃ to 180 ℃ under a partial vacuum for a time sufficient to form the triglyceride, wherein the partial vacuum is 1mmHg to 20 mmHg;

wherein the method excludes column chromatography or distillation.

2. The method of claim 1, wherein the glycerol is mixed with an excess of the fatty acid.

3. The method of claim 1 or 2, wherein the heating temperature in step (c) is about 175 ℃.

4. The method of claim 1, wherein the partial vacuum is about 10 mmHg.

5. The method of any one of claims 1 to 4, wherein the heating step (c) is for a period of 8 to 24 hours.

6. The process of any one of claims 1 to 5, wherein the catalyst is tungsten oxide, tungsten chloride, tungsten carbonyl, calcium oxide, calcium chloride, magnesium oxide, magnesium chloride, zinc oxide, zinc chloride, molybdenum oxide, molybdenum chloride, chromium oxide, or chromium chloride.

7. The method of claim 6, wherein the catalyst is calcium oxide, tungsten oxide, or zinc oxide.

8. The method of any one of claims 1 to 7, wherein each of the medium-chain length fatty acids contains a chain of 6 carbons.

9. The method of any one of claims 1 to 7, wherein each of the medium-chain length fatty acids contains a chain of 8 carbons.

10. The method of any one of claims 1 to 7, wherein each of the medium-chain length fatty acids contains a chain of 10 carbons.

11. The method of any one of claims 1 to 7, wherein each of the medium-chain length fatty acids contains a 12-carbon chain.

12. The method of any one of claims 1 to 7, wherein the medium-chain length fatty acids comprise fatty acids having a chain of 8 carbons and fatty acids having a chain of 10 carbons.

13. The method of any one of claims 1 to 7 and 9 to 12, wherein each of the medium-chain length fatty acids contains a chain of 8 to 12 carbons, the method further comprising the steps of:

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding hot alcohol so as to form an alcohol solution, wherein the temperature of the hot alcohol varies from 60 ℃ to an alcohol boiling temperature;

g) filtering the alcohol solution and obtaining a filtered solution; and

h) maintaining the filtered solution at a temperature between 0 ℃ and 20 ℃ for a time sufficient to crystallize the triglycerides formed.

14. The method of claim 13, wherein the hot alcohol is ethanol and has a temperature of about 80 ℃.

15. The method of claim 13 or 14, further comprising a step performed prior to step (h), wherein cold alcohol is added to the filtered solution of step (g), wherein the cold alcohol has a temperature of 0 ℃ to 5 ℃.

16. The method of claim 13, wherein the alcohol is ethanol or isopropanol.

17. The process according to any one of claims 13 to 16, wherein the temperature is maintained in step (h) for at least 1 hour.

18. The process of any one of claims 1 to 7, wherein each of the medium-chain length fatty acids contains a chain of 6 to 7 carbons, the process further comprising the steps of:

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding an organic solvent for dissolving the triglyceride to form an organic solution;

g) adding an aqueous sodium hydroxide solution to the organic solution;

h) recovering the organic solution and discarding the aqueous solution;

i) treating the organic solution with a desiccant;

j) filtering the organic solution through silica gel;

k) treating the organic solution with a desiccant; and

l) evaporating the organic solvent.

19. The method of claim 18, wherein the organic solvent is hexane, dichloromethane, ethyl acetate, or an ether.

20. The method of claim 18 or 19, wherein the desiccant is magnesium sulfate or sodium sulfate.

21. The process according to any one of claims 1 to 7, wherein the process produces triglycerides in a yield of 75% to 95% and a purity of at least 99%, wherein the process comprises the steps of:

a) mixing glycerol with at least 3 molar equivalents of the medium-chain length fatty acids, wherein each medium-chain length fatty acid contains a chain of 8 to 12 carbons;

b) reacting the mixture of step (a) with calcium oxide, tungsten oxide or zinc oxide;

c) heating at a temperature of about 175 ℃ under a partial vacuum of about 10mmHg for a period of about 22 hours such that the triglyceride is formed;

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding hot alcohol at a temperature of about 80 ℃ to form an alcohol solution;

g) filtering the alcohol solution and obtaining a filtered solution; and

h) maintaining the filtered solution at a temperature between 0 ℃ and 5 ℃ for a period of about 2 hours.

22. The process of claim 21, wherein the process produces triglycerides having a purity of at least 99.5%.

23. The process according to any one of claims 1 to 7, wherein the process produces triglycerides in a yield of 75% to 95% and a purity of at least 99%, wherein the process comprises the steps of:

a) mixing glycerol with at least 3 molar equivalents of the medium-chain length fatty acids, wherein each of the medium-chain length fatty acids contains a chain of 6 to 7 carbons;

b) reacting the mixture of step (a) with calcium oxide, tungsten oxide or zinc oxide;

c) heating at a temperature of about 175 ℃ under a partial vacuum of about 10mmHg for a period of about 22 hours such that the triglyceride is formed;

d) removing the partial vacuum;

e) cooling at a temperature of 80 ℃ or less;

f) adding an organic solvent for dissolving the triglyceride to form an organic solution;

g) adding 1-2% (w/w) NaOH aqueous solution;

h) recovering the organic solution and discarding the aqueous solution;

i) treating the organic solution with a desiccant;

j) filtering the organic solution through silica gel;

k) treating the organic solution with a desiccant; and

l) evaporating the organic solvent.

24. The process of claim 23, wherein the process produces triglycerides having a purity of at least 99.5%.