WO2013057110A1

WO2013057110A1 - Method for the synthesis of citric acid esters

Info

Publication number: WO2013057110A1
Application number: PCT/EP2012/070501
Authority: WO
Inventors: Hans-Josef Altenbach; Karsten Lange; Sukhendu Nandi; Rachid Ihizane; Bernd Jakob; Manfred Schneider
Original assignee: Bergische Universität Wuppertal
Priority date: 2011-10-19
Filing date: 2012-10-16
Publication date: 2013-04-25
Also published as: EP2768795A1; DE102011054602A1

Abstract

The present invention discloses a targeted synthesis method for the synthesis of asymmetric monoesters and/or symmetrical diesters of citric acid through acidic esterification by using boric acid or a boronic acid as a catalyst. The boric/boronic acid simultaneously acts as a catalyst, as well as a "protecting group" for the tertiary carboxylic acid, and therefore specifically only the asymmetric monoesters or symmetrical diesters are created.

Description

Process for the synthesis of citric acid esters

The present invention relates to the targeted synthesis of citric acid esters.

Citric acid esters are of industrial interest, as they may i.a. be used as emulsifiers or surfactants. Of particular importance are the monoesters of fatty alcohols, polyethoxylated fatty alcohols and mono- and diglycerides. Such esters are already used in the food industry, in cosmetics and in

Detergents. The advantages are the good compatibility (non-toxic, non-irritating to the skin), the biological degradation work and their production starting from renewable

Raw materials.

Due to the chemical structure of citric acid, there are two isomeric mono- and diesters of citric acid (see US Pat. No. 4,866,203 and the state of the art cited therein), favorable and efficient syntheses of citric acid esters, in particular mono- and diesters, which are specifically (predominantly) provide only one of the Citronensäureesterisomeren, but are so far essentially unknown.

The object thus is a process for the targeted synthesis of

Citric acid mono- and diesters provide which predominantly provides only one isomer and which is particularly feasible under mild conditions. This object is solved by claim 1 of the present invention. Accordingly, a process for the synthesis of asymmetric mono- and / or symmetrical diesters of citric acid is presented, comprising the step a) reaction of citric acid with alcohol in the presence of boric acid and / or at least one boronic acid.

Surprisingly, it has been found that the asymmetric mono- or symmetrical diesters of citric acid are produced almost exclusively (depending on the amount of alcohol used) by this process.

By "asymmetric citric acid monoesters" is meant esters which have been esterified to one of the primary carboxylic acid function of citric acid, i.e., in particular have the following structure:

It should be noted that these esters are chiral. In the process according to the invention, the racemate or the achievable ee is usually minimal.

By "symmetrical citric acid diesters" is meant esters which have been esterified on both primary carboxylic acid functions of citric acid, while the tertiary carboxylic acid is unesterified, ie in particular esters of the following structure:

It will be understood by those skilled in the art that R and R 'may be the same or different depending on the reaction, also R and R' may form a ring, i. be connected to each other.

The term "alcohol" is not to be understood as restricting that an alcohol mixture can not also be used, which may very well constitute a preferred embodiment of the invention.Also, the term "alcohol" should not be understood to mean that phenols can not be used ,

It should be noted that polyhydric alcohols / polyols can also be used; then, as expected, higher oligomers are formed. This surprising finding has been studied more closely and, without being fixed, the following mechanism is believed to be most plausible

In the case of boric acid, it is assumed that the following complex arises initially:

The proton "remains" - so the assumption - in the vicinity of the complex and can thus protonate one of the carboxylic acids, something like this:

This would explain why even a substoichiometric amount of boric acid is enough to selectively carry out the reaction. Finally, a common acid-catalyzed esterification, probably analogous to the mechanism of "Fischer esterification".

In the event that boronic acids are used, an analogous complex with only one citric acid is suspected.

It should be noted at this point that the boric acid can also be generated from precursors or in situ, e.g. from sodium borohydride or borane / THF. These reagents also react. Thus, "boric acid" in the sense of the invention means any boron compound which reacts under reaction conditions (alcohol, acid) at least partially to form boric acid or the boron-citric acid complex indicated above Preferred boronic acids are (due to their increased stability and availability) arylboronic acids or Heteroarylboronic acids. It has been found that

in particular, electron-rich phenylboronic acids such as, for example, 2,4,6-trimethyl-, 4-methoxy- and 4-dimethylamino-phenylboronic acid are particularly suitable and preferred. Particular preference is thus given to 2,4,6-trimethylphenylboronic acid, 4-methoxyphenylboronic acid and 4-dimethylaminophenylboronic acid and mixtures of these acids.

Of course, the boronic acid may also be suitable, analogous to boric acid

Precursors are synthesized in situ. Thus, "boronic acid" in the context of the invention means any boron compound which under reaction conditions (alcohol, acid) at least partially reacts to form a boronic acid or directly to a boronic acid / citric acid complex.

The reaction can of course also with a mixture of boric acid and

Boronic acid (s) are performed. The boric acid and / or the boronic acid is preferably used in step a) in a molar fraction of> 1 to <60%, preferably> 5 to <40% (in the case of mixtures, the molar fraction refers to the sum of the components). This procedure has proven itself in practice, since such a speedy implementation takes place. Preferably, step a) takes place at a temperature of> -20 ° C and <100 ° C, preferably> 0 ° C and <80 ° C and most preferably at> 15 ° C and <30 ° C instead.

Preferably, step a) takes place in the presence of a dipolar aprotic solvent, preferably selected from the group consisting of ethyl acetate, tetrahydro-uran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, Ν, Ν-dimethylformamide, dimethyl sulfoxide, 1,2-dichloroethane, acetone, Ν , Ν-dimethylacetamide, dimethoxyethane, still preferably ethyl acetate, tetrahydro-uranium, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, 1, 2-dichloroethane, Ν, Ν-dimethylacetamide, chlorobenzene, toluene, Dimethoxyethane, hexane, o-dichlorobenzene, more preferably 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, 1, 2-dichloroethane, Ν, Ν-dimethylacetamide and chlorobenzene or mixtures thereof. These solvents have proven themselves in practice. Alternatively, step a) can also be carried out without a solvent if the alcohol used is liquid.

The duration of the reaction of step a) depends strongly on the temperature used; Usually the reaction is carried out until no further product is formed. The reaction takes place only in the acid, so by addition of base, the reaction can be stopped in a simple manner.

The preferred ratio of alcohol to citric acid depends on whether specific mono- or diesters are to be synthesized.

In the case that monoesters are to be synthesized, a ratio of

Citric acid to alcohol (mohmol) of> 1: 1 and <10: 1, preferably> 1.5: 1 and <5: 1 proven and is insofar preferred. In the event that diesters are to be synthesized, the ratio of alcohol to citric acid (mohmol) of> 2: 1 and <20: 1, preferably> 3: 1 and <10: 1, is preferred.

In some cases, however, mono / diester mixtures are the preferred reaction products, in which case a ratio of alcohol to citric acid (mokmol) of> 1.5: 1 and <5: 1 is preferably used The recovery of the reaction product can be carried out in various ways and also depends on its physical properties such as melting point or solubility. In practice, the following work-up methods have proven effective when using boric acid: Removal of the boric acid (eg via extraction in weak acid and / or addition of a complexing agent such as mannitol etc.)

Removal / recovery of boric acid and optionally excess citric acid by extraction of the reaction product with a suitable, sufficiently nonpolar

Solvents (e.g., chloroform or ethyl acetate / hexane mixtures). Boron and

Citric acid remain as an insoluble residue.

Removal / recovery of boric acid and possibly excess citric acid by extraction with water or acid

Precipitation of monoesters as (e.g.) disodium salt by reaction with base

When using boronic acids, the following work-up methods have proven useful: precipitation of monoesters as (for example) disodium salt by reaction with base

Chromatoraphic purification on silica gel; This is a proven method, especially for diesters. Further details, features and advantages of the subject matter of the invention will become apparent from the subclaims and from the following description of the accompanying examples in which - by way of example - several embodiments of the invention Method are shown. The examples are purely illustrative and not restrictive.

General working instructions (AAV) on the boron / boronic acid-catalyzed esterification of citric acid with alcohols

AAV1: Synthesis of "technical" monoester / diester mixtures without isolation of the

Individual components The alcohol (1.5-3 equivalents), citric acid (1 equivalent) and boron / boronic acid (5-40%, based on the citric acid) are added at room temperature or below

Heating (preferably <80 ° C) reacted. In general, the use of a

Solvent not required. If so, for example, tetrahydrofuran or acetone can be added. The reaction can be stopped / stopped by adding about one equivalent of a base according to the boron / boronic acid used.

Alternatively, boric acid can also be removed by means of aqueous extraction. This is particularly well achieved by using dilute acids (e.g., 0.1N hydrochloric acid) or a boric acid-complexing agent, e.g. Mannitol is used.

This method is particularly suitable for the use of polyethoxylated fatty alcohols.

AAV2: Synthesis and Isolation of Unsymmetrical Citric Acid Monoesters The citric acid (1.5-5 equivalents) is dissolved in a solvent such as THF or acetone. The alcohol (1 equivalent) and the boron boronic acid (5-40% based on the citric acid used) are reacted at room temperature or with heating (preferably <70 ° C). The conversion of alcohol is usually 85-95%. The excess citric acid can be recovered (especially when using boric acid). For this purpose, the solvent is optionally removed and the product is extracted with a suitable solvent (eg chloroform or

Ethyl acetate / hexane mixtures). The citric acid and a part of the boric acid then remain as insoluble residue, can be separated and reused. The citric acid monoester (crude product) obtained after removal of solvents can be further purified by recrystallization. Alternatively, boric acid and citric acid can be removed by aqueous extraction. For this purpose, volatiles are removed in vacuo and then, e.g. Ethyl acetate added. With an aqueous extraction (see AAV1) citric acid and boric acid are removed. After washing (e.g., saturated NaCl solution), drying (e.g.

Magnesiumsultat) and removing solvents obtained citric acid monoester (crude product) can be further purified by recrystallization.

The citric acid monoesters (crude products) obtained according to AAV2 can also be used as salts, e.g. as disodium salt. For this purpose, the following procedure has proved particularly advantageous: A solution of the citric acid monoester is added to a saturated solution of sodium acetate (2 equivalents) in a methanol / acetone mixture. The precipitate is filtered off with suction and dried. When using boronic acid as

Catalyst, this work-up method is usually the simplest and most proven in practice. AAV3: Synthesis and Isolation of Symmetric Citric Acid Esters

The alcohol (2-10 equivalents), citric acid (1 equivalent) and boron / boronic acid (5-40%, based on the citric acid used) are reacted at room temperature or with heating (preferably <80 ° C). As a solvent (which is not absolutely necessary For example, tetrahydrofuran or acetone may be added. The conversion to the diester can be increased by removing the water of reaction. This is possible, for example, by the addition of magnesium sulfate, in low-volatility alcohols can

Reaction water can also be removed in vacuo.

For the purification of the diester (when using boric acid as catalyst), for example, ethyl acetate is added and the boric acid is removed by means of aqueous extraction (see AAV1). The crude product is generally still contaminated by monoesters, excess alcohol and possibly also triesters. The monoester can often be removed by shaking it out with an aqueous base (in some cases the diester precipitates as a sparingly soluble salt after base addition and can be isolated directly).

Excess alcohol can also be removed in the vacuum in the case of low-boiling alcohols. For high-boiling alcohols, a chromatographic separation is possible. Alternatively, the diester can also be purified by recrystallization. However, in the case of fatty alcohols, the diester then accumulates as an adduct of one equivalent

Fatty alcohol out.

example 1

Synthesis of a technical citric acid mono / diester mixture with polyethoxylated fatty alcohols (Walloxen LM 40)

3.84 g of triturated anhydrous citric acid (20 mmol), 14.80 g of Walloxen LM 40 (40 mmol, technical mixture of polyethoxylated C12 / C14 fatty alcohols) and 124 mg of boric acid (2 mmol) were combined and stirred at room temperature for 5 days a colorless, clear solution formed. By adding 252 mg (3 mmol) of sodium bicarbonate, the reaction was stopped.

Example 2 Synthesis of a technical citric acid monoester with polyethoxylated fatty alcohols (Walloxen LM 40) - isolation as disodium salt

4.80 g of anhydrous citric acid (25 mmol), 7.40 g of Walloxen LM 40 (20 mmol) and 124 mg of boric acid (2 mmol) were suspended in 6 ml of acetone and stirred at room temperature for 5 days. After addition of 200 ml of ethyl acetate, 100 ml of a solution consisting of 2.5 g of mannitol, 70 ml of water, 4 ml of dil. HCl and 26 ml of sat. Shaken out NaCl solution in two portions (50 ml). The organic phase was washed twice with saturated NaCl solution.

washed, dried over magnesium sulfate and concentrated on a rotary evaporator, whereupon 9.4 g (86%) of a colorless oil were obtained.

7.29 g (13.4 mmol) of crude product were dissolved in 15 ml of methanol and 15 ml of acetone. 3.35 g (41 mmol) of sodium acetate were dissolved in 50 ml of methanol, 50 ml of acetone were added, the solutions were combined and allowed to stand overnight. The precipitate was filtered off with suction, washed with a little MeOH / acetone and dried in air or in a high vacuum.

There were obtained 3.35 g of a colorless solid. Example 3

Synthesis of unsymmetrical citric acid monododecyl ester

200 g of triturated, anhydrous citric acid (1.04 mol) were dissolved in 450 ml of tetrahydrofuran. 100 g of dodecanol (537 mmol) and 3.4 g of boric acid (55 mmol) were added.

On a rotary evaporator 240mL of solvent were separated. The remaining solution was stirred for 3 days at room temperature. After addition of 350 ml of ethyl acetate was washed twice with 600 ml of a solution of 200 ml of IN HCl, 200 ml of deionized water and 200mL sat.

NaCl solution, washed 2x with 200 ml sat. Washed with NaCl solution and dried over magnesium sulfate. After concentration on a rotary evaporator was the

Residue was recrystallized from 700 ml of cyclohexane, whereupon 107.9 g (54.8%)

Citric acid monoesters were obtained as a colorless solid. 1H-NMR (600.1 MHz, acetone-d6): δ = 10.50 (very wide, 1-2H); 4.06 (t, 2H); 2.98-2.84 (4xd, 4H); 1.63 (t, 2H); 1.30 (s, br. 18H); 0.89 (t, 3H) ppm

13 C-NMR (150.9 MHz, acetone-d6): δ = 175.62; 172.40; 171.01; 74.31; 65.81; 44.37; 43.84; 33.24; 31.00; 30.97; 30.94; 30.88; 30.76; 30.69; 30.63; 30.61; 30.50; 30.37; 30.24; 29.91; 27.21; 23.94; 15.00 ppm

Example 4

Synthesis of unsymmetrical citric acid monohexadecyl ester

200 g of triturated, anhydrous citric acid (1.04 mol) were dissolved in 250 ml of THF and 330 ml of acetone. 126.2 g of hexadecanol (521 mmol) and 4.79 g of boric acid (77.4 mmol) were added. The reaction mixture was stirred at 35 ° C for 3 days. After addition of 400 ml of ethyl acetate with 600 ml of a solution consisting of 200 ml of IN HCl, 200 mL of deionized water and 200 ml of sat. Shaken out NaCl solution, washed twice with 300 ml sat. NaCl solution and dried over magnesium sulfate. After concentration on

Rotary evaporator, the residue was recrystallized from 600 ml of cyclohexane, thereby 153.2g (70.7%) of citric acid monoesters were obtained as a colorless solid.

1H-NMR (400 MHz, CDC13): δ = 12.5-8.5 (s, 1-2H); 4.07 (t, 2H); 2.97 (d, 1H); 2.95 (d, 1H); 2.87 (d, 1H); 2.86 (d, 1H); 1.64 (quint., 2H); 1.31 (s, 26H); 0.90 (t, 3H) ppm

13 C-NMR (100.6 MHz, CDC13): δ = 175.56; 172.33; 171.07; 74.45; 65.89; 44.46; 43.90; 33.31; 31.07; 31.04; 31.00; 30.93; 30.88; 30.73; 30.69; 30.67; 30.50; 30.31; 30.11; 30.03; 27.29; 23.99; 15.01 ppm

Example 5

Synthesis of Unsymmetrical Citric Acid Monooleyl Ester - Isolation as Disodium Salt 23.82 g of triturated, anhydrous citric acid (124 mmol) was dissolved in 50 ml of THF. 23.82 g (82.7 mmol) of technical grade oleyl alcohol (60%) and 511 mg of boric acid (8.3 mmol) were added. It was stirred for 5 days at room temperature, then added to 450 ml of ethyl acetate and extracted by shaking twice with 100 ml of 0.25 N HCl. The org. Phase was 2x with 110 ml sat. NaCl Washed solution, dried over MgSO 4 and concentrated on a rotary evaporator. The crude product (35.6 g) was dissolved in 40 ml of acetone and 40 ml of MeOH. A solution of 14.0 g (171 mmol) of sodium acetate in 200 ml of MeOH and 175 ml of acetone was added. After 1.5 h, the precipitate was filtered off with suction, washed with 80 ml of MeOH / acetone 1: 1 and dried under high vacuum. 26.63 g (66%) of the citric acid monoester were obtained as a colorless solid.

Example 6

Synthesis of Unsymmetrical Monooleoylglyceride Citric Acid Monoester - Isolation as a) Free Dicarboxylic Acid and b) Disodium Salt

3.84 g of triturated, anhydrous citric acid (20 mmol) were dissolved in 8 ml of tetrahydrofuran, 3.56 g of monooleyl glycerol (10 mmol) and 123 mg of boric acid (2 mmol) were added. It was stirred for one day at room temperature, removed on a rotary evaporator about 4 ml of solvent and stirred for a further two days at room temperature. 100 ml of ethyl acetate were added and washed with 0.5 N HCl. It was then washed with water

Extracted triethanolamine solution. The aqueous phase was acidified with hydrochloric acid and extracted with 100 ml of ethyl acetate. The org. Phase was 2x with sat. NaCl solution, dried over MgSO 4 and concentrated on a rotary evaporator and at the HV. A) 2.19 g (41%) of a colorless oil were obtained. MS (Flowinjection; ESI-): [M-H] - = 529.303 (main signal)

b) 1.5 g of the monoester (2.83 mmol) were dissolved in 3 ml of acetone and 2 ml of methanol. 451 mg of sodium acetate (5.5 mmol) were dissolved in 8 ml of methanol, then 6 ml of acetone were added. Both solutions were combined, after six hours of standing, the precipitate was filtered off and dried under high vacuum. Yield: 0.8 g (49%) of colorless solid.

13 C NMR (100.6 MHz; D20): □ = 182.1; 180,5; 176.6; 174.2; 131.6; 131.4; 76.7; 69.0; 67.4; 66.7; 47.7; 45.6; 35.7; 33.8; 31.5; 31.2; 31.0; 29.1; 29.0; 26.6; 24.5; 15.7 ppm.

Example 7 Synthesis of Symmetric Citric Acid Dimethyl Ester - Isolation as Monohydrate 50.0 g of anhydrous citric acid (260.2 mmol) and 1.5 g of boric acid (24.3 mmol) were initially charged. 70 ml of methanol and 80 ml of acetone were added. It was stirred for 3 days at RT. Thereafter, 80 ml of acetone were added and cooled in an ice bath for 2 hours. The precipitate was filtered off, washed with 60 ml of acetone: methylene chloride (1: 1) and dried under high vacuum. Yield: 49.4 g (79.7%); colorless solid

1H-NMR (600 MHz, d6-DMSO): δ = 3.56 (s, 6H); 2.79 (q, 4H) ppm

13 C-NMR (150.9 MHz; d6-DMSO): □ = 174.34; 170.02; 72.66; 51.48; 42.76 ppm Example 8

Reaction of citric acid with benzyl alcohol - Isolation of a) symmetrical

Citric acid dibenzyl ester (as sodium salt) and b) unsymmetrical

Citronensäuermonobenzylesters

150 g of anhydrous citric acid (780 mmol), 212 g of benzyl alcohol (1960 mmol) and 5 g of boric acid (62 mmol) were stirred for 3 days at room temperature (clear solution). 400 ml

Ethyl acetate was added, then adjusted to pH = 8 with 10% NaOH solution. This resulted in a suspension (the sodium salt of the dibenzyl ester precipitated as a solid in the organic phase). To complete the precipitation was allowed to stand for two days. It was sucked off via a suction filter. The precipitate was washed with water and ethyl acetate, dried under high vacuum to give a) 53.8 g of the symmetrical dibenzyl ester as the sodium salt. For analytical characterization, a small sample was acidified, extracted with CDC13, dried over magnesium sulfate and analyzed by NMR spectroscopy.

1H-NMR (400 MHz, CDC13): δ = 12.5-8.5 (s, 1H); 7.36 (s, 10H); 5.17 (s, 4H); 3.00 (q, 4H) ppm

13 C-NMR (100.6 MHz; CDC13): □ = 177.14; 169.74; 135.09; 128.47; 128.29; 128.19; 73.01; 66.90; 42.67 ppm For filtrate b), the phases were separated. The aqueous phase was acidified with 6N HCl and extracted 2 x with 400 ml of ethyl acetate. The united org. Phases were 2x with sat. NaCl solution, dried over magnesium sulfate and on

Concentrated rotary evaporator. The residue (92 g) was dissolved in 400 ml of chloroform, and after addition of seed crystals, 350 ml of iso-hexane were slowly added dropwise with stirring. After 20 h, the precipitate was filtered off with suction and dried in a high vacuum, whereupon 60.0 g of the unsymmetrical Citronensäuremonobenzylesters were obtained as a colorless solid.

1H-NMR (400 MHz, CDC13): δ = 12.0-9.5 (s, 1-2H); 7.42-7.30 (m, 5H); 5.14 (s, 2H); 3.06-2.87 (m, 4H) ppm

13C-NMR (100.6 MHz, CDC13): □ = 175.61; 172.41; 170.88; 137.73; 129.87; 129.45; 74.35; 67.39; 44.39; 43.86 ppm

Example 9

Reaction of citric acid with decane-1, 10-diol biscitric acid monoester

80.3 g of anhydrous, triturated citric acid (418 mmol) were dissolved in 200 ml of THF. 9.1 g of decanediol (52.3 mmol) and 618 mg of boric acid (10 mmol) were added. After 5 h of stirring at room temperature, 85 g of THF were removed on a rotary evaporator. The mixture was stirred at RT for 5 days, the solvent was removed on a rotary evaporator, 500 ml of ethyl acetate were added, with a mixture of water / dil. HCl and sat. Washed NaCl solution, dried over magnesium sulfate and concentrated on a rotary evaporator and at the HV. The crude product (29.8 g) was dissolved in methanol and added to a solution of 17.2 g of NaOAc in 350 ml of methanol, in which case the tetrasodium salt precipitated, was filtered off, washed with methanol and acetone and dried in vacuo. Yield: 26.3 g (82%)

1 H NMR (400 MHz, D 2 O): δ = 4.05 (t, 4H); 2.90-2.52 (m, 8H); 1.60 (quint., 4H); 1.27 (s, br. 12H) ppm

13 C-NMR (100.6 MHz; D20): □ = 181.59; 179.25; 174.63; 76.32; 67.48; 46.81; 45.28;

30.57; 30.34; 29.65; 27.04 ppm Example 10

Reaction screening; Reaction of citric acid with various alcohols

In each case 1 ml of the relevant alcohol was reacted with 350 mg of anhydrous, triturated citric acid (1, 8 mmol) and 11 mg of boric acid. The conversion was monitored by NMR. In all cases, the formation of citric acid mono- and was

Citric acid diesters observed. Alcohols used: 2-phenylethanol, allyl alcohol, glycol, butane-1,4-diol, 2-butanol, tert-butanol, glycerol Example 11

Catalyst Screening; Reaction of citric acid with benzyl alcohol

In each case 0.2 g of citric acid, 0.8 ml of benzyl alcohol and 10 mg (10 μΐ) of catalyst were stirred for 1-6 days at room temperature. The following catalysts or catalyst precursors were used: phenylboronic acid, 3-nitrophenylboronic acid, 4-dimethylaminophenylboronic acid, 4-trifluoromethylphenylboronic acid, 2,4,6-trimethylphenylboronic acid, 3-thiophenylboronic acid, 3-trifluoromethoxyphenylboronic acid, 4- Methoxyphenylboronic acid, boric acid, sodium borohydride, BH3-THF (1 molar).

Since the citric acid is not / hardly soluble in benzyl alcohol, initially there is a suspension. As the reaction progressed, a clear solution formed in all cases (except sodium borohydride). The reaction was also monitored by TLC (silica gel 60 on aluminum foil, eluent: hexane / ethyl acetate / formic acid = 4: 6: 0.1, detection UV 254 nm). Rf = 0.48 (benzyl alcohol); Rf = 0.27 (symmetrical dibenzyl ester); Rf = 0-0.14 (asymmetric monobenzyl ester). The formation of citric acid mono- and diesters could be detected in all cases, the diester content was often low. The Reactivity was lowest for sodium borohydride. The reactivity can thus be classified approximately qualitatively as follows:

Boric acid> 3-nitrophenylboronic acid ~ 4-trifluoromethylphenylboronic acid ~ 4-methoxyphenylboronic acid> 3-thiophenylboronic acid ~ 3-trifluoromethoxyphenylboronic acid>

Phenylboronic acid ~ 4-dimethylamino-phenylboronic acid ~ 2,4,6-trimethyl-phenylboronic acid ~ BH3-THF> sodium borohydride

A high proportion of diester formation was found in the following catalysts: boric acid, 2,4,6-trimethylphenylboronic acid and 4-methoxyphenylboronic acid.

A strikingly low proportion of diester formation was found when using 4-dimethylamino-phenylboronic acid. Example I 1a

Isolation of the Asymmetric Monobenzyl Ester as Disodium Salt - Catalyst: 4-dimethylphenylboronic acid After 6 days reaction time, 20 ml of ethyl acetate were added. It was with a

Mixture of 1 ml IN HCl, 3 ml water and 1 ml sat. Shaken out NaCl solution and washed with 10 ml sat. Washed NaCl solution. The org. Phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 1 ml of methanol and 1 ml of acetone, and this solution was added to a solution of 165 mg of sodium acetate in 3 ml of Metahnol and 3 ml of acetone. After standing overnight, the precipitate was filtered off, washed with acetone and dried under high vacuum. This gave 136 mg as a colorless solid. 1 H NMR (400 MHz, D 2 O): δ = 7.34 (s, 5H); 5.05 (s, 2H); 4.66 (s, 1H), 2.89-2.44 (m, 4H) ppm

13 C NMR (100.6 MHz, D 2 O): δ = 182.04; 180.48; 174.42; 137.42; 130.57; 130.27; 129.94; 76.61; 68.63; 47.48; 45.11 ppm

Example I Ib

Isolation of the symmetrical dibenzyl ester as monosodium salt - Catalyst: 4-Methoxyphenylboronic acid

After 6 days of reaction, 4 ml of ethyl acetate were added. A saturated

Sodium bicarbonate solution was added portionwise with shaking until the pH of the aqueous phase became 7 (0.8 ml). After standing overnight, a precipitate had formed in the organic phase, which was filtered off and dried. This gave 25 mg of a colorless solid.

5 mg was taken up in 0.5 ml of ethyl acetate and acidified with 2N HCl. In the DC only one product was recognizable. Rf = 0.27 (symmetrical citric acid citric acid ester)

The individual combinations of the components and the features of the already mentioned embodiments are exemplary; the exchange and substitution of these teachings with other teachings contained in this document with the references cited are also expressly contemplated. The person skilled in the art recognizes that variations,

Modifications and other embodiments described herein may also occur without departing from the spirit and scope of the invention. Accordingly, the above description is illustrative and not restrictive. The word used in the claims does not exclude other ingredients or steps. The indefinite article "a" does not exclude the meaning of a plural, the mere fact that certain measurements are in mutually different Claims are recited, does not make it clear that a combination of these dimensions can not be used to advantage. The scope of the invention is defined in the following claims and the associated equivalents.

Claims

1. A process for the synthesis of asymmetric mono- and / or symmetrical diesters of citric acid, comprising the step a) reaction of citric acid with alcohol in the presence of boric acid

and / or at least one boronic acid

2. The method of claim 1, wherein the boric acid / boronic acid in step a) in a molar ratio of> 1 to <60% based on the citric acid is used.

3. The method of claim 1 or 2, wherein step a) takes place at a temperature of> -20 ° C and <100 ° C.

4. The method according to any one of claims 1 to 3, wherein step a) takes place in the presence of a dipolar aprotic solvent

5. The method according to any one of claims 1 to 3, wherein step a) without solvent

is carried out.