DE102011054602A1 - Process for the synthesis of citric acid esters - Google Patents

Abstract

The present invention discloses a specific synthesis method for the synthesis of asymmetric mono- and / or symmetrical diesters of citric acid by acid esterification by means of boric acid or a boronic acid as catalyst. The boron / boronic acid simultaneously acts as a catalyst as well as a "protecting group" for the tertiary carboxylic acid, so that specifically only the asymmetric mono- or symmetrical diesters are formed.

Description

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, cosmetics and detergents. The advantages are the good compatibility (non-toxic, non-irritating to the skin), the biological degradation work as well as 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 below) US 4,866,203 and the prior art cited therein), favorable and efficient syntheses of citric acid esters, especially mono- and diesters, which selectively provide (predominantly) only one of the citric acid ester isomers, however, are hitherto essentially unknown.

It is therefore the object to provide a process for the targeted synthesis of citric acid mono- and diesters, which predominantly provides only one isomer and which can be carried out in particular under mild conditions.

This object is solved by claim 1 of the present invention. Accordingly, a method for the synthesis of asymmetric mono- and / or symmetric 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, ie 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 esterified on both primary carboxylic acid functions of citric acid while the tertiary carboxylic acid is unesterified, i. 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 limiting that an alcohol mixture can not be used; this may well represent a preferred embodiment of the invention. Likewise, 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 context 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) aryl boronic acids or heteroaryl boronic acids. It has been found that in particular electron-rich phenylboronic acids such as 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 also 4-dimethylaminophenylboronic acid and mixtures of these acids.

Of course, the boronic acid may also be synthesized in situ from suitable precursors in analogy to boric acid. 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 be carried out with a mixture of boric acid and boronic acid (s).

The boric acid and / or boronic acid is preferably used in step a) in a molar proportion 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.

Preferably, step a) takes place in the presence of a dipolar aprotic solvent, preferably selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, 1,2-dichloroethane, acetone , N, N-dimethylacetamide, dimethoxyethane, still preferably ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane, N, N-dimethylacetamide, chlorobenzene, toluene, dimethoxyethane , Hexane, o-dichlorobenzene, more preferably 1,4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane, N, N-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 event that monoesters are to be synthesized, a ratio of citric acid to alcohol (mol: mol) of ≥ 1: 1 and ≦ 10: 1, preferably ≥ 1.5: 1 and ≦ 5: 1 has proved successful and is insofar prefers.

In the event that diesters are to be synthesized, the ratio of alcohol to citric acid (mol: mol) 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 (mol: mol) of ≥ 1.5: 1 and ≦ 5: 1 is preferably used

• – Entfernen der Borsäure (z.B. über Extraktion im schwach Sauren und/oder Zugabe eines Komplexierungsmittels wie Mannitol etc.)
• – Entfernen/Rückgewinnen von Borsäure und ggf. überschüssiger Citronensäure durch Extraktion des Reaktionsprodukts mit einem geeigneten, genügend unpolaren Lösemittel (z.B. Chloroform oder Ethylacetat/Hexan-Gemische). Bor- und Citronensäure verbleiben als unlöslicher Rückstand.
• – Entfernen/Rückgewinnen von Borsäure und ggf. überschüssiger Citronensäure durch Extraktion mit Wasser bzw. Säure
• – Ausfällen von Monoestern als (z.B.) Dinatriumsalz durch Umsetzung mit Base

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 successful when boric acid is used:

• Removing the boric acid (eg by extraction in a weak acid and / or adding 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 solvent (eg chloroform or ethyl acetate / hexane mixtures). Boron and citric acid remain as insoluble residue.
• Removal / recovery of boric acid and possibly excess citric acid by extraction with water or acid
• - precipitation of monoesters as (for example) disodium salt by reaction with base

• – Ausfällen von Monoestern als (z.B.) Dinatriumsalz durch Umsetzung mit Base
• – Chromatoraphische Reinigung über Kieselgel; dies ist vor allem bei Diestern eine bewährte Methode.

When using boronic acids, the following work-up methods have proven to be successful:

• - 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 method according to the invention 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 used) are reacted at room temperature or with heating (preferably <80 ° C). In general, the use of a solvent is 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). To this end, the solvent is optionally removed and the product extracted with a suitable solvent (e.g., 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. The citric acid monoester (crude product) obtained after washing (e.g., saturated NaCl solution), drying (e.g., magnesium sulfate), and removing solvents 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 boronic acid is used as a 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 can be added. The conversion to the diester can be increased by removing the water of reaction. This is e.g. by adding magnesium sulfate possible, in low-volatile alcohols, the 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 precipitates as an adduct with one equivalent of fatty alcohol.

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 1N HCl, 200 ml of deionized water and 200mL sat. NaCl solution, 2 more times with 200 ml of sat. Washed with NaCl solution and dried over magnesium sulfate. After concentration the residue was recrystallized from 700 ml of cyclohexane on a rotary evaporator, whereupon 107.9 g (54.8%) of citric acid monoester 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 was with 600 ml of a solution consisting of 200 ml of 1N 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 a rotary evaporator, the residue was recrystallized from 600 ml of cyclohexane to give 153.2 g (70.7%) of citric acid monoester as a colorless solid.
1 H NMR (400 MHz, CDCl 3): 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
13C-NMR (100.6 MHz, CDCl3): 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 ground, 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 2 × with 100 ml of 0.25 N HCl. The org. Phase was washed 2 × with 110 ml. NaCl solution, dried over MgSO4 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

= 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.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 extracted with aqueous triethanolamine solution. The aqueous phase was acidified with hydrochloric acid and extracted with 100 ml of ethyl acetate. The org. Phase was 2 times with sat. NaCl solution, dried over MgSO4 and concentrated on a rotary evaporator and at the HV. A) 2.19 g (41%) of a colorless oil were obtained. MS (Flowinjection, ESI -): [MH] = 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.
13C NMR (100.6 MHz; D2O):

= 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 symmetrical citric acid dimethyl ester - isolation as monohydrate

= 174,34; 170,02; 72,66; 51,48; 42,76 ppm50.0 g of anhydrous citric acid (260.2 mmol) and 1.5 g of boric acid (24.3 mmol) were 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 the a) symmetrical citric acid citric acid ester (as sodium salt) and b) unsymmetrical citric acid monobenzyl ester

= 177,14; 169,74; 135,09; 128,47; 128,29; 128,19; 73,01; 66,90; 42,67 ppm150 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 of ethyl acetate were added, then adjusted to pH = 8 with 10% NaOH solution. This resulted in a suspension (the sodium salt 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 CDCl3, dried over magnesium sulfate and analyzed by NMR spectroscopy. 1H-NMR (400 MHz, CDCl3): 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, CDCl 3):

= 177.14; 169.74; 135.09; 128.47; 128.29; 128.19; 73.01; 66.90; 42.67 ppm

= 175,61; 172,41; 170,88; 137,73; 129,87; 129,45; 74,35; 67,39; 44,39; 43,86 ppmFor filtrate b), the phases were separated. The aqueous phase was acidified with 6N HCl and extracted 2x with 400 ml of ethyl acetate. The united org. Phases were washed 2 × with sat. NaCl solution, dried over magnesium sulfate and concentrated on a 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 under high vacuum, whereupon 60.0 g of the unsymmetrical citronate monobenzyl ester were obtained as a colorless solid.
1H-NMR (400 MHz, CDCl3): 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; CDCl3):

= 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 to biscitric acid monoester

= 181,59; 179,25; 174,63; 76,32; 67,48; 46,81; 45,28; 30,57; 30,34; 29,65; 27,04 ppm80.3 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
13C NMR (100.6 MHz; D2O):

= 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 citric diesters was 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 ul) of catalyst were stirred for 1-6 days at room temperature. As catalysts or catalyst precursors were used: phenylboronic acid, 3-nitrophenylboronic acid, 4-dimethylamino-phenylboronic acid, 4-trifluoromethyl-phenylboronic acid, 2,4,6-trimethyl-phenylboronic 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-trifluoromethyl-phenylboronic 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-dimethylaminophenylboronic acid.

Example 11a

Isolation of the asymmetric monobenzyl ester as disodium salt - Catalyst: 4-dimethylamino-phenylboronic acid

After 6 days of reaction time, 20 ml of ethyl acetate were added. It was washed with a mixture of 1 ml of 1N HCl, 3 ml of water and 1 ml of 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 11b

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. Those skilled in the art will recognize that variations, modifications and other implementations 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 measures are recited in mutually different claims 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.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 4866203 [0003]

Claims (5)

A process for the synthesis of asymmetric mono- and / or symmetric 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 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. The method of claim 1 or 2, wherein step a) takes place at a temperature of ≥ -20 ° C and ≤100 ° C. Method according to one of claims 1 to 3, wherein step a) takes place in the presence of a dipolar aprotic solvent Method according to one of claims 1 to 3, wherein step a) is carried out without solvent.