UA62017C2 - A method for producing glyoxylic acid esters or hydrates thereof - Google Patents

Abstract

The invention relates to a method for producing glyoxylic acid esters from glyoxylic acid ester hemiacetals which a) are directly transesterified with an alcohol in the presence of a catalyst; or b) are firstly converted into the corresponding glyoxylic acid whole acetals and are then transesterified with an alcohol in the presence of a catalyst, whereupon after a) and b) the acetals are divided into the desired, free glyoxylic acid ester or the hydrate thereof.

Description

Description of the invention

Glyoxyl esters, for example, ethyl glyoxylate, methyl glyoxylate, benzyl glyoxylate or 2II-(-)Y-menthylglyoxylate, are important reagents in organic chemistry, since the A-oxo ester group is a highly reactive group that can participate in a number of reactions, and -(-) γ-Menthyl glyoxylate (MON) is, for example, an important Co building block for asymmetric synthesis, for chiral acetals, for oxathiolanes, for addition reactions to stereocontrolled alkenes and nitroalkanes, or for Grignard reactions.

The preparation of glyoxylic esters from the corresponding diesters of maleic or fumaric acids by means of a two-step process of ozonolysis and reduction is already known from a number of literature references.

So, for example, according to u). Oh SPpet 1982, 47, year 891-892, ethyl, methyl, or benzyl glyoxylates are obtained by ozonolysis of the corresponding maleic diesters in dichloromethane, followed by reduction of this ozonide with dimethyl sulfide and subsequent distillation.

UMO 96/22960 also describes a two-stage process for the preparation of menthyl glyoxylate as intermediate 12 for menthyl dihydroxyacetate, where dimentyl maleate or dimentyl fumarate is ozonated in the first stage in a halogenated hydrocarbon or carboxylic acid ester, preferably in the presence of a lower aliphatic alcohol, and in the second stage the resulting the ozonolysis product is either reduced by dialkyl sulfide or by catalytic hydrogenation with hydrogen to form menthyl glyoxylate.

However, the disadvantage of the aforementioned already known processes is that after the ozonolysis stage, ozonolysis products containing peroxides are present, which must then be regenerated in the second stage either by catalytic hydrogenation or in the presence of dialkyl sulfides, or aryl sulfides, trialkyl phosphides with the formation of the corresponding glyoxylic esters.

To eliminate these problems, EP Mo0884232 A1 proposes, for example, to obtain MON by ozonolysis of the sodium salt of the monomethyl ester of maleic acid as a starting material. Although in such a process the previously required reduction stage is excluded, the used raw material is not available on the market and therefore must be Ge) obtained at an additional stage by the reaction of maleic anhydride with menthol.

OE Mo 4435647 discloses a process in which a 5095 solution of glyoxylic acid is esterified with an excess of menthol using sulfuric acid and azeotropic extraction of water. MON monohydrate is isolated from the reaction mixture by the formation of a bisulfite adduct and phase separation followed by isolation from this adduct. "--

The disadvantage of this method is the complicated extraction process, the need for very careful drying of this product, and a significant amount of waste. at

In Teigapeagop GI ey. 39, 4223-4226 (1998) disclosed the transesterification of ethyl glyoxylate of diethyl acetal with the help of titanium (IM) ethoxide. However, in this reaction, firstly, expensive starting material is used and, secondly, the described treatment of the reaction mixture after the completion of the reaction by hydrolysis of the catalyst and e.e. flash chromatography is problematic and too expensive for industrial scale.

Therefore, the subject of this invention was to invent a method of obtaining glyoxylic esters, which does not have the above-mentioned disadvantages inherent in previously known processes. "

Therefore, the present invention relates to a method of obtaining glyoxyl esters, which includes a) C 50 transesterification of a glyoxyl ester hemiacetal directly with alcohol in the presence of a catalyst, or c B) primary conversion of a glyoxyl ester hemiacetal into a corresponding glyoxyl ester acetal with

With" its subsequent transesterification with alcohol in the presence of a catalyst, as a result of which, according to a) and B), this acetal is split with the formation of the desired free glyoxylic ester or its hydrate.

According to the present invention, the starting material used is hemiacetal of glyoxyl ester.

Suitable glyoxyl ester hemiacetals are described, for example, in EP-RMo 0099981. b Preference is given to methyl hemiacetal of methyl ester of glyoxylic acid (OMNA), hemiacetals of ethyl ester of glyoxylic acid, hemiacetals of propyl ester of glyoxylic acid, hemiacetals of isopropyl ester of glyoxylic acid, or hemiacetals I- -butyl ester of glyoxylic acid. A special advantage is given to the use of ZMNA as a starting compound. -k 70 Glyoxyl esters or their hydrates obtained by the method of this invention are compounds whose ester component is obtained from chiral or non-chiral primary, secondary or tertiary alcohols. Esters of primary alcohols are mainly obtained from ethanol, butanol, propanol and hexanol. Preference is given to obtaining esters of secondary or tertiary alcohols, in particular, acyclic, monocyclic, bicyclic terpene alcohols, or acyclic, monocyclic, tricyclic sesquiterpene alcohols, di- or 25 triterpene alcohols, which may be unsubstituted or substituted.

GF) End products that are given special preference are glyoxylic esters or their hydrates obtained from monocyclic or bicyclic terpene alcohols substituted as needed with various substituents, for example, from menthols, phenylmenthol, borneol, fenhol and the like.

In the method of this invention, hemiacetals can be transesterified either directly (option a)) to form the desired glyoxyl ester, or can be first converted to the corresponding acetal (option B)), which is then transesterified in a similar way to option a).

This hemiacetal is converted into the corresponding acetal in a known manner by alcohol and acid catalysis.

Acetalization is mainly carried out using alcohol, which is already present in this hemiacetal. However, it is also possible to obtain mixed acetals. Suitable alcohols are methanol, ethanol, propanol, butanol,

hexanol Therefore, these hemiacetals are mainly converted into dimethyl acetals of glyoxylic acid esters, diethyl acetals, and so on. Particular preference is given to dimethyl acetal of methyl ester of glyoxylic acid.

The appropriate alcohol for acetalization is used in liquid or vapor state. It is better when acetalization is carried out using alcohol vapor.

Suitable catalysts are conventional acids such as H 2503, p-toluenesulfonic acid, acid ion exchangers, and the like. Preference is given to the use of Nzo,.

The extracted water is removed mainly along with the superheated alcohol vapor and thus 70 is continuously removed from the reaction mixture.

Transesterification of hemiacetals or acetals is carried out in alcohol as a reaction medium. Preference is given to the use of anhydrous alcohols.

Therefore, to obtain the glyoxylic esters described above, such an alcohol is used that leads to the formation of the desired ester component in the final product.

Suitable alcohols are chiral or non-chiral, primary, secondary or tertiary alcohols, preferably secondary or tertiary, in particular, acyclic, monocyclic, bicyclic terpene alcohols, monocyclic or tricyclic sesquiterpene alcohols, di- or triterpene alcohols.

Therefore, special preference is given to mono- or bicyclic terpene alcohols substituted, if necessary, by various substituents, for example, menthols, phenylmenthols, borneol, fenhol and the like.

The corresponding alcohol can be used in equimolar amounts, but also in excess or in deficiency.

Thus, in the case of cheap alcohols, it is preferred to add them in excess to a given hemiacetal or acetal, while in the case of expensive alcohols, such as menthol or the like, an excess of this acetal is used.

In addition to the alcohol used, an anhydrous solvent can also be used, for example, unsubstituted or substituted Cb5-Co0 alkanes, for example, hexane and heptane and the like, and alkenes, organosilicon compounds, for example, silicone oil and the like, or other solvents that are inert under the conditions of i) reaction.

According to the present invention, transesterification occurs in the presence of specific catalysts. Tin, titanium or zirconium esters, lithium compounds and basic Mzo catalysts are considered as catalysts.

Suitable catalysts from the group of tin catalysts are dialkyltin dicarboxylates having 1-12 carbon atoms in the alkyl component. As dicarboxylate components, diacetates, dilaurates, o maleates, diisooctanoates or mixed dicarboxylates, in particular, with esters of long-chain fatty acids are considered.

Examples of such compounds are dibutyltin diacetate, dibutyltin dilaurate, dibutyltin diisooctoate, dibuc z5 Piolin maleate, dioctyltin dilaurate, and the like. co

Preference is given to the use of dibutyltin diacetate, mixed dibutyltin dicarboxylates with esters of long-chain fatty acids and dioctyltin dilaurates.

Suitable titanium catalysts are titanium (IM) ethoxide, isopropoxide, propoxide, butoxide, isobutoxide, and the like. "

Preference is given to the use of titanium (IM) isopropoxide. Suitable catalysts from the group of zirconium catalysts are zirconates, such as tetrapropylzirconate, tetraisopropylzirconate, tetrabutylzirconate, citric acid diethyl ester zirconate, etc. z Lithium catalysts that can be used are lithium salts, for example chlorides, lithium alkoxides or lithium hydroxides, but also organolithium compounds, for example butyllithium. The advantage among lithium catalysts is given to the use of butyllithium. b However, especially in the case of option B), basic catalysts can also be used, for example, alkali metal compounds (Ma, K), alkaline earth metal compounds (Mao) or aluminum compounds. Examples of such compounds are hydroxides, alkoxides or organometallic compounds. o Preference is given to the use of tin, titanium or lithium catalysts.

In the case of direct transesterification of hemiacetal according to option a), preference is given to the use of dialkyl tin dicarboxylates as catalysts. "M The amount of catalyst used is from 0.001 to 20 mol.bo, better from 0.005 to 5 mol.Ob, and best from 0.02 to 3 mol.bb.

The reaction mixture, both in option a) and in option B), is heated, preferably, to the boiling point of this reaction mixture, so that the reaction temperature, depending on the reagents, varies from 20 to 2002C.

Transesterification can be carried out at atmospheric pressure, but also at reduced pressure and (F) elevated pressure from 0.001 to 200 bar. Pressure from 0.01 to 10 bar is preferred, atmospheric pressure is even more preferred. It is better when the alcohol extracted during transesterification is continuously distilled off.

If the alcohol used is not anhydrous alcohol, then before adding the catalyst, the reaction mixture is heated, the water is driven off, and only then is the catalyst added.

Removal of the catalyst after the completion of the reaction gives a good yield during its washing with water, hydrolysis and filtering of the precipitated metal oxide, or, better, during the distillation of this product from the catalyst, preferably on a thin-film or molecular evaporator. In addition, it is possible, especially during the distillation of this product, to recycle the removed catalyst or the distillation residue in a new reaction mixture.

As a result of the transesterification reaction, the acetal is split with the formation of a free glyoxylic ester or its hydrate. The cleavage of this acetal is carried out by acid catalysis or in the presence of lanthanide catalysts. Suitable catalysts for acid catalysis are acids where the risk of hydrolysis of the ester component is minimized. Examples of such acids are NzoO, p-toluenesulfonic acid and the like, and in particular for option B), formic acid, acetic acid and the like. Various compounds of cerium, lanthanum, ytterbium, samarium, etc. are considered as lanthanides. In particular, they are chlorides, sulfates, carboxylates.

When acetals are split, free aldehyde groups of glyoxylic ester are formed with the extraction of the corresponding alcohol. In this case, it is better when the alcohol is continuously driven off. 70 The preferred final product is the hydrate of the desired glyoxyl ester, so that the free glyoxyl ester is, if necessary, converted to the hydrate by the addition of water.

In one embodiment, the methyl hemiacetal or glyoxyl ester acetal is cleaved after completion of transesterification with formic acid. In this case, the reaction between the extracted methanol and the formic acid produces methyl formate and water. The methyl formate is removed, and the reaction /5 Water forms the directly required glyoxyl ester hydrate.

In a particularly preferred embodiment, the acetal of a) or B) is heated with formic acid for a short period of time, i.e. brought to the boiling point in less than an hour, the methyl formate is removed and the remaining reaction mixture is rapidly cooled. The considered version of the method has special advantages in obtaining menthyl ester, since it is possible to avoid the formation of a side product, that is, menthene. The remaining formic acid is extracted or, better, driven off. The remaining reaction mixture is dissolved, preferably in hexane, directly in a warm state or after heating. The hexane solution is then washed with hot water, and the final product is crystallized from this organic phase.

The hexane mother liquor can be recycled and used again in subsequent separations without loss of quality of the final product. Option b) is preferred in the preparation of the required end products.

With the method of the present invention, a degree of conversion of up to 10095 is achieved, with yields exceeding i) 9590, while according to previous experience (Te(gapedhop) yields only reached 8095. Due to the mild conditions of transesterification, the purity of the product can reach more than 99.995, up to 100965 .

Example 1: M zo a) Preparation of dimethyl acetal of methyl ester of glyoxylic acid 1200 g (10 mol) of methyl hemiacetal of methyl ester of glyoxylic acid and 40 g of concentrated sulfuric (87) acid were heated to 1057"C in a still consisting of a vessel for the bottom phase, a stirrer, and a distillation column (10 plates) and a distillation nozzle with a phlegm separator. 300 g (9.4 mol) of methanol was pumped per hour through the coil of a stainless steel tube that was thermostated at 1107C per s in a heating bath. The methanol vapor coming out of the outlet of the heating coil was introduced into "o reaction solution by means of a submerged tube at the bottom of the vessel for the bottom phase. The reflux separator at the top of the distillation column was set at a feed-to-return ratio of about 101, resulting in rapid steady state conditions with a top temperature of about 70"C and a bottom temperature of 105 "7C. After 6 hours, the reaction is complete, and the introduction of methane steam olu was stopped, and "

Heating is off. Then the reaction mixture was neutralized with solid sodium bicarbonate. The apparatus was pumped out and the reaction mixture was subjected to fractional distillation. 1270 g (9.5 mol) of dimethyl acetal of methyl ester of glyoxylic acid with a content of 99.5956 (5C (gas chromatography)) was obtained. Thus, output based on ;" of methyl hemiacetal of methyl ester of glyoxylic acid was 9595.

B) Transesterification of dimethyl acetal of methyl ester of glyoxylic acid into I-menthyl glyoxylate

Dimethyl acetal

402 g (Zmol) of dimethyl acetal of the methyl ester of glyoxylic acid, 312 g (2 mol) of I-menthol and 1 g of dibutyltin diacetate were heated to 105-7C in the apparatus described in stage a). The methanol formed as a result of transesterification was continuously extracted in at the top of the column. The reaction was complete after 15 hours. The residual I-menthol content was 0.195 (gas chromatography). The reaction mixture was released

From the specified catalyst in the molecular evaporator at 10 mbar with the formation of approximately 15 g of the catalyst solution at the bottom of the molecular evaporator and 635 g of the reaction mixture in the distillate of the molecular evaporator. "M Then this reaction mixture was subjected to fractional distillation under reduced pressure. 130 g (0.97 mol) of dimethyl acetal of the methyl ester of glyoxylic acid and 501 g (1.94 mol) of I-menthyl glyoxylate of dimethyl acetal with a content of 9995 were obtained. The yield is based on of dimethyl acetal of methyl ester of glyoxylic acid was 9790 from the theoretical.

The catalyst solution formed at the bottom of the molecular evaporator was used in a new operation

F) instead of fresh dibutyltin diacetate. After carrying out an experiment using 402g of dimethylacetal and methyl ester of glyoxylic acid and 312g of I-menthol, as defined above, 509g (1.95 mol) were obtained

1-menthyl glyoxylate of dimethyl acetal with a content of 9995. Thus, the yield based on dimethyl acetal of methyl bo ester of glyoxylic acid was 9895 of the theoretical. c) Cleavage of the acetal I-menthyl glyoxylate dimethylacetal to obtain i-menthyl glyoxylate monohydrate 100 g (0.39 mol) of I-menthyl glyoxylate dimethyl acetal and 400 g of formic acid were heated to boiling for 12 minutes in the apparatus described in stage a). Methyl formate was removed at the top of the column, while 65 Formic acid was retained in the reaction system at a bottom temperature of approximately 1007C. Then the reaction mixture was quickly cooled to room temperature, the apparatus was pumped, and the formic acid was removed.

The residue was dissolved in 800 g of n-hexane by briefly heating to the boiling point. The hexane solution was washed twice, each time with 400 ml of water at 60"C. Then the hexane solution was cooled with crystallization

Y-menthyl glyoxylate monohydrate. The crystals were filtered, the precipitate on the filter was washed with 100 g of cold hexane and dried at room temperature under reduced pressure. 64.6 bg (0.28 mol) of I-menthyl glyoxylate monohydrate with a purity of 99.895 (HPLC (high-performance liquid chromatography)) was obtained. Optical rotation angle (A o - -747, s - 1 g/100 ml, acetonitrile/water 95:5), Fourier transform IR spectra and H NMR spectra gave consistent results.

The mother liquor and washing hexane were combined, concentrated to 800 g and used in a new 70 operation instead of fresh p-hexane. After carrying out the experiment using 100 g of I-menthyl glyoxylate dimethyl acetal and 400 g of formic acid, as defined above, 86.4 g (0.38 mol) of I-menthyl glyoxylate monohydrate with a purity of 99.895 (high-performance liquid chromatography) were obtained. Optical rotation angle (Ar - -742, s - 1 g/100 ml, acetonitrile/water 95:5), Fourier transform IR spectra and "H NMR spectra gave 18 consistent results. Thus, the yield was 97905 from the theoretical .

Claims (18)

The formula of the invention 1. The method of obtaining glyoxyl esters, which includes the transesterification of the hemiacetal of the glyoxyl ester directly with alcohol in the presence of a catalyst, as a result of which this acetal is split with the formation of the desired free glyoxyl ester or its hydrate. 2. The method according to claim 1, which differs in that the used hemiacetals of glyoxylic acid ester are hemiacetals of methyl ester of glyoxylic acid, ethyl ester, n-propyl ester, isopropyl ester, or tert- or n-butyl ester. with C. The method according to claim 1, characterized in that the conversion to the completed acetal is carried out with d) using a liquid or gaseous alcohol selected from the group consisting of methanol, ethanol, propanol, butanol and hexanol, in the presence of an acid as a catalyst. 4. The method according to claim 1, which is characterized by the fact that transesterification is carried out using a chiral or non-chiral, primary, secondary or tertiary alcohol. - 5. The method according to claim 4, which differs in that the alcohol used is an acyclic, "- monocyclic, bicyclic terpene alcohol, acyclic, monocyclic or tricyclic sesquiterpene alcohol, di- or triterpene alcohol. at 6. The method according to claim 1, which is characterized by the fact that the used catalyst is a tin, titanium or zirconium ester, a lithium compound or a basic catalyst, which is an alkali metal compound, an alkaline earth metal compound, or an aluminum compound. ise) 7. The method according to point b, which differs in that the used catalyst is dialkyl lead dicarboxylate, which has 1-12 carbon atoms in the alkyl component, titanium (IM) ethoxide, titanium (IM) isopropoxide, titanium (IM) n- propoxide, titanium (IM) n-butoxide or titanium (IM) isobutoxide, or butyllithium. " 8. The method according to claim 1, which is characterized by the fact that the acetal is split by acid catalysis in the presence of NiobO, p-toluenesulfonic acid, formic acid or acetic acid, or in the presence of a lanthanide catalyst. "» 9. The method according to claim 8, characterized in that the acetal is split by briefly heating the acetal for up to 1 hour to the boiling point with formic acid, extracting the formate formed and rapid cooling, as a result of which the product crystallizes from the diluent, if the latter retains the appropriate properties after preliminary extraction of impurities with water, and isolate. Me. 10. The method of obtaining glyoxyl esters, which includes the primary transformation of the hemiacetal of the glyoxyl ester into the corresponding acetal of the glyoxyl ester followed by its transesterification with alcohol in the presence of a catalyst, as a result of which this acetal is split to form the desired free glyoxylic ester or its hydrate. - about 70 11. The method according to claim 10, which differs in that the used hemiacetals of glyoxylic acid ester are hemiacetals of methyl ester of glyoxylic acid, ethyl ester, n-propyl ester, m-isopropyl ester or tert- or n-butyl ester. 12. The method according to claim 10, characterized in that the conversion to the completed acetal is carried out using a liquid or gaseous alcohol selected from the group consisting of methanol, ethanol, propanol, butanol and hexanol, in the presence of an acid as a catalyst. GF) 13. The method according to claim 10, which is characterized by the fact that transesterification is carried out using a chiral or non-chiral, primary, secondary or tertiary alcohol. at 14. The method according to claim 13, which is characterized by the fact that the alcohol used is an acyclic, monocyclic, bicyclic terpene alcohol, an acyclic, monocyclic or tricyclic sesquiterpene 60 alcohol, di- or triterpene alcohol. 15. The method according to claim 10, which is characterized by the fact that the used catalyst is a tin, titanium or zirconium ester, a lithium compound or a basic catalyst, which is an alkali metal compound, an alkaline earth metal compound or an aluminum compound. 16. The method according to claim 15, which is characterized by the fact that the used catalyst is a dialkyl tin bo dicarboxylate, which has 1-12 carbon atoms in the alkyl component, titanium (IM) ethoxide, titanium (IM) isopropoxide, titanium (IM) n-propoxide, titanium (IM) n-butoxide or titanium (IM) isobutoxide, or butyllithium. 17. The method according to claim 10, which is characterized by the fact that the acetal is split by acid catalysis in the presence of H»ZO,), p-toluenesulfonic acid, formic acid or acetic acid, or in the presence of a lanthanide catalyst. 18. The method according to claim 17, characterized in that the acetal is cleaved by briefly heating this acetal for up to 1 hour to the boiling point with formic acid, extracting the formate formed and rapidly cooling, as a result of which the product crystallizes from the diluent, if the latter retains the appropriate properties after preliminary extraction of impurities with water, and isolate. 0. и и и 0. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 12, 15.12.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c schi 6) y "- "c) s (Se) - and? (o) has) ((c) - 70 that has) 60 b5