AU767512B2 - Process for preparing glyoxylic esters or their hydrates - Google Patents

Description

WO 00/39068 PCT/EP99/09517 Process for preparing glyoxylic esters or their hydrates Glyoxylic esters, for example ethyl glyoxylate, methyl glyoxylate, benzyl glyoxylate or L-(-)-menthyl glyoxylate, are important reagents in organic chemistry, since the a-oxo ester group is a highly reactive group which can take part in a number of reactions. L-(-)-Menthyl glyoxylate (MGH) is, for example, an important C 2 building block for asymmetric synthesis, for chiral acetals, for oxathiolanes, for stereo-controlled addition reactions to alkenes and nitroalkanes, or for Grignard reactions.

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

Thus, for example, according to J. Org. Chem.

1982, 47, pp. 891-892 ethyl, methyl or benzyl glyoxylates are obtained by ozonolysis of the corresponding maleic diesters in dichloromethane, subsequent reduction of the ozonide by means of dimethyl sulfide and subsequent distillation.

WO 96/22960 also describes a two-stage process for preparing menthyl glyoxylate as intermediate for menthyl dihydroxyacetate, in which dimenthyl maleate or dimenthyl fumarate is ozonized in the first stage in a halogenated hydrocarbon or carboxylic ester, preferably in the presence of a lower aliphatic alcohol, and in the second stage the resultant ozonolysis product is either reduced with a dialkyl sulfide or by catalytic hydrogenation with hydrogen to give menthyl glyoxylate.

The disadvantage with the previously known processes, however, is that after the ozonolysis step, peroxide-containing ozonolysis products are present, which must then be reduced in a second step, either by means of catalytic hydrogenation or in the presence of dialkyl sulfides or aryl sulfides, trialkyl phosphides, to give the corresponding glyoxylic esters.

2 To avoid these problems, EP 0 884 232 Al proposed, for example, preparing MGH via ozonolysis of maleic acid monomenthyl ester sodium salt as starting material. Although in this process the previously necessary reduction step is omitted, the starting material used is not available on the market and must therefore be prepared in an additional stage by reacting maleic anhydride with menthol.

DE 44 35 647 further discloses a process in which a 50% strength glyoxylic acid solution is esterified with an excess of menthol using sulfuric acid and azeotropic removal of water. The monohydrate of MGH is isolated from the reaction mixture by forming a bisulfite adduct and phase separation with subsequent release from the adduct.

The disadvantage of this process is the complex isolation, the necessity of very gentle drying of the product, and the considerable amount of waste.

Tetrahedron Lett. 39, 4223-4226 (1998) 20 discloses the transesterification of ethyl glyoxylate diethyl acetal with titanium(IV) ethoxide. However, in this reaction, first, an expensive starting material is Sused, and secondly, the described workup of the reaction mixture after the reaction mixture has ended, by hydrolysis of the catalyst and flash chromatography, is problematic and too expensive for an industrial scale.

It would therefore be advantageous if at least preferred embodiments of the present invention provide a process for preparing glyoxylic esters which does not have the abovementioned disadvantages of previously known processes.

The present invention provides a process for preparing glyoxylic esters which comprises a) transesterifying a glyoxylic ester hemiacetal directly with an alcohol in the presence of a catalyst, 2a or b) first converting a glyoxylic ester hemiacetal into the corresponding glyoxylic ester aceta. and then 3 transesterifying it with an alcohol in the presence of a catalyst, whereupon, following a) and b, the acetal is cleaved to give the desired free glyoxylic ester or its hydrate.

According to the invention the starting material used is a glyoxylic ester hemiacetal. Suitable glyoxylic ester hemiacetals are described, for example, in EP-P-0 099 981.

Preference is given to glyoxylic acid methyl ester methyl hemiacetal (GMHA), glyoxylic acid ethyl ester hemiacetals, glyoxylic acid propyl ester hemiacetals, glyoxylic acid isopropyl ester hemiacetals, glyoxylic acid t- or n-butyl ester hemiacetals.

Particularly preferably, GMHA is used as starting compound.

Glyoxylic esters or their hydrates which are obtained by the inventive process are compounds whose ester moiety is derived either from chiral or nonchiral primary, secondary or tertiary alcohols. Esters of primary alcohols are preferably derived from ethanol, butanol, propanol and hexanol. Preferably, esters of secondary or tertiary alcohols, in particular acyclic, monocyclic, bicyclic terpene alcohols, or of acyclic, monocyclic, tricyclic sesquiterpene alcohols, di- or triterpene alcohols are prepared, which may be unsubstituted or substituted.

Particularly preferred end products are glyoxylic esters or their hydrates which are derived from optionally variously substituted monocyclic or bicyclic terpene alcohols, for instance from menthols, phenylmenthol, borneol, fenchol, etc.

In the inventive process, the hemiacetal can be transesterified either directly (variant a) to give the desired glyoxylic ester, or it can first be converted into the corresponding acetal (variant which is then transesterified in a similar manner to variant a).

The hemiacetal is converted into the corresponding acetal in a manner known per se by means of an alcohol and acid catalysis.

4 The acetalization is preferably performed using the alcohol which is already present in the hemiacetal.

However, it is also possible to prepare mixed acetals.

Suitable alcohols are methanol, ethanol, propanol, butanol, hexanol. Preferably, the hemiacetals are therefore converted into glyoxylic acid ester dimethyl acetals, diethyl acetals, etc. Particular preference is given to glyoxylic acid methyl ester dimethyl acetal.

The corresponding alcohol is used either in the liquid stage or vapor stage for the acetalization.

Preferably, the acetalization is carried out using alcohol vapor.

Suitable catalysts are customary acids, such as H 2 S0 4 p-toluenesulfonic acid, acid ion exchangers, etc.

Preferably, H 2 S0 4 is used.

The water eliminated is preferably discharged together with the superheated alcohol vapor and is thus continuously taken off from the reaction mixture.

The transesterification of the hemiacetals or acetals is performed in an alcohol as reaction medium.

Preferably, anhydrous alcohols are used.

To obtain the above-described glyoxylic esters, therefore the alcohol is used which leads to the desired ester moiety in the end product.

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

Particularly preferred alcohols are therefore again optionally variously substituted mono- or bicyclic terpene alcohols, for example menthols, phenylmethols, borneol, fenchol, etc.

The corresponding alcohol can be used in an equimolar amount, but also either in excess or in a deficiency.

Thus, it is preferred, in the case of cheaper alcohols, to add these in excess to the hemiacetal or acetal, 5 whereas in the case of expensive alcohols, for instance menthol etc., the acetal is used in excess.

In addition to the alcohol used, a further anhydrous solvent can be used, for instance unsubstituted or substituted C 5

-C

20 alkanes, for example hexane and heptane etc., and alkenes, silicon compounds, for instance silicone oil etc., or other solvents which are inert under the reaction conditions.

The transesterification takes place according to the invention in the presence of specific catalysts.

Catalysts which come into consideration are stannic, titanic or zirconic esters, lithium compounds, and basic catalysts.

Suitable catalysts, from the group of the tin catalysts, are dialkyltin dicarboxylates having 1-12 carbon atoms in the alkyl moiety. Dicarboxylate moieties which come into consideration are diacetates, dilaurates, maleates, diisooctanates, or mixed dicarboxylates, in particular with longer-chain fatty acid esters.

Examples of these are dibutyltin diacetate, dibutyltin dilaurate, dibutyltin diisooctoate, dibutyltin maleate, dioctyltin dilaurate, etc.

Preferably dibutyltin diacetate, mixed dibutyltin dicarboxylates with longer-chain fatty esters and dioctyltin dilaurate are used.

Suitable titanium catalysts are titanium(IV) ethoxide, isopropoxide, propoxide, butoxide, isobutoxide, etc.

Preferably, titanium(IV) isopropoxide is used.

Suitable catalysts from the group of zirconium catalysts are zirconates, such as tetrapropyl zirconate, tetraisopropyl zirconate, tetrabutyl zirconate, citric acid diethyl ester zirconate, etc.

Lithium catalysts which can be used are lithium salts, for example chlorides, lithium alkoxides or lithium hydroxides, but also organic lithium compounds, for 6 instance butyllithium. A preferred lithium catalyst is butyllithium.

However, in particular in the case of variant basic catalysts can also be used, for instance alkali metal (Na,K) compounds, alkaline earth metal (Mg) compounds or aluminum compounds. Examples of these are hydroxides, alkoxides or organometallic compounds.

Preferably, tin catalysts, titanium catalysts or lithium catalysts are used.

In the direct transesterification of the hemiacetal according to variant preferably dialkyltindicarboxylates are added as catalysts.

The amount of catalyst used is 0.001 to mol%, preferably 0.005 to 5 mol%, and particularly preferably 0.02 to 3 mol%.

The reaction mixture, in both variant a) and variant is preferably heated to the boiling point of the reaction mixture, so that the reaction temperature, depending on the reactants, is between 20 0 C and 200 0 C. The transesterification can be carried out further at atmospheric pressure, but also at reduced pressure or superatmospheric pressure from 0.001 to 200 bar. Preferably, the pressure is between 0.01 and 10 bar, particularly preferably it is atmospheric pressure. The alcohol eliminated in the transesterification is preferably distilled off continuously.

If the alcohol used is a non-anhydrous alcohol, the reaction mixture is heated before the catalyst is added, the water is distilled off and only then is the catalyst added.

Removal of the catalyst after the reaction ended succeeds in good yield by washing with water, hydrolyzing the catalyst and filtering the metal oxide which precipitated out or, preferably by distilling off the product from the catalyst, preferably on a thinfilm or short-path evaporator. It is also possible, in particular in the case of removal by distilling off the 7 product, to recycle the removed catalyst or the distillation residue to a new reaction mixture.

Subsequently to the transesterification reaction, the acetal cleavage is performed to give the free glyoxylic ester or its hydrate. The acetal cleavage is carried out by acid catalysis or in the presence of lanthanide catalysts. Suitable catalysts for the acid catalysis are acids in which the risk of hydrolyzing the ester moiety is as low as possible.

Examples of these are H2S0 4 p-toluenesulfonic acid, etc., and, in particular for variant formic acid, acetic acid, etc. Lanthanides which come into consideration are various compounds of cerium, lanthanum, ytterbium, samarium, etc.

These are, in particular, chlorides, sulfates, carboxylates.

In the acetal cleavage, the free aldehyde groups of the glyoxylic ester are formed with elimination of the corresponding alcohol. The alcohol is preferably distilled off continuously in this case.

The preferred end product is the hydrate of the desired glyoxylic ester, so that the free glyoxylic ester is, if appropriate, converted into the hydrate by addition of water.

In a particular embodiment, the glyoxylic ester methyl hemiacetal or acetal is, after transesterification is complete, cleaved by means of formic acid. In this case, the reaction between the methanol being eliminated and the formic acid forms methyl formate and water. The methyl formate is separated off, and the reaction water forms directly the desired hydrate of the glyoxylic ester.

In a particularly preferred embodiment, the acetal of variant a) or b) is heated with formic acid for a short period, that is to say to the boiling point in less than one hour, the methyl formate is taken off and the remaining reaction mixture is rapidly cooled.

This process variant is particularly advantageous in the preparation of the menthyl ester, since byproduct 8 formation, i.e. menthene formation, is avoided.

Residual formic acid is extracted or preferably distilled off. The remaining reaction mixture is preferably dissolved in hexane either directly while still warm or after heating.

The hexane solution is then washed with hot water and the end product is crystallized out from the organic phase.

The hexane mother liquor can be recycled and reused for subsequent isolations without loss of quality to the end product.

Preferably, the desired end products are prepared by variant b).

By means of the inventive process, conversion rates of up to 100% are achieved, the yields are above while according to the prior art (Tetrahedron), yields of only up to 80% are achieved. Owing to the mild transesterification conditions, product purities of greater than 99.9% up to 100% can be achieved.

9 Example 1: a) Preparation of glyoxylic acid methyl ester dimethyl acetal 1200 g (10 mol) of glyoxylic acid methyl ester methyl hemiacetal and 40 g of concentrated sulfuric acid were heated to 105 0 C in a distillation apparatus consisting of a bottom vessel, stirrer, distillation column (10 plates) and distillation head with reflux divider. 300 g (9.4 mol) of methanol were pumped per hour through a spiral of a stainless steel tube which was thermostated to 1100C in a heating bath. The methanol vapor exiting at the outlet of the heating spiral was introduced into the reaction solution using a submerged tube at the bottom of the bottom-phase vessel. The reflux divider at the top of the distillation column was set to a ratio of take-off to reflux of approximately 10:1, as a result of which stationary conditions were rapidly established with a top temperature of approximately 70 0 C and a bottom temperature of 105°C. After 6 h the reaction was complete, the introduction of methanol vapor was stopped and the heating was shut off. The reaction mixture was then neutralized with solid sodium hydrogen carbonate. The apparatus was evacuated and the reaction mixture fractionally distilled. 1270 g (9.5 mol) of glyoxylic acid methyl ester dimethyl acetal having a content of 99.5% (GC) were obtained. The yield based on glyoxylic acid methyl ester methyl hemiacetal was thus b) Transesterification of glyoxylic acid methyl ester dimethyl acetal to L-menthyl glyoxylate dimethyl acetal 402 g (3 mol) of glyoxylic acid methyl ester dimethyl acetal, 312 g (2 mol) of L-menthol and 1 g of dibutyltin diacetate were heated to 1050C in the apparatus described in step Methanol formed by the transesterification was taken off continuously at the top of the column. The reaction was complete after 10 h. The residual L-menthol content was 0.1% (GC).

The reaction mixture was freed from the catalyst in the short-path evaporator at 10 mbar, with approximately g of catalyst solution being produced at the bottom of the short-path evaporator, and 635 g of reaction mixture in the distillate of the short-path evaporator.

The reaction mixture was then fractionally distilled under reduced pressure. 130 g (0.97 mol) of a glyoxylic acid methyl ester dimethyl acetal and 501 g (1.94 mol) of L-menthyl glyoxylate dimethyl acetal having a content of 99% were obtained. The yield, based on glyoxylic acid methyl ester dimethyl acetal was 97% of theory.

The catalyst solution arising at the bottom of the short-path evaporator was used in a new operation instead of the fresh dibutyltin diacetate. After carrying out the experiment using 402 g of glyoxylic acid methyl ester dimethyl acetal and 312 g of L-menthol as specified above, 509 g (1.95 mol) of L-menthyl glyoxylate dimethyl acetal having a content of 99% were obtained. The yield, based on glyoxylic acid methyl ester dimethyl acetal, was therefore 98% of theory.

c) Acetal cleavage of L-menthyl glyoxylate dimethyl acetal to give L-menthyl glyoxylate monohydrate 100 g (0.39 mol) of L-menthyl glyoxylate dimethyl acetal and 400 g of formic acid were heated to boiling for 12 min in the apparatus described in step Methyl formate was taken off at the top of the column, while formic acid was held in the reaction system at a bottom temperature of approximately 100 0

C.

The reaction mixture was then rapidly cooled to room temperature, the apparatus was evacuated and the formic acid was taken off. The residue was dissolved in 800 g of n-hexane by brief heating to boiling temperature.

The hexane solution was washed twice, each time with 400 ml of water at 60 0 C. The hexane solution was then cooled, with L-menthyl glyoxylate monohydrate 11 crystallizing out. The crystals were filtered off, the filter cake was washed with 100 g of cold hexane and dried at room temperature under reduced pressure.

64.6 g (0.28 mol) of L-menthyl glyoxylate monohydrate having a purity of 99.8% (HPLC) were obtained. The angle of rotation (a20 -740, c 1 g/100 ml, acetonitrile/water 95:5) and the FTIR spectra and 1 H-NMR spectra were in correspondence.

The mother liquor and the washing hexane were combined, concentrated to 800 g and used in a new operation instead of the fresh n-hexane. After the experiment was carried out using 100 g of L-menthyl glyoxylate dimethyl acetal and 400 g of formic acid as specified above, 86.4 g (0.38 mol) of L-menthyl glyoxylate monohydrate having a purity of 99.8% (HPLC) were obtained. The angle of rotation (ad 20 -74°, c 1 g/100 ml, acetonitrile/water 95:5) and the FTIR spectra and 1 H-NMR spectra were in correspondence. The yield was therefore 97% of theory.

20 It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia or in any other country.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive 30 sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of oo *further features in various embodiments of the invention.

9

Claims (10)

1. A process for preparing glyoxylic esters, which comprises a) transesterifying a glyoxylic ester hemiacetal directly with an alcohol in the presence of a catalyst, or b) first converting a glyoxylic ester hemiacetal into the corresponding glyoxylic ester acetal and then transesterifying it with an alcohol in the presence of a catalyst, whereupon, following a) and the acetal is cleaved to give the desired free glyoxylic ester or its hydrate.

2. The process as claimed in claim 1, wherein the glyoxylic acid ester hemiacetals used are glyoxylic acid methyl ester, ethyl ester, n-propyl ester, isopropyl ester, or t- or n-butyl ester hemiacetals.

3. The process as claimed in claim 1, wherein the conversion to the complete acetal is performed using a liquid or vaporous alcohol selected from 25 the group consisting of methanol, ethanol, propanol, butanol and hexanol in the presence of an acid as catalyst.

4. The process as claimed in claim 1, wherein the transesterification is performed using a chiral or nonchiral, primary, secondary or tertiary alcohol.

The process as claimed in claim 4, wherein the S* alcohol used is an acyclic, monocyclic, bicyclic terpene alcohol, an acyclic, monocyclic or tricyclic sesquiterpene alcohol, di- or triterpene alcohol. 13

6. The process as claimed in claim 1, wherein the catalyst used is a stannic ester, titanic ester or zirconic ester, a lithium compound or, the basic catalyst used is an alkali metal compound, alkaline earth metal compound or aluminum compound.

7. The process as claimed in claim 6, wherein the catalyst used is dialkyltin dicarboxylate having 1-12 carbon atoms in the alkyl moiety, titanium(IV)ethoxide, titanium(IV) isopropoxide, titanium(IV) n-propoxide, titanium(IV) n-butoxide or titanium(IV) isobutoxide, or butyllithium.

8. The process as claimed in claim 1, wherein the acetal is cleaved by acid catalysis in the presence of H 2 S0 4 p-toluenesulfonic acid, formic acid or acetic acid, or in the presence of a lanthanide catalyst.

9. The process as claimed in claim 8, wherein the acetal is cleaved by brief heating of the acetal for up to 1 hour up to boiling point with formic acid, removal of the formate formed and rapid 25 cooling, whereupon the product is crystallized out of a diluent, if appropriate after previous extraction of impurities with water, and isolated.

10. A process for preparing glyoxylic esters 30 substantially as herein described with reference to Example 1. Dated this 29th day of August 2003 DSM FINE CHEMICALS AUSTRIA NFG GMBH CO KG By their Patent Attorneys GRIFFITH HACK