KR20010085517A - Process for preparing malonic diesters by continuous transesterification - Google Patents

Abstract

PURPOSE: Provided is a method of preparing malonic acid diester capable of obtaining in high purity and yield by adapting specified transesterification catalyst and/or desirable reaction temperature and retention time in a reaction-distillation tower. CONSTITUTION: The method is conducted by means of a continuous transesterification reaction to produce the malonic diester represented by general formula(1) or (2) (wherein R1 is a linear or branched chain alkyl or alkenyl group, cycloalkyl or aralkyl group having C1-C30; R2 and R3 are independently linear or branched chain alkyl or alkenyl groups, cycloalkyl or aralkyl groups having C1-C30). The transesterification reaction is conduced in the reaction-distillation column having alternative trays operating under super atmospheric pressure. The transesterification catalyst is preferably ortho-titanic ester.

Description

Process for preparing malonic diester by continuous transesterification

Malonic acid diesters of formula (1) are of great industrial importance as organic intermediates, for example in the manufacture of pharmaceuticals, crop protectants, perfumes and perfumes.

In Formula 1 above,

R ¹ is a straight or branched chain alkyl or alkenyl group, a cycloalkyl group or an aralkyl group having 1 to 30, preferably 1 to 12, carbon atoms.

Although compounds of formula 1 may often be prepared directly by carbonylation of haloacetic acid esters and reaction with monovalent acids (see JP 57 183 741), this process is not always suitable on an industrial scale. Thus, the preparation of compounds of formula 1 by carbonylation and reaction with monovalent acids is associated with a number of processing steps and high production costs. In addition, the haloacetic acid ester required as starting material is not available in an appropriate amount.

Therefore, when a relatively small amount of the compound of Formula 1 is to be prepared, the compound of Formula 2 may be synthesized by transesterification with an alcohol of Formula R ¹ OH. However, especially for compounds of formula (I), in which the R ¹ radical is a C ₂ -C ₄ alkyl group, this process will only compete with direct synthesis only if very high yields are achieved based on the compound of formula (II) used. Can be.

If the compounds of formula (1) are intended to be used for the preparation of a medicament, they must meet very high purity requirements. Impurities that interfere with this are by-products substituted at the 2-position of the mixed malonic acid diesters of formulas 3 and 4, in particular malonic acid diesters. When the latter compounds are used, for example, to prepare heterocycles, they react like the malonic acid diesters which are unsubstituted in the 2-position, so that the resulting impurities cannot generally be removed at a reasonable cost.

In the above formula 2 to 4,

R ¹ is as defined above,

R ² and R ³ are each a straight or branched chain alkyl or alkenyl group, a cycloalkyl group or an aralkyl group having 1 to 30 carbon atoms different from R ¹ .

It is known that the compound of formula 2 can be transesterified with an excess of alcohol of formula R ¹ OH in the presence of a catalyst such as sodium hydroxide or p-toluenesulfonyl chloride (see LS Bondar et al., Bull Acad.Sci.USSR, 1968 No. 4, 851-854). In this case, however, yields of less than 70% are often achieved, but this is not sufficiently satisfactory for industrial scale processing methods. In addition, the use of basic catalysts, such as sodium hydroxide, has been found to produce a wider range of by-products than when using alkoxides such as sodium methoxide with much higher catalytic activity. The most prominent by-products in the transesterification reaction of dialkyl malonates, in particular dimethyl malonate, which are particularly suitable as starting materials are up to 0.6% of the corresponding dialkyl-2-methyl mals, based on the amount of the compound of formula 1 to be separated. Nates, especially dimethyl-2-methylmalonate. They can be separated by distillation from the desired compound of formula 1, but are quite difficult. When an acid catalyst such as sulfuric acid or p-toluenesulfonic acid is used or when an industrial ortho titanic acid ester such as industrial tetraethyl titanate is used as a catalyst, 2-methylmaloic acid diesters have been observed to be formed (by batch method). A lesser degree than for base catalysis.

Better product purity and yield (eg, 95.0%) in the transesterification of dimethyl malonate with ethanol to produce diethyl malonate can be obtained when an organic tin compound is used as a catalyst (JP 63rd). 255 247). Although the document emphasizes the use of the claimed organic tin catalysts, the by-product formation is reduced, but this has been found to be unacceptable in view of the above very high purity requirements from compounds of formula (I). Thus, when repeating the transesterification reaction from dimethyl malonate to diethyl malonate described in the Examples, the newly formed by-products, which do not take into account the ethyl methyl malonate present in the reaction mixture, can be used to determine the amount of diethyl malonate formed As a reference, an amount of> 0.2 FID area% was observed. In addition, the reported reaction time, for example 15 hours, results in an unacceptable space-time yield in changing the process to industrial scale. Finally, the claimed organic tin compounds are generally very toxic and also generally have the disadvantage of having to be used in relatively large amounts based on the compounds of formula (2).

Accordingly, it is an object of the present invention to transesterify a compound of formula 2 with an alcohol of formula R ¹ OH to form a compound of formula 3 and / or 4 without forming alkylation byproducts or other byproducts. It is to provide a method for producing a high yield.

Surprisingly, it has now been found that the formation of these by-products can be avoided by continuously transesterifying the compound of formula 2 with an excess of alcohol of formula R ¹ OH.

Accordingly, the present invention provides a process for treating malonic acid diester of formula 2 by continuously transesterifying malonic acid diester of formula 2 with an alcohol of formula R ¹ OH, wherein R ¹ is as defined below, in the presence of a transesterification catalyst. Provided are methods for making diesters.

Formula 1

Formula 2

In Chemical Formulas 1 and 2 above,

R ¹ is a straight or branched chain alkyl or alkenyl group, cycloalkyl group or aralkyl group having 1 to 30 carbon atoms, preferably 1 to 12 carbon atoms,

R ² and R ³ are each independently of each other a straight or branched chain alkyl or alkenyl group, cycloalkyl group or aralkyl group having 1 to 30 carbon atoms, preferably 1 to 12 carbon atoms.

Thus, for example, the process of the invention can be carried out using a four step process in a stirred vessel. In practice, however, it has been found to be particularly advantageous to carry out the reaction using a reaction distillation column as a reactor. Here, for example, the alcohol of formula R ¹ OH can be fed continuously to the column bottom, and the compound of formula 2 can be fed continuously to the top of the column with the catalyst. In some cases, it has been found to be practically advantageous to feed the compound of formula (2) and the catalyst to another point in the reaction distillation column, for example if there is a risk of solid formation as a downstream product of the homogeneous catalyst used.

Based on the amount of malonic acid diester of formula (2) used, it is preferred to use an alcohol of formula R ¹ OH in a 2 to 10 fold excess.

Regarding the design of the reactive distillation column, it has been found advantageous to have a large holdup at least in the column compartment in order to achieve a satisfactory level of conversion of the compound of formula (2) of at least 99.99%. Therefore, it is preferred to use a column with separated trays, with bubble cap tray columns being particularly preferred. In addition to this particularly preferred column type, it is also possible to use columns equipped with tunnels for esterification, thormann or valve trays.

It is also advantageous to use a combination of one or more column compartments having separate trays, preferably bubble cap trays, and column compartments containing a charge.

Further, In general, the bottom product from the subsequent column still contained, and the reaction distillation column in an excess of alcohol of formula R ¹ OH was found to be advantageous to not containing alcohol of formula R ¹ OH. Removal of these alcohols in subsequent columns can optionally be carried out at a different pressure than the ester reaction column. The alcohol of formula R ¹ OH recovered in the subsequent column may be recycled to the reaction distillation column.

The method of the present invention can be used in two ways for preparing a compound of formula 1 from a compound of formula 2 having a relatively high boiling point and also for preparing a compound of formula 1 from a compound of formula 2 having a relatively low boiling point.

As a catalyst for the process of the present invention, a fixed bed catalyst such as titanium silicalite can be used. However, in terms of homogeneous titanium containing, zirconium containing and / or zinc containing compounds minimize by-product formation, in particular the formation of 2-alkylated malonic acid diesters such as 2-methylated dialkyl malonates and higher space-time yields. It turned out to be advantageous. Zinc compounds that are at least partially soluble in the reaction mixture, such as zinc acetylacetonate, zinc acetate, zinc 2-ethylhexanoate or combinations thereof, as well as zirconate and ortho titanoic acid esters, have been found to be particularly useful. Thus, the specified compounds are particularly preferred as catalysts.

Quite surprisingly, in the ortho-titanic acid ester Titanium tetra-halide, preferably titanium tetrachloride and of the formula R ¹ OH direct synthesis from an alcohol or the formula R ¹ OH of the alcohol or the formula R ¹ OH alcohol with formula R ² OH of the alcohol Esters of the compounds of formula (2) with alcohols of formula (R ¹ OH) using relatively reactive ortho titanic esters only when prepared by direct synthesis from commercial ortho titanates evaporated to dryness by single or multiple treatment with the mixture It was found that even in the exchange reaction, a 2-substituted product such as 2-methylmalonic acid diester, which occupies a content of less than 0.02% based on the amount of the malonic acid ester of Formula 1 formed, was not formed. It has also been found that the chloride content in the ortho titanic acid esters, preferably lower than 100 ppm, has a beneficial effect on the product purity achieved.

The amount of catalyst required to achieve quantitative conversion of the compound of formula (2) naturally depends on the type of catalyst chosen and is generally higher when using heterogeneous catalysts than when using homogeneous catalysts. In the general sense, however, this indicates that the amount of catalyst required for the process of the invention is generally lower than for batch mode reactions. Thus, for continuous transesterification reactions, a catalyst amount of about 0.8 to 1.3% is usually sufficient, based on the amount of compound of formula (2) used.

In order to achieve sufficient space-time yields for the use of the process on an industrial scale in the transesterification reaction of the compound of formula 2 by the process of the invention, a reaction temperature of at least 50 ° C, preferably 60 to 200 ° C, Need to use However, depending on the catalyst used, formation of a total of 0.1% perceivable byproducts is observed at temperatures above 165 ° C., for example based on the amount of the compound of Formula 1 prepared, while below 85 ° C. Typically only unsatisfactory space-time yields are achieved. Therefore, the temperature range of 85-155 degreeC is especially preferable. For industrially important transesterification reactions of compounds of formula 2 with low boiling alcohols of formula R ¹ OH, the reaction distillation column must be operated at superatmospheric pressure in order to be able to operate in the preferred temperature range of the process of the invention. .

When a heterogeneous catalyst is used to carry out the process of the invention, if necessary, the compound of formula 1 can be separated from the reaction mixture by a simple method by distilling off the alcohol used after filtration.

When using a homogeneous catalyst, if necessary, the reaction mixture is made free of alcohols of the formula R ¹ OH, either by neutralization followed by suitable processing steps such as filtration or hydrolysis and subsequent filtration or by friction, and then The homogeneous catalyst can be separated from the mixture. However, preference is given to separating the esters from the reaction mixture by distillation, particularly preferably using a falling film evaparator or a thin film evaporator or possibly a combination of both. Using distillation to separate homogeneous catalysts has the advantage that they can be recycled to the process in a simple manner. In addition, the finding that the purity requirement required for the compound of formula 1 can be met even after separating the compound of formula 1 from the catalyst without fractionating the compound of formula 1 represents a very specific advantage of the process of the present invention. .

Based on the amount of the compound of formula 2 used, the yield of the compound of formula 1 obtained by the process of the invention is generally significantly higher than that obtained according to the prior art. Thus, for example, by transesterification from dimethyl malonate to diethyl malonate, the isolated product is provided in a yield of 97-98% with a purity of at least 99.8%. The impurities present in the target product are necessarily due to their ethanol content and the impurities in the starting materials used. Diethyl malonate substituted in the 2-position is not formed.

The following examples serve to illustrate the method of the present invention but do not limit its application.

Example 1 Transesterification of Dimethyl Malonate to Diethyl Malonate (Comparative Example of Batch Mode)

A mixture of 264.2 g of dimethyl malonate, 460.7 g of ethanol and 4.98 g of dibutyltin oxide are stirred with heating to 81-88 ° C. Methanol formed is removed through a packed column. After 15 hours of reaction time, the reaction mixture is analyzed by gas chromatography. The content of the (newly formed) by-product (apart from ethyl methyl malonate) was found to be> 0.2 FID area%, based on the total amount of malonic acid ester.

Example 2 Transesterification of Dimethyl Malonate to Diethyl Malonate (Comparative Example of Batch Method)

The procedure of Example 1 is repeated except that the reaction is carried out at a reaction temperature of 150 ° C. After a reaction time of 0.5 hours, the reaction mixture is analyzed by gas chromatography. The content of newly formed byproducts (apart from ethyl methyl malonate) in the mixture was found to be> 0.4 FID area%, based on the total amount of malonic acid ester.

Example 3 Transesterification of Dimethyl Malonate to Diethyl Malonate (Comparative Example of Batch Mode)

A mixture of 264.2 g of dimethyl malonate, 460.7 g of ethanol and 2.6 g of tetraethyl ortho titanate is stirred with heating to 81-88 ° C. Methanol formed is removed through a packed column. After 8 hours of reaction time, the reaction mixture is analyzed by gas chromatography. The content of the newly formed byproduct (apart from ethyl methyl malonate) was found to be 0.2 FID area%, based on the total amount of malonic acid ester.

Example 4 Transesterification of Dimethyl Malonate to Diethyl Malonate (According to the Invention)

The procedure of Example 3 is repeated except that the transesterification reaction of dimethyl malonate is carried out continuously using a bubble cap tray column and a 6-fold excess of ethanol. Dimethyl malonate and the transesterification catalyst (bi-made pure tetraethyl titanate described herein) are fed to each different tray at the top of the column, while ethanol is fed directly above the bottom of the column. Free methanol can be removed at the top with a portion of excess ethanol. This gives a bottom product which still contains a significant amount of ethanol. The latter is distilled off under reduced pressure in the subsequent column and recycled to the reaction distillation column.

By-product formation (limit of detection: 100 ppm), especially the formation of diethyl 2-methylmalonate, was not detected in the bottom product produced from the reaction distillation column. The ethyl methyl malonate content in the mixture is less than 100 ppm.

Diethyl malonate can be finally separated from the catalyst using a thin film evaporator. In this way, it is possible to obtain 97-98% of diethyl malonate of theory based on the amount of dimethyl malonate used. The product content measured by gas chromatography is from 99.6 FID area% to 99.8 FID area% of the dimethyl malonate used. Alkylation of the malonic acid diester in two positions is not detected by gas chromatography.

The desired malodiene diester can be obtained in high purity and high yield without forming alkylation byproducts or other byproducts by the process using the continuous transesterification reaction according to the invention.

Claims (16)

The malonic acid diester of formula (2) is continuously transesterified in the presence of a transesterification catalyst with an alcohol of the formula (R ¹ OH), wherein R ¹ is as defined below to produce the malonic acid diester of formula (1) Way. Formula 1 Formula 2 In Chemical Formulas 1 and 2 above, R ¹ is a straight or branched chain alkyl or alkenyl group, a cycloalkyl group or an aralkyl group having 1 to 30 carbon atoms, R ² and R ³ are each independently a linear or branched alkyl or alkenyl group, a cycloalkyl group or an aralkyl group having 1 to 30 carbon atoms. The process of claim 1 wherein the transesterification reaction is carried out in a reaction distillation column. The process of claim 2 wherein the reaction distillation column is a column with separate trays. The process of claim 2, wherein the reaction distillation column combines one or more column compartments with separate trays and one or more column compartments containing a charge. The process according to claim 2, wherein the reaction distillation column is operated under superatmospheric pressure. The process of claim 1 wherein the transesterification catalyst used is an ortho titanic acid ester. The process according to claim 1 or 6, wherein the transesterification catalyst used is an ortho titanic acid ester prepared by direct synthesis from titanium tetrachloride and the corresponding alcohol. The process of claim 1 wherein the catalyst used is zirconate. The process of claim 1 wherein the catalyst used is zinc acetylacetonate and / or zinc acetate and / or zinc 2-ethylhexanoate. The process of claim 1 wherein the catalyst used is a fixed bed catalyst. The process of claim 1 wherein the alcohol of formula R ¹ OH is used in a 2 to 10 fold excess based on the amount of malonic acid diester of formula 2 used. The process of claim 1 or 11, wherein at least some of the excess alcohol is withdrawn through the bottom of the reaction distillation column. 13. A compound according to any one of the preceding claims consisting of a compound of formula ¹ , at least a portion of the excess alcohol of formula R ¹ OH used in the transesterification reaction and a soluble catalyst obtained at the bottom of the reaction distillation column. Wherein the mixture does not contain an alcohol of formula R ¹ OH present in the mixture of subsequent columns. The process according to claim 1, wherein the excess alcohol of formula R ¹ OH is at least partially recycled to the reaction distillation column. The process according to claim 1, wherein the product is separated from the catalyst and possibly further components in the reaction mixture by distillation. The method of claim 15, wherein the separation is performed using a bottom film evaporator and / or a thin film evaporator.