JP2001233823A - Method of preparing malonic acid diester by continuous transesterification - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of preparing malonic acid diester capable of obtaining in high purity and yield. SOLUTION: This method carries out a continuous transesterification reaction using a specific transesterification catalyst and keeping a constant reaction temperature and retention time in a reaction-distillation tower.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing malonic diester.

[0002]

BACKGROUND OF THE INVENTION General formula I:

[0003]

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[Wherein R ¹ is 1 to 30, preferably 1 to
Represents an unbranched or branched alkyl or alkenyl group having 12 carbon atoms, a cycloalkyl group or an aralkyl group] as malonic acid diesters as organic intermediates such as medicaments, pesticides, fragrances and It is of great industrial importance for producing fragrances.

The compounds of the general formula I can indeed be prepared in many ways directly by carbonylation of halogen acetates and reaction with monohydric alcohols (JP 571).
However, such a method is not always meaningful on an industrial scale. The preparation of compounds of the general formula I, for example by carbonylation and reaction with monohydric alcohols, is associated with numerous process steps and high investment costs. The halogen acetates required as starting materials are also not entirely available to the same extent.

Accordingly, if compounds of general formula I are to be prepared in relatively small quantities, general formula II:

[0007]

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The synthesis of this compound has been found by transesterification of the compound with an alcohol of the general formula R ¹ OH. However, in particular, compounds of the general formula I in which the radical R ¹ is C ₂ -C ₄
In the case of the particularly important compounds of formula (II), the process can only compete directly with the synthesis if very high yields are achieved for the compounds of the general formula II used.

Very high demands are placed on the purity of the compounds of the general formula I in the context of their use for the manufacture of medicaments.
In this case, the general formula III:

[0010]

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And the general formula IV:

[0012]

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Wherein R ¹ is as defined above, and R 1
² and R ³ each represent, independently of R ¹ , an unbranched or branched alkyl or alkenyl group having 1 to 30 carbon atoms, a cycloalkyl group or an aralkyl group] In addition to the mixed malonic acid diesters, in particular, by-products substituted at the 2-position of the malonic acid diester are hindered. When the last-mentioned compounds are used, for example, for the preparation of heterocyclic compounds, the resulting compounds react in the same way as malonic diesters which are not substituted in the 2-position, so that the impurities formed are usually no longer at common costs. Cannot be separated.

It is known that compounds of general formula II can be transesterified with an excess of an alcohol of general formula R ¹ OH in the presence of a catalyst such as sodium hydroxide or p-toluenesulfonic acid chloride (LS Bondar et al. .
al., Bull.Acad. Sci, USSR, 1968, No. 4, 851-85
Four). However, the yields achieved in this case which are partly lower than 70% are completely unsatisfactory for carrying out the process on an industrial scale. When using a base catalyst, such as sodium hydroxide, but on a much larger scale using a catalytically substantially more active alcoholate, such as sodium methoxide (sodium methanolate), a series of secondary It was found that a product was formed. The main by-products in the transesterification of malonic acid dialkyl esters, especially malonic acid dimethyl ester, which are particularly suitable as starting materials, correspond to up to 0.6% of the amount of the compound of the general formula I which is isolated. Dialkyl methylmalonic acid, especially also dimethyl 2-methylmalonic acid. These can be separated from the desired compounds of general formula I only by significant costs by distillation. Also when using acid catalysts such as sulfuric acid or p-toluenesulfonic acid or when using industrial orthotitanates such as industrial tetraethyl titanate as catalyst (in the case of discontinuous operating methods). )) The formation of 2-methylmalonic acid diester is observed, albeit on a smaller scale than with the base catalyst.

When an organotin compound is used as a catalyst,
Transesterification of dimethyl malonate with ethanol gives better product purity for the production of diethyl malonate and a yield of, for example, 95.0% (JP63255247). The authors emphasize the formation of slight by-products when using the claimed organotin catalysts, but still accept the very high purity requirements imposed on the compounds of general formula I. It turned out not to be possible. For example, the transesterification of malonic acid dimethyl ester to malonic acid diethyl ester as described, except for the optional malonic acid ethyl methyl ester contained in the reaction mixture, reduces the amount of malonic acid diethyl ester formed. On the other hand, it was found that by-products exceeding 0.2 FID area percent were newly formed. A reaction time of, for example, 15 hours leads to unacceptable space-time yields when moving the process to an industrial scale. The last-claimed organotin compounds generally have the disadvantage of very high toxicity and more usually have to be used in relatively large amounts for the compounds of the general formula II.

[0016]

It is therefore an object of the present invention to provide a process for the transesterification of a compound of the general formula II with an alcohol of the general formula R ¹ OH, by means of which the compounds of the general formulas III and / or The compounds of the general formula I are obtained in high yields without the compounds of the general formula IV and without the formation of alkylation products or other by-products.

[0017]

Surprisingly, the formation of said by-products is carried out by continuously transesterifying the compound of the general formula II with an excess of the alcohol of the general formula R ¹ OH. It was found that it could be avoided.

The subject of the present invention is the general formula I:

[0019]

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Wherein R ¹ is 1 to 30, preferably 1 to
Represents an unbranched or branched alkyl or alkenyl group having 12 carbon atoms, a cycloalkyl group or an aralkyl group].
Formula II in the presence of a transesterification catalyst:

[0021]

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Wherein R ² and R ³ are each independently 1-30, preferably 1-12, unbranched or branched alkyl or alkenyl groups, Represents a cycloalkyl group or an aralkyl group], wherein the transesterification is carried out continuously, wherein the transesterification is carried out by transesterification of a malonic diester of the general formula R ¹ OH.
This is a method for producing malonic diester.

The process according to the invention can thus be carried out, for example, using a four-stage stirred vessel cascade. However, in practice it has proven particularly advantageous to carry out the reaction in a reaction-distillation column as a reactor. Here, for example, the alcohol R ¹ OH is added to the bottom of the column and the general formula II
Can be continuously fed to the top of the column together with the catalyst. In some cases, it is practically advantageous to feed the compound of the general formula II and the catalyst at different points in the reaction-distillation column, for example if there is a risk of forming a solid as a subsequent product of the homogeneous catalyst used. It turned out to be.

The alcohol of the general formula R ¹ OH is preferably used in a 2 to 10-fold molar excess, based on the amount of malonic diester of the general formula II used.

For the installation of the reaction-distillation column, 99.99
In order to achieve a sufficient conversion of the compound of the general formula II above%, a large hold up in at least a part of the column is advantageous. Thus, the use of a tower with discrete trays is advantageous, and the use of a bubble tower is particularly advantageous. However, in addition to the particularly preferred column embodiments described above, it can also be carried out with the use of a column with a Tunnel-, Thormann- or valve tray arrangement.

Also advantageous is a combination of one or more tower sections with discrete trays, preferably bubble trays, and one or more tower sections with packing material.

[0027] More generally still contains an alcohol excess of the general formula R ¹ OH in the reaction - from the bottom product of the distillation column, that alcohols of general formula R ¹ OH is advantageously removed in a subsequent tower stand did. The separation of this alcohol in the subsequent column can optionally be carried out under a different pressure than in the esterification column. General formula R ¹ O recovered in the subsequent tower
The alcohol of H can be returned to the reaction-distillation column.

The process according to the invention is thus used both for preparing compounds of the general formula I from high-boiling compounds of the general formula II and for preparing compounds of the general formula I from low-boiling compounds of the general formula II be able to.

As catalysts for the process according to the invention, use can be made of fixed-bed catalysts, for example titanium silicalite. However, regarding the formation of minimal by-products,
For the formation of alkylated malonic diesters, for example 2-methylated malonic dialkyl esters, and with regard to high space-time yields, homogeneous titanium-, zirconium- and / or zinc-containing compounds have proved to be further advantageous. Zinc compounds which are at least partially soluble in the reaction mixture, such as zinc acetylacetonate, zinc acetate or zinc (2-ethyl-hexanoate) or combinations thereof, and zirconates and orthotitanates have proven to be particularly advantageous. . The compounds mentioned are therefore particularly advantageous as catalysts.

It is quite surprising that the relatively reactive
General formula R using totitanates¹Al of OH
In transesterification of a compound of general formula II using coal
Preferably, titanium tetrahalide, preferably titanium tetrachloride
And the general formula R¹From OH alcohol or for industrial use
Commercially available orthotitanates may optionally have the formula R ¹
OH alcohol or R¹OH and R²Al of OH
Multiple treatments with a mixture of coals, each time steaming
Orthotitanate by direct synthesis by evaporation to dryness.
When making steles, 2-substituted products, such as
No 2-methylmalonic diester is formed, ie
Based on the amount of malonic ester of general formula I formed
The content was found to be less than 0.02%. Further
100 ppm of the orthotitanate used.
An advantageously low chloride content of less than m is advantageously achieved.
Product purity.

The amount of catalyst required to achieve a quantitative reaction of the compound of the general formula II depends, of course, on the type of catalyst chosen and, if a heterogeneous catalyst is used, generally a homogeneous catalyst is used. Higher than you would. However, it has very generally been found that the amount of catalyst required for the process according to the invention is usually lower than in the case of discontinuous (batchwise) reactions. Thus, in the case of continuous transesterification, a catalyst amount of about 0.8 to 1.3%, based on the amount of compound of the general formula II, is usually sufficient.

In order to achieve a suitable space-time yield by the process according to the invention during transesterification of the compound of the general formula II on an industrial scale, the reaction temperature is generally at least 50 ° C. , Preferably a temperature of from 60 to 200 ° C must be selected. However, above 165 ° C., depending on the catalyst used, the already prepared general formula I
Significant by-product formation, for example a total of 0.1%, is observed with respect to the amount of the compound of the formula (1), whereas below 85 ° C. only an unsatisfactory space-time yield is often achieved. A temperature range of from 85 to 155 ° C. is therefore particularly preferred. In the case of the transesterification of compounds of the general formula II of industrial importance with low-boiling alcohols of the general formula R ¹ OH, the reaction-distillation column is of course also added, since the process according to the invention can be operated in the advantageous temperature range. You have to operate under pressure. The use of a pressure column is therefore advantageous in this case.

The isolation of the product of the general formula I from the reaction mixture can be effected, if a heterogeneous catalyst is used for carrying out the process according to the invention, by distilling off the alcohol used, optionally after prior filtration. By doing so, it can be performed in an easy manner.

If a homogeneous catalyst is used, the catalyst is separated from the reaction mixture, optionally freed of alcohols of the general formula R ¹ OH, by suitable process steps, for example neutralization and subsequent filtration or hydrolysis and subsequent filtration or washing. can do. However, it is advantageous to separate the ester from the reaction mixture by distillation, particularly preferably using a falling-film evaporator and a thin-film evaporator and optionally a combination of both. Working up by distillation for the separation of a homogeneous catalyst has exactly the advantage that the catalyst can be returned to the process in an easy manner. Furthermore, the observation that after the compound of general formula I is separated from the catalyst without rectification of the compound of general formula I, the purity requirements set for the compound of general formula I can be satisfied. From this, particular advantages of the method according to the invention can be seen.

The general formula I obtained by the process according to the invention
Are generally significantly higher than the prior art yields relative to the amount of compound of general formula II used.
Thus, for example, when transesterifying malonic acid dimethyl ester to malonic acid diethyl ester, a 97-98% isolated yield was achieved with a product purity of ≥99.8%. The impurities contained in the end product are substantially due to the ethanol content and to the impurities of the starting materials used. No malonic acid diethyl ester substituted at the 2-position was formed.

[0036]

The following examples illustrate in detail the method according to the invention, but do not limit its scope.

Example 1: Transesterification of malonic acid dimethyl ester with malonic acid diethyl ester (discontinuous comparative example) Malonic acid dimethyl ester 264.2 g, ethanol 4
A mixture consisting of 60.7 g and 4.98 g of dibutyltin oxide was heated to 81-88 ° C. with stirring. The generated methanol was removed by a packed tower. After a reaction time of 15 hours, the reaction mixture was checked by gas chromatography. The content of (freshly formed) by-products (other than ethyl malonate) was determined to> 0.2 FID area percent relative to the total content of malonate.

Example 2: Transesterification of malonic acid dimethyl ester to malonic acid diethyl ester (discontinuous comparative example) The procedure was as in example 1, but the reaction was
Performed at a reaction temperature of ° C. After a reaction time of 0.5 h, the reaction mixture was checked by gas chromatography. The content of newly formed by-products (other than ethyl malonate) in the mixture was confirmed to> 0.4 FID area percent relative to the total content of malonate.

Example 3: Transesterification of malonic acid dimethyl ester to malonic acid diethyl ester (discontinuous comparative example) 264.2 g of malonic acid dimethyl ester, ethanol 4
A mixture consisting of 60.7 g and 2.6 g of tetraethyl orthotitanate was heated to 81-88 ° C. with stirring. The generated methanol was removed by a packed tower. After a reaction time of 8 hours, the reaction mixture was checked by gas chromatography. The content of newly formed by-products (other than malonic acid ethyl methyl ester) was determined to 0.2 FID area percent relative to the total content of malonic acid ester.

Example 4 Transesterification of Malonic Acid Dimethyl Ester to Malonic Acid Diethyl Ester (According to the Invention) The same procedure was carried out as in Example 3, but the transesterification of malonic acid dimethyl ester was continuously carried out in a bubble column. The reaction was carried out and using a 6-fold molar excess of ethanol. In this case, malonic acid dimethyl ester and the transesterification catalyst (pure tetraethyl titanate) prepared as described in the present invention were each fed to a different tray at the top of the column, while the ethanol feed was added to the column. Performed slightly above the bottom. The liberated methanol was removed via the top along with a portion of the excess of ethanol.
A bottom product was thus obtained which still contained significant amounts of ethanol. The product is distilled off in a subsequent column under vacuum,
And returned to the reaction-distillation tower.

The reaction-distillation column thus obtained was subjected to gas chromatography in the bottom product (detection limit: 10
(0 ppm) No by-product was observed (especially, no formation of diethyl 2-methylmalonic acid was observed). The content of malonic acid ethyl methyl ester in the mixture was less than 100 ppm. Separation of the malonic acid diethyl ester from the catalyst was finally performed using a thin layer evaporator. 97-98% of theory of malonic acid diethyl ester, based on the amount of malonic acid dimethyl ester used, was obtained. The content of the product measured by gas chromatography was 99.8 FID area percent when the content of malonic acid dimethyl ester used was 99.6 FID area percent. No alkylation at the 2-position of the malonic acid diester was detected by gas chromatography.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Frank Bauer Germany Haltern Römer Straße 59 Ah (72) Inventor Christophe Tys Germany Niederkassel auf Demm Homerich 24 Ah (72) Inventor Emanuel Fioritakis Germany Dulmen Johannes Strasse 2

Claims (16)

[Claims] 1. A compound of the general formula I:[Wherein, R¹Is an unbranched chain having 1 to 30 carbon atoms
Or branched alkyl or alkenyl
Group, cycloalkyl group or aralkyl group]
Lonic acid diester is generally used in the presence of a transesterification catalyst.
Formula II:[Wherein, R²And R³Is 1 to 30 irrespective of each
Unbranched or branched chain alkyl having two or more carbon atoms
A kill group or an alkenyl group, a cycloalkyl group or
A malonic acid diester of the general formula R
¹OH [wherein R ¹Represents the above.] Alcohol
In the production process by transesterification with
Characterized in that transesterification is carried out continuously.
A method for producing a lonic acid diester. 2. The process according to claim 1, wherein the transesterification is carried out in a reaction-distillation column. 3. The process according to claim 2, wherein the reaction-distillation column is a column having discrete trays. 4. The process according to claim 2, wherein the reaction-distillation column is a combination of a column portion having discrete trays and one or more column portions having packing material. 5. The process as claimed in claim 2, wherein the reaction-distillation column is operated under pressure. 6. The process according to claim 1, wherein orthotitanate is used as the transesterification catalyst. 7. The process according to claim 1, wherein the transesterification catalyst used is an orthotitanate produced by direct synthesis from titanium tetrachloride and the corresponding alcohol. 8. The process according to claim 1, wherein zirconate is used as the catalyst. 9. The process according to claim 1, wherein zinc acetylacetonate and / or zinc acetate and / or zinc (2-ethylhexanoate) are used as the catalyst. 10. The process according to claim 1, wherein a fixed bed catalyst is used as the catalyst. 11. The process according to claim 1, wherein the alcohol of the general formula R ¹ OH is used in a 2 to 10-fold molar excess with respect to the amount of malonic diester of the general formula II used. 12. The process as claimed in claim 1, wherein the excess alcohol is at least partially discharged via the bottom of the reaction-distillation column. 13. A compound of the formula I obtained at the bottom of the reaction-distillation column, at least a portion of the excess alcohol of the formula R ¹ OH used for the transesterification and optionally dissolved catalyst. 13. The process according to claim 1, wherein the alcohol of the general formula R ¹ OH contained in the mixture is removed from the resulting mixture in a subsequent column. 14. The process as claimed in claim 1, wherein the excess alcohol used of the general formula R ¹ OH is at least partially returned to the reactor-distillation column. 15. The separation of the product from the catalyst and optionally other components of the reaction mixture by distillation.
The method according to any one of claims 1 to 14. 16. The method according to claim 15, wherein the separation is performed using a falling film evaporator and / or a thin film evaporator.