HU227138B1 - Method for producing dialkyl-3-oxo-glutarates - Google Patents

Abstract

Preparation of diethyl/dimethyl-3-oxoglutarate (I) involves reacting citric acid, or its monohydrate, with chlorosulfonic acid (C1) in a lower chlorinated aliphatic hydrocarbon (H1), followed by reaction with methanol/ethanol. The volume ratio of (H1):(C1) is 0.1:1 - 1:1 and the rate of addition of citric acid is 1 - 2 kg/minute.

Description

The scope of the description is 10 pages (including 3 sheets)

22 227 138 1

The present invention relates to a process for the preparation of dialkyl-3-oxoglutarates which is advantageously achievable on an industrial scale, resulting in a high purity product.

The dimethyl 3-oxoglutarate of formula (I) wherein R is methyl is a valuable pharmaceutical intermediate.

Many methods are known in the art for preparing compounds of formula (I).

European Patent Publication No. 47 514 discloses a process for the preparation of the corresponding ethyl ester (diethyl 3-oxoglutarate) from chloroacetic acid ethyl ester. The starting material is carbonylated in ethanol medium in the presence of potassium carbonate and dicobalt octocarbonyl; the reaction mixture was heated under carbon monoxide at 100 bar for 7 h at 65 ° C to yield about 60% of diethyl 3-methylbutarate. The process is not suitable for industrial realization due to the extremely dangerous and degradable nature of dicobalt-octacarbonyl.

According to U.S. Patent No. 3,963,775, dimethyl 3-oxoglutarate is obtained by reacting ketene, phosgene and methanol at a yield of about 50%. The disadvantage of the process is the poor extraction, on the one hand, and the use of highly toxic phosgene on the other. This procedure is not recommended for industrial implementation.

European Patent Publication No. 108,332 and Japanese Patent No. 60/120838 disclose acetone dicarboxylic acid diesters by reaction of diketene, carbon monoxide and nitrite esters in the presence of palladium halides and copper salts. Dimethyl-3-oxoglutarate is prepared by reacting diketene, carbon monoxide and methyl nitrite at 60 ° C for 3 hours in the presence of palladium chloride and copper (II) chloride in a yield of about 60%. The disadvantage of the process is the use of medium yields and the use of diketene that can be used unfavorably in industrial conditions.

Chem. Pharm. Bull. 29, (10), 2762-2768 (1981), the malonic acid monomethyl ester is reacted with 1,1-carbodiimidazole, and the resulting intermediate is treated with dilute hydrochloric acid. The disadvantage of the process is that the 1,1-carbodiimidazole used is a very expensive reagent, the price of which is about four times the price of dimethyl 3-oxoglutarate.

A Recl. Trav. Chim. Pays-Bas, 108, (2) 51-56 (1989) discloses the formation of a salt of methylacetoacetate with lithium diisopropylamide in tetrahydrofuran at -45 ° C, which is converted to dimethyl-3-oxoglutarate by alkylation with dimethyl carbonate.

The method of Swiss Patent No. 659,060 also uses methyl acetoacetate as starting material, which is converted to a secondary amine (e.g. pyrrolidine) enamine, the resulting enamine is reacted with liquid ammonia in sodium amide, and the anion obtained is alkylated with methyl chloroformate, finally, dilute hydrochloric acid hydrolysis yields dimethyl 3-oxoglutarate.

The disadvantage of the latter two processes is that the reagents used and the reaction temperature required (reaction with lithium diisopropylamide at -45 ° C, and the use of sodium amide and liquid ammonia) require special measures that can reasonably be achieved under operating conditions (perfect inerting; exclusion of moisture traces, intensive cooling, for example using a refrigerant consisting of a dry ice-acetone mixture).

The Org. Synth. Coll. Vol. I, 10, 237 (1946) discloses acetone dicarboxylic acid produced from citric acid monohydrate in fuming sulfuric acid, which is converted into the corresponding diester in 40% ethanol in the presence of a sulfuric acid catalyst. The process has several disadvantages. Extraction requires weak, large amounts of fuming sulfuric acid, and the resulting degradable acetone dicarboxylic acid must be isolated.

However, a somewhat more effective method similar to the above procedure was found in Findley, S. P., J. Org. Chem., 22, 1385 (1957). According to the process, anhydrous citric acid is converted into acetone dicarboxylic acid in fuming sulfuric acid, which is esterified with anhydrous methanol without isolation. Dimethyl 3-oxoglutarate is obtained after isolation and distillation in a yield of 64%. The disadvantage of the process is that it provides only medium yield in laboratory sizes.

Indians J. Chem. Sect. B 37, (4), 397-398 (1998) act in a manner similar to that described in the preceding literature, but instead of citric acid monohydrate are reacted with concentrated sulfuric acid and the resulting acetone dicarboxylic acid is isolated. without esterification with methanol. After distillation of the crude oil, dimethyl 3-oxoglutarate was obtained in 52% yield. The aim of the authors is to develop a larger-scale synthesis of dimethyl 3-oxoglutarate compared to previous methods. However, the process can be carried out only in medium yields in the order of 100-200 g.

German Patent No. 1,092,900 discloses the implementation of the process described in the above-mentioned disclosure in the order of about 100 kg. Dimethyl 3-oxoglutarate is obtained in crude form only in 58% yield.

According to German Patent No. 1 160 841, citric acid is reacted on a laboratory scale with chlorosulfonic acid and then with methanol instead of sulfuric acid or oleum. The crude dimethyl 3-oxo-glutarate is obtained in 90% yield by vacuum distillation.

In the above processes, the acid acetic dicarboxylic acid preparation step includes both sulfuric acid, oleum and chlorosulfonic acid as both reagent and solvent. This is disadvantageous in industrial scale synthesis as a significant amount of non-regenerating waste acid is produced during the reaction. The processing of waste acid is a significant cost to the environment (neutralization, etc.). A further disadvantage of the above-described solvent-free processes is that due to the violent gas evolution (carbon monoxide released during the reaction), the exact temperature range can be difficult to achieve and

It is problematic to handle an industrial scale process.

The above-mentioned disadvantage is addressed by Belgian Patent 879,537. Chlorosulfonic acid is first added to the methylene chloride solvent and citric acid is added. The resulting intermediate is esterified with methanol, isolating the desired product to yield dimethyl 3-methyl-glutarate (94-96%).

Belgian Patent No. 879,537 was published in 1979. Over the past two decades, pharmaceutical requirements have been significantly tightened. Pharmacopoeias generally allow up to 0.1% identified or unidentified impurities and 0.5% total contamination. Obviously, there is also an increasingly stringent requirement for intermediate products because the impurities in the intermediate product may be incorporated into the final product on the one hand, and, on the other hand, by creating undesirable side reactions, they may lead to the formation of further impurities.

In the process of reproducing the process described in Belgian Patent No. 879,537, it has been found that the reaction conditions described in the examples show that many side reactions occur and the removal of significant by-products is a costly process requiring additional operations on the one hand and dimethyl 3- on the other hand by-products. oxo-glutarate is difficult to select. There was a need for a high purity dimethyl-3-methylglutarate production process with high purity by-products in accordance with the prior art requirements.

It is an object of the present invention to provide a high purity dimethyl 3-oxoglutarate production process that meets the above requirements.

The above object is solved by the present patent.

The present invention relates to a dialkyl-3-oxoglutarate of the formula (I) wherein R is the reaction of a citric acid or a monohydrate of formula (II) with a lower chlorinated aliphatic hydrocarbon in the form of a lower chlorinated aliphatic hydrocarbon, followed by an intermediate. by reaction of the product with methanol or ethanol using the lower chlorinated aliphatic hydrocarbon and chlorosulfonic acid in a volume ratio of 0.1: 1 to 1: 1 and the citric acid is added at a rate of 1-2 kg / min to the chlorine. sulphonic acid and a lower chlorinated aliphatic hydrocarbon mixture.

In a preferred embodiment of the present invention, dimethyl 3-oxoglutarate of formula I wherein R is methyl is prepared.

The reaction medium may be a lower chlorinated aliphatic hydrocarbon such as methylene chloride, ethylene chloride or chloroform, preferably methylene chloride or ethylene chloride, particularly methylene chloride.

During the addition of the citric acid and until the subsequent evolution of the gas, the temperature of the reaction mixture is preferably maintained at 10-15 ° C.

In the study of the process for the preparation of dimethyl 3-oxoglutarate, it has been found that the following side reactions are possible.

As shown in Scheme 1, dimethyl 3-oxoglutarate is also present in the equilibrium process in an equilibrium process, indirectly via dimethyl-3-methoxypentene diode, via the ester of the ketene compound formed in the aqueous dewatering, or in an acidic medium. produced. Due to the small boiling point difference, this "enol ether" cannot be separated from the dimethyl 3-oxoglutarate by vacuum distillation and remains in the main distillate at practically constant levels in addition to dimethyl 3-oxoglutarate. The amount of 'enol ether' also reaches 4-5%.

As shown in Scheme 2, citric acid trimethyl ester is formed from citric acid in the presence of methanol in the presence of methanol, which contaminates the dimethyl-3-methylglutarate in an amount of 2-3%.

As shown in Scheme 3, citric acid (without decarbonylation), trimethylaconitate contamination is formed by water de-ionization of a molecule and subsequent esterification in an amount of 0.4-1.0%.

Due to the small boiling point difference, trimethyl aconite cannot be separated by distillation from dimethyl-3-methylglutarate.

The invention is based on the recognition that the above-mentioned impurities are produced in a considerably lower amount in the process for the preparation of dimethyl 3-oxoglutarate according to the invention.

Surprisingly, it has been found that the formation of dimethyl 3-methoxypentenedioate (enol ether) in the reaction of citric acid and chlorosulfonic acid with a low chlorinated aliphatic hydrocarbon medium depends on the ratio of the lower chlorinated aliphatic hydrocarbon to the chlorosulfonic acid. Reducing the amount of solvent relative to chlorosulfonic acid suppresses the formation of undesired "enol ether". In the process of the present invention, the volume ratio of low chlorinated aliphatic hydrocarbon to chlorosulfonic acid (0.1: 1) to (1: 1), preferably (0.4: 1) to (0.6: 1) is particularly preferably 0.5. : first As shown in Example 1, the enol ether content of the product obtained was 0.81% by volume. In contrast, the methylene chloride: chlorosulphonic acid = 2.83: 1 used in Example 1 of Belgian Patent No. 879,537 contains dimethyl 3-methylglutarate, which contains 4.78% enol ether.

Another basis of the present invention is the recognition that the formation of undesirable citric acid trimethyl ester contamination can be reduced by reducing the rate of addition of citric acid. The citric acid is not soluble in the reaction mixture, therefore, in addition to the rapid addition of citric acid, non-reactive spheres with chlorosulfonic acid are formed, which can be found in the process.

When reacting with the methanol added as the esterifying agent in the preceding stage, the trimethyl ester of citric acid is formed. According to the invention, citric acid is added at a rate of 1-2 kg / min, preferably 1.1-1.8 kg / min, particularly preferably 1.25-1.5 kg / min, of chlorosulfonic acid and lower chlorinated aliphatic. hydrocarbon mixture. Example 1 of the present invention shows a citric acid trimethyl ester content of 0.09% of the product obtained. In contrast, in the reproduction of 879,537 (Comparative Example 2), the methylene chloride: chlorosulphonic acid volume ratio of 2.83: 1 contains the dimethyl 3-oxoglutarate obtained, containing 2.27% citric acid trimethyl ester.

The invention is further based on the discovery that the formation of the trimethylaconate by-product can also be suppressed using the method of the invention. The trimethylaconitrate content of the product of Example 1 was 0.28%. Conversely, when used in Example 1 of Belgian Patent No. 879,537, the dimethyl 3-oxoglutarate produced contains 0.46% trimethyl aconate impurity.

It has also been discovered that the amount of impurities present in the product of the present invention is less than the reaction temperature of 10-15 ° C during the course of citric acid digestion and gas evolution.

Comparative analytical studies show that the product of the present invention has a significantly higher purity than the known method. According to Example 1, which illustrates the process of the invention, the dimethyl 3-oxoglutarate content of the product is 98.33%, compared to the 91.07% purity obtained in Example 2 reproducing the Belgian patent 879,537.

The process of the present invention is preferably carried out as follows:

A 0.5: 1 mixture of lower chlorinated aliphatic hydrocarbon and chlorosulfonic acid is prepared. The process requires the use of an anhydrous solvent. The temperature of the mixture was adjusted to 10-20 ° C, preferably 10 to 15 ° C, and citric acid was added at a rate of 1-2 kg / min. Anhydrous citric acid or, preferably, citric acid monohydrate can be used for this purpose. During the addition, the temperature is maintained at 10-22 ° C, preferably 10-15 ° C, which is readily available without the above citric acid addition rate. Upon completion of the addition, the reaction mixture is stirred at 10-22 ° C, preferably 10-15 ° C until gas evolution ceases. This operation takes at least 6 hours, preferably 7-8 hours.

The reaction mixture was then cooled to 3-5 ° C and then methanol or ethanol was added slowly. Dosage usually takes about 4 to 6 hours. Methanol or ethanol is added at such a rate that the internal temperature does not exceed 25 ° C. After completion of the addition of methanol or ethanol, the mixture was heated to 30-35 ° C and then stirred for about 1-3 hours to complete the esterification reaction.

After completion of the reaction, the mixture was cooled to 10-12 ° C.

Water was added to the resulting mixture gently at a rate below 15 ° C. Methylene chloride is then added. The mixture was stirred and settled to separate the phases. The organic layer was separated. The aqueous layer was extracted with methylene chloride. The organic phases are combined, washed with water and then with basic aqueous solution, preferably with an aqueous alkali metal hydrogen carbonate solution. The pH of the aqueous phase was adjusted to about 7 by the washing operation. The organic layer was separated, washed with water and concentrated in vacuo. Dimethyl 3-oxo-glutarate is also obtained in high yields on industrial scale, in pure form, so that the product can be used in the next step without further purification.

The present invention has the following advantages:

- can be carried out without the use of toxic, explosive and expensive reagents;

- can be easily and easily implemented on an industrial scale;

- contains substantially fewer by-products compared to known methods;

- can be produced on an industrial scale with an excellent yield of over 95%.

The following examples further illustrate the invention without limiting the invention to the examples.

Example 1

Chlorosulfonic acid (1320 kg, 753 L) was added with anhydrous methylene chloride (490 kg, 370 L, volume ratio of methylene chloride: chlorosulfonic acid = 0.5: 1). The temperature of the mixture was adjusted to 10-15 ° C and then 665.0 kg of citric acid monohydrate was added at a rate of 1.25 kg / min; meanwhile the temperature of the reaction mixture is 10-15 ° C. After the addition is complete, the reaction mixture is stirred at 10-15 ° C for at least 6 hours until gas evolution ceases.

The reaction mixture was then cooled to 3-5 ° C, and anhydrous methanol (640 kg, 800 L) was added over a period of 4-6 hours at a rate such that the internal temperature did not exceed 25 ° C. After addition of methanol, the reaction mixture was heated to 30-35 ° C and stirred at this temperature for 2 hours. The esterification reaction is complete during this time.

The reaction mixture was cooled to 10-12 ° C and then 1300 L of water was added at a rate that did not rise above 15 ° C. Methylene chloride (800 L) was added and the mixture was stirred for 15 minutes. The biphasic mixture was sedimented for 30 minutes and the organic layer was separated. The aqueous layer was extracted with 3 x 400 L of methylene chloride. The combined organic phases were washed with 1000 L of water and then a solution of 75 kg of sodium bicarbonate in 1000 L of water; by adding alkaline sodium bicarbonate to a value of about 7. The organic layer was separated, washed with water (2x750 L) and washed in vacuo to give

The temperature does not rise above 30 ° C. The mixture was stirred for 15 minutes and then the pH of the aqueous phase was evaporated if necessary. Vacuum evaporation is carried out at a pressure of 3-5 kPa up to an internal temperature of 75 ° C. 535 kg of dimethyl 3-oxoglutarate is obtained which can be used without further purification for further transformation.

Gas chromatographic rating: GC purity test:

Device: HP-6850 Gas Chromatograph Method: Column: HP — 1.25 m * 0.32 mm

0.17 pm film thickness Carrier gas: Hydrogen Program: 80 ° C-5 min-10 ° C / min-200 ° C-8 min Detector: FID 280 ° C Injector: 200 ° C

Expected retention times:

Methyl acetoacetate 1.18 min Dimethyl-3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10.11 minutes Citric acid trimethyl ester 10.42 minutes Izoftálsavszármazék 18.76 minutes Rating: Area Normalization Result: Methyl acetoacetate: 0.31% Dimethyl 3-oxoglutarate: 98.33% Enol-ether: 0.81% Trimethyl aconitate: 0.28% Citric acid trimethyl ester 0.09% Izoftálsavszármazék: - Other alien (greater than 0.2%): -

Example 2

To a mixture of 100.0 g (58 ml) of chlorosulfonic acid and 30 ml of methylene chloride at 50 DEG C., 30.0 g of citric acid monohydrate was added over 30 minutes. The mixture was stirred at this temperature until the evolution of gas, i.e., 46 hours, was then cooled to 3-5 ° C and 60 ml of methanol was added over 15 minutes at a rate such that the temperature was max. 25 ° C. The reaction mixture was stirred at 30-35 ° C for 2 hours, then cooled to 15 ° C and water (100 mL) was added over 15 minutes. The resulting mixture was extracted with methylene chloride (3 x 50 mL) and the combined organic phases were washed with 100 mL of saturated sodium hydrogen chloride solution and then with 100 mL of water and concentrated in vacuo. 40.8 g of dimethyl-3-methylglutarate are retained. Yield: 98.5%.

Device: HP-6850 Gas Chromatograph Method: Column: HP-1.25 m * 0.32 mm

0.17 pm film thickness Carrier gas: Hydrogen Program: 80 ° C-5 min-10 ° C / min-200 ° C-8 min Detector: FID 280 ° C Injector: 200 ° C

Expected retention times:

Methyl acetoacetate 1.18 min Dimethyl-3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10.11 minutes Citric acid trimethyl ester 10.42 minutes Izoftálsavszármazék 18.76 minutes Rating: Area Normalization Gas chromatographic rating (a method Parameters described in Example 1 to do ): Result: Methyl acetoacetate: 0.49% Dimethyl 3-oxoglutarate: 97.62% Enol-ether: 0.98% Trimethyl aconitate: 0.29% Citric acid trimethyl ester 0.13% Izoftálsavszármazék: 0.07% Other alien (greater than 0.2%): -

Example 3 (Comparative Example)

Example 1 of Belgian Patent No. 879,537 is a mixture of 212 mL of chlorosulfonic acid and 600 mL of methylene chloride (methylene chloride: chlorosulphonic acid volume ratio = 2.83: 1). 200.0 g of citric acid was added over 15-20 minutes; the citric acid dosing rate is 13.3 kg / min. The addition temperature is 20-22 ° C. The reaction mixture was stirred at this temperature for 5 hours, cooled to 3-5 ° C, and then 320 ml of methanol was added over 15 minutes at a rate that did not exceed 25 ° C. The reaction mixture was stirred for 2 hours at 30-35 ° C, cooled to 15 ° C, poured into 800 ml of water, and the phases were separated after vigorous stirring for 15 minutes and settling for 15 minutes. The aqueous phase was extracted with 3 * 150 mL of methylene chloride. The combined organic phases were washed once with 400 ml of saturated sodium bicarbonate solution and then with 2 x 200 ml of water and concentrated in vacuo. 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield 87.3%.

Gas chromatographic rating (method 1)

): Methyl acetoacetate: 0.21% Dimethyl 3-oxoglutarate: 91.07% Enol-ether: 4.78% Trimethyl aconitate: 0.46% Citric acid trimethyl ester 2.27% Izoftálsavszármazék: 0.53% Other alien (greater than 0.2%): -

Claims (8)

A process for the preparation of dialkyl 3--glutarates of formula I wherein R is methyl or ethyl, by reacting the citric acid or monohydrate of formula II with chlorosulfonic acid in a lower chlorinated aliphatic hydrocarbon, followed by formation of the intermediate and methanol. or ethanol The reaction is characterized in that the lower chlorinated aliphatic hydrocarbon and the chlorosulphonic acid are used in a volume ratio (0.1: 1) to (1: 1) and the citric acid is added at a rate of 1-2 kg / min. sulfonic acid and a lower chlorinated aliphatic hydrocarbon. 2. The process according to claim 1, wherein the lower chlorinated aliphatic hydrocarbon is methylene chloride, ethylene chloride or chloroform. 3. A process according to claim 2, wherein methylene chloride is used. A process according to claim 3, wherein the methylene chloride and chlorosulfonic acid are used in a volume ratio of (0.4: 1) to (0.6: 1). The process of claim 4, wherein the methylene chloride and the chlorosulfonic acid are used in a ratio of 0.5: 1 by volume. 6. The process according to any one of claims 1 to 5, wherein the citric acid is added at a rate of 1.1 to 1.8 kg / min to a mixture of chlorosulfonic acid and a lower chlorinated aliphatic hydrocarbon. 7. A process according to claim 6 wherein the citric acid is added at a rate of 1.25 to 1.5 kg / min to a mixture of chlorosulfonic acid and a lower chlorinated aliphatic hydrocarbon. 8. A process according to any one of claims 1 to 3, wherein during the addition of the citric acid and until the subsequent evolution of gas ceases, the reaction mixture The temperature is maintained between 10 and 15 ° C.