GB2033391A

GB2033391A - Process for Synthesis of Keto Acids or Esters

Info

Publication number: GB2033391A
Application number: GB7936181A
Authority: GB
Original assignee: Mallinckrodt Inc
Current assignee: Mallinckrodt Inc
Priority date: 1978-10-19
Filing date: 1979-10-18
Publication date: 1980-05-21
Also published as: FR2439177A1; BE879537A; FI793220A; SE7908597L; NL7907734A; JPS5594336A; DE2942105A1

Abstract

Keto acids or esters, or precursors thereof, e.g., acetone dicarboxylate diesters, are prepared by reacting an alpha -hydroxy acid, e.g. citric acid, or a derivative thereof, with an anhydrous inorganic acid or carboxylic acid anhydride in the presence of an inert, water-immiscible organic solvent. Processing difficulties can be reduced when the keto acids or esters are prepared in a reaction medium containing such an organic solvent.

Description

SPECIFICATION Process for Synthesis of Keto Acids or Esters The present invention relates to an improved process for the preparation of keto acid or esters, or precursors thereof, e.g., acetone dicarboxylate diesters. These materials are produced by reacting an ahydroxy acid, such as citric acid, with an anhydrous inorganic acid or carboxylic acid anhydride.

Acetone dicarboxylate esters, for example, are useful as catalysts for the polymerization of chloroprene and can also be reacted with primary amines and haloacetone to produce substituted pyrrole ester pharmaceuticai products. Acetone dicarboxylate esters can be prepared by treating citric acid or esters thereof with a strong acid, followed if necessary, by esterification with an ester-forming alcohol. Hamilton et ai.: U.S. Pat. 2,887,508; issued May 19, 1959 and Smith, U.S. Pat. 2,848,480; issued August 1 9, 1 958, for example, both disclose reaction of citric acid with concentrated sulfuric acid or oleum to produce acetone dicarboxylic acid which can be subsequently esterified.Boehringer Sohn; German Pat. 1,160,841; published July 16, 1964, discloses the reaction of citric acid with chlorosulfonic acid followed by alcohol addition to the reaction mixture in order to prepare acetone dicarboxylate esters.

Citric acid/strong acid reactions of the type disclosed in these references are generally accompanied by the evolution of carbon monoxide and possibly other gaseous reaction products such as HCI. This gas evolution can cause rather pronounced and undesirable reaction mixture foaming to occur during production of acetone dicarboxylate esters. Control of such reaction mixture foaming can be especially troublesome when producing acetone dicarboxylate esters on a commercial scale.

Reactants must be combined at a much slower than desirable rate in order to minimize foaming.

Reaction mixture foaming also interferes with mixing of reactants which may result in longer reaction times and possibly lower product yieids. Given these problems of producing keto acids and esters, e.g., acetone dicarboxylic acid and its esters, from a-hydroxy acids, e.g., citric acid, there is a continuing need for improved procedures for producing such commercially valuable materials.

Accordingly, it is an object of the present invention to provide an improved process for reacting ahydroxy acids such as citric acid with an acidic reagent to produce keto acids or esters such as acetone dicarboxylate acid or esters thereof.

It is a further object of the present invention to provide such an improved acetone dicarboxylate synthesis method which minimizes the reaction mixture foaming problems generally associated with reactions of this type.

It is a further object of the present invention to provide such an improved acetone dicarboxylate synthesis method which can be successfully carried out for production of commercial quantities of the desired acetone dicarboxyiate esters.

In accordance with the present invention an a-hydroxy acid, such as citric acid, or an ester thereof is reacted with an anhydrous inorganic acid or carboxylic acid anhydride to form a keto acid or ester or precursor thereof, e.g., acetone dicarboxylic acid or ester thereof. The reaction is carried out in the reaction medium comprising an inert organic solvent which is immiscible with water. If the desired reaction product is a keto acid ester such as acetone dicarboxylate ester, the instant process optionally involves further reaction of the a-hydroxy acid/acidic reagent reaction product with an alcohol in the same water-immiscible inert organic solvent in order to form, for example, a diester such as diethvl acetone dicarboxylate.It has been surprisingly discovered that by utilizing such an organic liquid solvent reaction medium, the production of keto acids, esters or precursors thereof, such as acetone dicarboxylic acid, acetone dicarboxylate esters, or precursors thereof, can be realized with decreased reaction times and with a substantial eiimination of reaction mixture foaming problems. Utilization of particular types of organic solvents can also facilitate the recovery of the ester reaction products after the reaction is complete.

The a-hydroxy acids used in the process of the present invention are exemplified by the general formula:

wherein R is H, alkyl of 1 to 10 carbon atoms or (CH2)XCH2COOH and x is 0 to 3. Examples of such ahydroxy acids include citric acid, malic acid, hydroxysuccinic acid and a-hydroxy adipic acid. Esters of such acids, e.g., lower C14 alkyl esters, may also be employed.

The preferred a-hydroxy acid for use in the present invention is citric acid in either its anhydrous or monohydrate form. Citric acid can be reacted with an acid such as chlorosulfonic acid to produce an acetone dicarboxylic acid of ester precursor according to the reaction:

The sulfonic anhydride intermediate can be hydrolyzed to acetone dicarboxylic acid or it can be esterified according to the reaction:

wherein R is an alcohol-forming hydrocarbyl group, e.g., alkyl.

Esters of a-hydroxy acids can also be utilized as the starting material in the reaction herein. Such ester reactants yield the corresponding keto esters upon reaction with the anhydrous inorganic acid or carboxylic acid anhydride without the necessity of the further esterification of the reaction product with an esterifying alcohol.

The acid reagent used to convert the a-hydroxy acids herein the corresponding keto acid or keto ester precursor can be an essentially anhydrous inorganic acid or carboxylic acid anhydride. Acids and anhydrides of this type are those which are liquids or can be dissolved in the liquid reaction medium employed in the present process. Examples of suitable anhydrous inorganic acids include chlorosulfonic acid, 100 percent sulfuric acid, fuming sulfuric acid (oleum), fuming nitric acid,100 percent orthophosphoric acid, anhydrous polyphosphoric acids such as metaphosphoric acid and pyrophosphoric acid, and the like.

The carboxylic acid anhydride employed can have up to 1 5 or more carbon atoms and may be aliphatic, e.g., alkanoic, aromatic or mixed aliphatic-aromatic structures. Examples of suitable carboxylic acid anhydrides include acetic anhydride, trifluoroacetic anhydride, maleic anhydride, benzoic anhydride, phthalic anhydride and the like. If a carboxylic acid anhydride is to be used, a strong acid catalyst such as fluorosulfonic acid may generally be employed in conjunction with the carboxylic acid anhydride in the reaction of the present invention. Of the acidic reagents which can be employed in the process herein, chlorosulfonic acid, 100 percent sulfuric acid and oleum are preferred.

Chiorosulfonic acid is the most preferred and may generally be employed in its commercially-available neat anhydrous liquid form.

In accordance with the present invention, the reaction of the a-hydroxy acid and acidic reagent is carried out in an inert organic liquid solvent which is immiscible with water. In the context of the present invention a solvent which is "inert" does not react with either the a-hydroxy acid or acidic reagent under conditions of the present process. The organic solvent can thus be an inert, waterimmiscible liquid which is composed primarily of carbon along with a minor weight percentage of hydrogen with or without a minor amount of one or more elements such as oxygen, nitrogen, halogen and the like. Generally such inert, water-immisible solvents are aliphatic hydrocarbons or aliphatic or aromatic halogenated hydrocarbons.Preferred solvents include, for example, halogenated alkanes such as carbon tetrachloride, chloroform, dichloromethane, 1 ,2-dichloroethane, and 1 ,1 -dichloroethane.

Halogenated aromatics such as chlorobenzene, p-dichlorobenzene and the like may also be employed.

To facilitate product recovery after completion of the reaction, the inert, water-immiscible organic solvent is preferably one which is heavier than water and is also preferably one which forms an azeotrope with water. Solvents which are heavier than water are more advantageously separated in commercial scale processes from aqueous materials which are added to the reaction mixture during product recovery operations. Solvents which form azeotropes with water also advantageously serve to remove water from the organic product recovered after completion of the reaction. Solvents of this type generally have a boiling point between about 350C and 1 750C. Preferred solvents which are both heavier than water and azeotrope-forming materials include dichloromethane and dichloroethanes.

The inert, water-immiscible organic solvent can be utilized in any amount which is sufficient to reduce reaction medium foaming and suspend the a-hydroxy acid in the acidic reagent-containing reaction medium. Preferably, the volume ratio of solvent to liquid acidic reagent ranges from about 1:1 to 6:1, more preferably from about 2:1 to 4:1.

The a-hydroxy acid and acidic reagent can be combined with the organic solvent reaction medium in any desired manner. In a preferred embodiment, however, the acidic reagent may be added to the organic solvent, and the a-hydroxy acid is subsequently added to the acid-containing reaction medium. Advantageously, the acidic reagent is employed in a molar excess of at least about 10 percent over stoichiometric concentration vis-a-vis the a-hydroxy acid. When anhydrous citric acid and chlorosulfonic acid are employed as reactants, for example, the molar ratio of chlorosulfonic acid to citric acid may be at least about 3.1:1.

The reaction between an a-hydroxy acid such as citric acid and the acidic reagent such as chlorosulfonic acid generally occurs at temperatures between about 1 50C to 850C, preferably from about 200C to 350C. External cooling or heating of the reaction mixture may be employed to maintain reaction temperatures within such ranges. Reactant addition usually takes place as rapidly as possible without creating undue foaming of the reaction mixture. Use of the organic solvent in the reaction generally permits faster addition of reactants than when no solvent is employed, since foaming from gas evolution is considerably reduced in the solvent-containing system.The reaction between ahydroxy acid and the inorganic acid or organic acid anhydride is generally continued for a period of time sufficient to complete the reaction to the desired extent and preferably until gas evolution substantially ceases. Usually reaction times of from about 1 to 7 or 8-hours are sufficient. If desired, the reaction medium can be agitated during and after reactant addition. Gas evolution, however, tends to keep the reaction medium in an agitated condition.

Reaction between a-hydroxy acid and the inorganic acid or organic acid anhyride is preferably conducted in a substantially anhydrous reaction medium. While small amounts of water can be tolerated, any water present in the reaction mixture may preferentially react with the inorganic acid or organic acid anhydride and thereby lower the yield of the desired acid or ester product.

If cw-hydroxy acid esters are employed as the starting material, the reaction product obtained in the process herein will be the corresponding keto ester. Such product can be recovered from the reaction mixture without further reaction or chemical alteration. If, however, a-hydroxy acid per se is employed as a starting material in the instant process, the a-hydroxy acid/acidic reagent reaction product may be further reacted with an alcoholic esterification agent in order to produce a recoverable product in the form of a keto ester, e.g., acetone dicarboxylate diester.

Such esterification is generally carried out by adding to the reaction mixture a suitable anhydrous alcoholic esterification agent. Esterification agents of this type are generally monohydric alcohols of the formula ROH wherein R is a suitable hydrocarbyl group. Examples of such esterification agents include the lower alkanols containing from one to six carbon atoms, including cycloalkanols, and aralkyl alcohols such as benzyl alcohol. Preferred esterification agents include anhydrous methanol, anhydrous ethanol and anhydrous isopropanol.

The alcoholic esterification agent is added to the reaction mixture after the reaction between ahydroxy acid and the anhydrous inorganic acid or carboxylic acid anhydride has been completed. Thus alcohol is generally added to the organic solvent-containing reaction mixture after gas evolution has substantially ceased. The alcoholic esterification agent is advantageously employed in stoichiometric excess to ensure acceptable yields of the desired ester product. Generally the molar ratio of alcoholic esterification agent to a-hydroxy acid depends upon the reactants utilized. For example, when citric acid is employed the molar ratio of alcoholic esterification agent to citric acid may be at least 2:1, more preferably at least 7.5:1.The esterification may be generally conducted at a temperature from about 200C to 1 500C depending upon the alcoholic esterification agent used. When ethanol is used, an esterification reaction temperature of from about 250C to 350C is advantageously employed. When the esterification agent is isopropanol, esterification temperatures of from about 300C to 500C can be utilized. Esterification reaction is allowed to continue until esterification is completed to the extent desired. Generally esterification reaction times of from about 1 to 8 hours are satisfactorily employed.

After esters such as acetone dicarboxylate diesters have been formed in the reaction mixture, which is preferably essentially anhydrous, the desired product esters can be recovered by means of various suitable separation and purification techniques. In a typical recovery process, water is added to the reaction mixture at the completion of the esterification reaction and is agitated with the reaction mixture for a time sufficient to dissolve the water-soluble acid products and/or reactants, e.g., H2SO4, remaining in the reaction mixture. The reaction mixture is then allowed to separate into 1) an aqueous phase containing dissolved acidic reactants and reaction products and a small amount of the desired ester product and 2) an organic phase containing substantially all of the ester reaction product.

The aqueous and organic phases so formed are separated, and the aqueous phase is then extracted with an additional amount of the organic solvent to remove what little ester product has remained in the aqueous phase. This extract can then be combined with the organic fraction originally separated from the reaction mixture. The resulting combined organic phase can be washed with an aqueous solution containing a neutralizing salt such as bicarbonate to remove any acid impurities remaining in the organic phase. A final water wash can serve to remove any remaining traces of the neutralizing sait.

If desired, the ester product in the organic phase can be isolated in its pure form by stripping off the organic solvent using conventional distillation procedures. Solvents so removed can be recycled for use in the acetone dicarboxylate ester synthesis process. If, as is preferred, the solvent forms an azeotrope with water, the solvent recovery distillation procedure also serves to dry the productcontaining organic phase by removing water from the organic phase through vaporization of the water/solvent azeotrope. In this manner, use of conventional but relatively inconvenient product drying techniques involving, for example, drying agents such as anhydrous sodium sulfate, can be eliminated.

The improved process of the present invention is illustrated by the following examples which are not limiting of the invention herein.

Example I 1 50 ml of 1,2-dichloroethane are placed in a 1 liter flask equipped with a gas outlet. With the dichloroethane at room temperature, 53 ml (0.8 mole) of chlorosulfonic acid (neat) are slowly added to the flask. A drop of 3-40C in temperature is noticed. 50 gm (0.26 mole) of anhydrous citric acid are then added in small portions over a period of 10-20 minutes while the temperature of the reaction mixture is maintained between 20-220C. The use of the dichloroethane solvent in such a procedure practically eliminates reaction mixture foaming during the reaction. After the addition of citric acid is complete, the mixture is held at 20-250C and stirred until no more gas evolution is observed (about 5 hours).

The reaction mixture is then cooled to 3-50C and 90 gm of anhydrous denatured ethanol are added over a period of 15 minutes in such a manner that the temperature of the reaction mixture does not rise above 250C. After ethanol addition is complete, the reaction mixture temperature is raised to 300C and is maintained between 30-350C while the reaction mixture is stirred for 2 hours.

After esterification is complete, the reaction mixture is cooled to 1 50C and 200 ml of water are added to the mixture over a 1 5 minute period. The reaction mixture is stirred for 5 minutes and then allowed to separate into an upper aqueous layer and a lower organic layer. The organic layer (200 ml) is separated, and the aqueous layer is extracted with 100 ml of additional dichloroethane. The dichloroethane extract is then combined with the original organic layer to form 300 ml of organic solution. This organic solution is washed first with 100 ml of 4 percent sodium bicarbonate solution and secondly with 100 ml of water.

The resulting organic fraction (300 ml) is distilled to collect about 250 ml of the dichloroethane solvent. The crude product remaining is diethyl acetone dicarboxylate which is obtained in a 94-96 percent yield based on the initial citric acid used.

Substantially similar production of diethyl acetone dicarboxylate is obtained when, in the Example I procedure, the citric acid is first added to the dichloroethane solvent and a neat chlorosulfonic acid is slowly added (5 ml every 1-1/2 minutes) to the reaction mixture.

Example II 150 ml of dichloromethane are placed in a 1 liter, 3-necked flask and cooled to 50C using an ice water bath. 55 ml of chlorosulfonic acid are added slowly to the flask with no appreciable increase in temperature. 54 gm of citric acid monohydrate are then added in increments over a 2-1/2 hour period.

Very little foaming is observed in the flask, and at the end of citric acid addition, the reaction mixture is stirred for 1-1/2 hours. The reaction mixture is then cooled to 1 00C and 180 gm of chilled absolute ethanol are added over a period of 20 minutes at such a rate that the temperature of the reaction mixture stays between 150 and 250C. The reaction mixture temperature is then raised to about 300C with warm water and is stirred for 2 hours at 30-350C. The reaction mixture is then cooled to 1 OOC, and 200 ml of ice-cold water are added.

The reaction mixture is transferred to a separatory funnel and separated into an organic layer (about 1 50 ml) and an aqueous layer (about 470 ml). The aqueous layer is extracted with two batches (75 ml; 50 ml) of dichloromethane, which batches are then combined with the originally separated organic layer (total 310 ml organic). The organic layer is then washed with 100 ml of a 5 percent sodium bicarbonate solution followed by a wash with 100 ml of water.

The washed organic fraction is azeotropically distilled for 3 hours to distill off 240 ml of dichloromethane solvent. The remaining crude product (85% yield) is transferred to another flask for vacuum distillation at 1 5-1 6 mm. Four fractions including charred residue are obtained as follows:: Fraction I, 1.3 gm at 120-1 380C Fraction 11,40.0 gm at 139-141 OC Fraction Ill, 0.4 gm at 1 420C Residue, 3.2 gm Example Ill A 1 liter, 3-necked round-bottom flask is set up with a temperature control bath and is equipped with a mechanical stirrer, a thermometer, a condenser, and an additional funnel. 1 00 gm of anhydrous citric acid and 400 ml of 1,2-dichloroethane are charged to the flask. While the reaction mixture is stirred and maintained at a temperature of 20-220C, 106 ml of chlorosulfonic acid are added. The mixture is stirred for about 3 hours at room temperature until gas evolution has stopped.

The reaction mixture is cooled to about 50C and 235 gm of absolute isopropanol are added while the reaction mixture temperature is maintained under 25"C. The mixture is then warmed to 500 C, stirred for 4 hours and allowed to stand overnight. With the reaction mixture at about 250C, 400 ml of water are added, and the mixture is transferred to a separatory funnel where it is separated into 670 ml of an upper aqueous phase and 510 ml of a bottom layer organic phase. The aqueous phase is extracted with 200 ml of dichloroethane producing 220 ml of organic extract which is combined with the original organic phase. The combined organic fractions are extracted with 200 ml of an aqueous 4 percent sodium bicarbonate solution and are then washed with 200 ml of water.The washed organic phase is stripped by azeotropic distillation to an oil which is crude di-iso-propyl acetone dicarboxylate.

A crude product yield of 84.5 percent is obtained based on citric acid.

Example IV 31 8 kg of chlorosulfonic acid are charged to a reaction vessel. 621 kg of 98 percent ethylene dichloride are then charged to the reactor. With the temperature between 20-250C, 163 kg of anhydrous granular citric acid USP are added to the reactor at a controlled rate of 5 kg per minute until all is added. The temperature of the reaction mixture is then held between 20--250C for 5 hours.

The reaction mixture is transferred to another cooled reaction vessel, and 297 kg of anhydrous denatured ethanol is added at a controlled rate of 3 kg per minute while maintaining the reaction mixture temperature less than 300C. After ethanol has been added, the reaction mixture is maintained between 30-350C for 2 hours.

659 kg (174 gal) of water are added to a separate reaction vessel and cooled to 5-1 00C. The reaction mixture containing the crude acetone dicarboxylate product is then cooled to 5-1 00C and transferred to the water-containing reaction vessel while the temperature in this vessel is maintained below 250C. The mixture is then agitated for 1/2 hour and allowed to settle for 1/2 hour and separate into an upper aqueous phase and a lower organic phase.

659 kg (174 gal) of water are added to a separate reaction vessel and cooled to 5-1 00C. The reaction containing the crude acetone dicarboxylic product is then cooled to 5-1 00C and transferred to the water-containing reaction vessel while the temperature in said vessel is maintained below 250C.

The mixture is then agitated for 1/2 hour and allowed to settle for 1/2 hour and separate into an upper aqueous phase and a lower organic phase.

The lower organic phase is transferred to a separate reaction vessel, and 411 kg of ethylene dichloride are charged to the vessel containing the aqueous phase. Extraction of the aqueous phase is carried out by agitating this vessel for 1/2 hour, allowing the mixture to settle and separate for 1/2 hour and by thereafter charging the lower organic extract phase to the vessel containing the organic phase originally separated from the reaction mixture.

The combined organic fractions are washed for 1/2 hour with a mixture of 82 gallons of water and 1 5 kg of sodium bicarbonate after which the washed organic layer is separated and charged to a separate reaction vessel. The organic phase is again washed for 1/2 hour with 96 gallons of water, separated from the aqueous wash and transferred to a heated reaction vessel equipped with a condenser. The organic mixture is heated to 80-900C with a low pressure steam, and 411 kg of ethylene dichloride is initially stripped from the mixture. Additional ethylene dichloride is stripped from the mixture by subsequently heating the mixture to 125-1 300C until all the ethylene dichloride is removed.

The crude product remaining is diethyl acetone dicarboxylate which is sampled for assay. A yield of about 97-99 percent based on initial citric acid charged is obtained.

Claims

1. A process for preparing keto acids, keto acids or anhydride precursors of said keto acids or keto esters, whereby an a-hydroxy acid of the formula:

wherein R is H, alkyl of 1 to 10 carbon atoms or (CH2)xCH2COOH and the symbols x represent integers, which may be the same or different, from 0 to 3, or an ester thereof, is reacted with an acidic reagent selected from anhydrous inorganic acids and carboxylic acid anhydrides, wherein the reaction is effected in a reaction medium comprising an inert organic solvent which is immiscible with water.

2. A process in accordance with claim 1 wherein the organic solvent employed forms an azeotrope with water.

3. A process in accordance with either of claims 1 and 2 wherein the a-hydroxy acid is unesterified citric acid and the acidic reagent is an anhydrous liquid inorganic acid.

4. A process in accordance with claim 3 wherein the reaction between citric acid and anhydrous liquid inorganic acid occurs at a temperature from about 1 50C to 850C.

5. A process in accordance with either claims 3 and 4 wherein the citric acid/anhydrous inorganic acid reaction product is subsequently esterified by addition to the reaction mixture of an anhydrous alcohol esterification agent.

6. A process in accordance with claim 5 wherein: A) the molar ratio of alcoholic esterification agent to citric acid is at least about 2:1; and B) the volume ratio of organic solvent to liquid inorganic acid ranges from about 1:1 to 6:1.

7. A process in accordance with either of claims 5 and 6 wherein the alcoholic esterification agent is a lower alkanol containing from 1 to about 6 carbon atoms.

8. A process in accordance with any one of claims 5 to 7 wherein the reaction between the citric acid/anhydrous inorganic acid reaction product and the alcohol esterification agent occurs at a temperature from about 200 to 1 500 C.

9. A process in accordance with any one of claims 5 to 8 wherein the alcoholic esterification agent is selected from anhydrous methanol, anhydrous ethanol and anhydrous isopropanol.

10. A process in accordance with any one of the preceding claims wherein the acidic reagent is anhydrous chlorosulfonic acid.

11. A process in accordance with any one of the preceding claims wherein the inert waterimmiscible organic solvent is selected from dichloromethane and dichloroethane.

12. A process for the preparation of keto acids, keto esters or anhydride precursors therefor substantially as herein described in any one of the Examples.

13. Keto acids, keto esters or anhydride precursors therefor whenever prepared by a process as claimed in any one of the preceding claims.