IL29862A - A process for producing ethyleneketal of gamma-ketocarboxylic acid esters - Google Patents

Description

A PROCESS FOH FSODUCING ΕΤίϊΥΤ,ΕΙΪΞΚΕΤΛΙ, OF ACID ESTERS ' τ ιτηπιΊη-πη ττ.ΤΓ ΓΤΤΙ ΡΙΡΪΤΡΙΡΡ Abstract of the Disclosure Ethylene ketals of γ-keto-carboxylic acid esters having the formula, R1-CH2-C-CH2-CH2-COOR2 0 0 / ! CH2 — CH2 I uryl or thieny¾/ wherein R-^ is a hydrogen atom, alkyl group -w aryl» roup; and R2 is a lower alkyl group, are produced by reacting in the presence of an acid catalyst, a lower alkyl ester of -keto-carboxylic acid having the formula, R1-CH2-C-CH2-CH2-000R2 0 wherein R-^ and R2 are as defined above, with ethylene glycol removing formed water and alcohol from the reaction mixture to yield the reaction mixture containing the desired ethylene ketal, ethylene glycol ester or ethylene glycol diester of ethylene ketal of γ-ketocarboxylic acid, etc. and reacting the obtained reaction mixture with a monohydric lower alcohol in the presence of an alkali metal monohydric lower alcoholate.

This invention relates to a process for producing ethylene ketals of -ketocarboxylic acid esters represented by the formula, CH2-CH2 yfuryl or thlenyl^/ wherein R-^ is a hydrogen atom, alkyl aryrj and Rg is a lower alkyl, from corresponding lower alkyl esters of y-keto-carboxylic acids represented by the formula, R1-, -CH2-C„-CH2-CH2-C00R2 0 wherein R^ and R2 are as defined above.

Some ethylene ketals of the present invention are known compounds as intermediates for production of such compounds as 5-benzyl-3-furylmethyl chrysanthemate, having insecticidal activity as seen in Nature 1967, Feb. 4, page 493, or as intermediates for production of medicines.

For the production of cyclic ethylene ketals from corresponding ketones, there has heretofore been adopted a method in which ethylene glycol and a ketone are heated in a suitable solvent in the presence of an acid catalyst and the ketalization reaction is effected by removing water formed in the reaction as an azeotropic mixture of an organic solvent.

It is also well known that the above method is widely applicable to ketones having carboxylic acid ester group.

The present inventors, however, found that when applied to carboxylic acid esters having ketone groups at the ^-position, said known method is not preferable for the production of desired ethylene ketal of (-ketocarboxylic acid esters for the following reasons: (1) Ethylene glycol employed as a ketalizing agent attacks the lower alkyl ester of ^-ketocarboxylic acid and the lower alkyl ester of ketal-carboxylic acid to bring about ester exchange reaction, whereby mono- and di-glycol esters are formed. The ester-exchange ratio varies depending on the structure of starting ^-ketocarboxylic acid ester. For example, when an ethyl levulinate is reacted with ethylene glycol in the presence of a p-toluenesulfonic acid catalyst, while dehydrating the system by removing water formed as benzene water azeotrope, ester-exchange reaction takes place together with ketalization reaction, and the ethylene ketal of ^-hydroxyethyl levulinate (III) is a main product and the ethylene ketal of ethyl levulinate (IV) is obtained in a poor yield.

C 0H5-J3f-CH2-CH2-C00C2H40H CH^-C-Ci^-CHg-COOC^ 0 0 (III) 0 0 (IV) / / / / CH2 — CH2 CH2 — CH2 In case an ester of ~-phenyl levulinic acid is used, the ratio of ester-exchange of said ester with highest,J ethylene glycol is noo'ft 1 groaft in the case of methyl ester. Further, the ester-exchange ratio reaches 20-40 in the case of ethyl ester, and 10 or more in the case of isopropyl ester. (2) When the ketalization progresses and the amount of the starting keto-ester in the reaction system becomes about 5-10 of ketal ester, the rate of ketalization reaction greatly lowers and becomes difficult to distinguish the rate of the ester exchange reaction with ethylene glycol from the rate of the side-reaction for polyethylene glycol formation which proceed together with the ketalization reaction. Therefore, even if the reduction in yield is conceded, it is extremely difficult to lower the content of starting keto ester to less than %. Further, not much difference in boiling point under reduced pressure is seen, in general, between ^ketocarboxylic acid esters and ethylene ketals thereof, and therefore the selective removal of the desired keto-esters by distillation is uneconomical from the industrial standpoint. (3) It is possible to decrease to a certain extent the degree of ester exchange due to ethylene glycol mentioned in the foregoing item (1), e.g. by increasing the dilution ratio of the reaction system by use of a solvent, or by lowering the concentration of ethylene glycol in the system. In response thereto, however, the rate of the ketalization, which is a main reaction, is lowered, and the reaction time is required to be prolonged to a great extent. Accordingly, such an attempt - cannot be any effective measure. ■ disadvantages In addition to (owh" indiag'Jo detailed above, peculiarity the present inventors further found the opooifioity that give rise to I Y-ketocarboxylic acid esters do not f ping noncyclic dialkyl ketal formation reaction and ketal exchange reaction esters are different n reaction behaviours from ordinary ketones.

Therefore, even If there le adopted th concept of the conventional ketallaation method of ketone, It is difficult to obtain essentially pure ethylene ketals of said esters In hi h yields wit commercial advantages.

The present Inventors have found that In the ketalisatio reaction of ¾-keto-esters, the keta formatio rate of ketone groups increases under the conditions i.e., increased molar ratios of ethylene glycol to the estere, higher reaction temperatures than commonly applied, etc., which increase the ester exchange rate with ethylene glycol. The inventors have further found that the ketal formation rate of keto-eeters vith ethylene glycol substantially reaches 100$. It is not like the conventional case -· i . ■ where an equilibrium reaches at 10-5$ of the ¾*keto-ester remained unreacted. [represented by the above formula (b)] of ethylene glycol undergoes a rgpidj having ah ethylene ketal group in the ^-position n¾~¾uiokl ester exchange* in an arbitrary primary lower monohydric alcohol in the presence of a catalytic amount of an alkali metal alcoholate with said primary lower monohydric alcohol, and is quantitatively converted into an ester of the primary lower monohydric alcohol without application of any such specific operation as to remove the liberated ethylene glycol out of the system.

One object of the present invention is to provide a process for producing ethylene ketals of ^-ketocarboxylic acid esters represented by the formula, R-, -CH -C-CHo-rCH -C00R 0 0 / / CH2-CH2 furyl or thienyl wherein is a hydrogen atom, alkyl group, ary-£j roup; and R^ is a lower alkyl group, and a mixture thereof.- Another object of the present invention will be apparent from the following description; In order to accomplish these objects-, the present invention provides a process for producing ethylene ketals of "J-ketocarboxylic acid esters represented by the formula, R1-CH2-C-CH2-CH2-C00R2 0 0 / / CH2-CH2 J f ryl or thienylJ wherein R-^ is a hydrogen atom, alkyl group, <¾c aryl,|group; and R2 is a lower alkyl group, and a mixture thereof, which comprises reacting in the presence of an acid catalyst a lower alkyl ester of Y-ketocarboxylie acid represented by the formula, R1-CH2-C-CH2-CH2-C00R2 0 above, with ethylene alcohol from the reaction mixture to yield a reaction mixture containing as the desired product ethylene ketal of fr'-ketocarboxylic acid ester and as byproducts ethylene glycol ester or ethylene glycol diester of ethylene ketal of γ-ketocarboxylic acid, and reacting the obtained reaction mixture with a monohydric lower alcohol in the presence of an alkali metal monohydric lower alcoholate catalyst wherein the alcohol and alcoholate have same alkyl moiety as R The process of the present invention, in which the above-mentioned findings are applied to a method for the production of ketals of lower monohydric alcohol esters of Y-keto-acid, is far more useful than the known ketal formation method in the following points: ar o-Jtfc-i .oombir-at-ian, and therefore the reaction rate can be made extremely high and the reaction time can be greatly shortened as compared with those employed in the conventional method. 2) The ketal formation can be easily made more complete than that in the conventional method, and therefore pure ketal esters can be readily obtained.

In the conventional method, the ester, which has been produced by ester exchange of ethylene ketal of ^-ketocarboxylic acid ester or -ketocarboxylic acid ester with ethylene glycol, is a by-product, and even when the reaction is effected while inhibiting the formation thereof as far as possible, the lowering in yield of ketal of monohydric alcohol ester of -ketocarboxylic acid is unavoidable. In the present process, however, no by-product is finally present, in fact, and therefore the desired product can be easily obtained in a quantitative yield. 4) The ketal formation, which accompanies the ester exchange due to ethylene glycol, and the subsequent ester exchange by means of a catalytic amount of metal alcoholate in the presence of a lower monohydric alcohol can be effected in one reactor by mere successive addition of the reagents. Accordingly, the present process, when practiced on commercial scale, is carried out in one step, though two-stage reactions are effected in principle, and no additional apparatus is required in the present process.

Since the amount of alkali metal alcoholate employed in the present process is a catalytic amount, the increase in cost of starting material is practically negligible.

The present process is explained in further detail below.

Usable as the starting y-ketocarboxylic acid ester is any. of lower alkyl esters of said acid.

Examples of the alkyl and aryl of R-, are methyl, t R-) also representing a fury! or thlenyl group.J ethyl, propyl, butyl, phenyl, i p l and . hioi½- ' Examples of the lower alkyl of are methyl, ethyl, propyl and butyl.

The use of methyl and ethyl esters is most preferable.

The amount of ethylene glycol to be used/¾t theoretically 2 mols per 1 mole of the f-ketocarboxylic acid ester. However, for the attainment of favorable results, all the esters are not always required to be once formed into ethylene glycol esters. For example, in the ketal formation of ethyl S-phenyl levulinate ester, the achievement ratio of ketal formation can be sufficiently increased under such conditions as to form 30 to 50 of mono- or di-ester of ethylene glycol. In some cases, therefore, ethylene glycol is used in an amount of less than 2 mols but in an amount of more than 1 mole per 1 mole of the y-ketocarboxylic acid ester. Further, more than 2 mols of ethylene glycol may naturally be used depending on the kind of y-keto-ester employed.

As the ketal formation catalyst, there may be used an alkylsulfonic acid such as methanesulfonic acid, an aromatic sulfonic acid such as benzenesulfonic or paratoluenesulfonic acid, a mineral acid such as sulfuric acid, or the like acid catalyst.

The reaction temperature of ketal formation of the present invention is not particularly limited, but a temperature somewhat higher than that generally employed in the ketal formation of ketones, i.e. a temperature ranging from 90° to 200°'C., may be adopted.

In practicing the present process, the use of solvent is not always necessary. However, it is desirable to use an organic solvent inert to the reaction to azeotropically remove water formed in the system and monohydric alcohol from the reaction mixture. Usable organic solvent is a halogenated hydrocarbon such as dichloroethane which can boil together with water and lower monohydric alcohols, or a hydrocarbon such as benzene or xylene which is not injurious to alkali metal alcoholate catalysts. Generally, however, the reaction rate is greatly lowered due to the addition of said solvent.

Therefore, it is rather undesirable to dilute the reaction system by addition of a large amount of solvent.

When the ketal formation has progressed to a desired level, the reaction mixture containing the desired ethyl ketal of the "^-ketocarboxylic acid and ethylene glycol ester or ethylene glycol diester produced by the ester exchange of the γ-ketocarboxylic acid ester or an amount ±aj ethylene ketal of the -ketocarboxylic acid ester |¾ ohaipgod Ladded w.>h an ojcooodS of a lower monohydric alcohol, e.g. methanol, ethanol, n-propanol or isopropanol, in an anhydrous state. Further, an alkali metal alcoholate of a monohydric alcohol, for example, sodium methylate, sodium ethylate or potassium ethylate is added in a catalytic amount.. Ordinarily, sufficient effects can be attained when such alcoholate is added in an amount of less than 0.05 mol per mol of the starting ester. The reaction temperature in the above case is not particularly limited, and preferably 50° - 100°C. However, when, in the case of the ketal of If the alcohol moiety of the Y-ketocarboxylic acid ester used as a starting material, the alcohol moiety of the alkali metal alcoholate and the lower monohydric alcohol are different from each other, the formed ethylene ketal of Y-ketocarboxylic acid ester becomes a mixture having different alcohol moieties of the ester group. Therefore, it is necessary to arrange the alcohol moiety of the alkali metal alcoholate and the lower monohydric alcohol to the alcohol moiety of the After-treatment in accordance with the present process is carried out in such a simple manner that the system, either as such or after removal of excess alcohol by distillation, is charged into water and the organic layer formed is recovered and subjected to distillation under reduced pressure, whereby a very pure ketal ester can be obtained in a high yield.

The ethylene ketal carboxylic acid esters having ethylene ketal group at the Y-position of the ester group which are obtained according to the present invention find many uses as intermediates to be used in the production of agricultural chemicals and medicines.

The process of the present invention is illustrated in detail below with reference to referential example and examples. All per cents are based on weight.

Referential Example. (General method for the synthesis of common ketal) . 200 g. of ethyl ^-phenyl-levulinate, 102 g. of ethylene glycol, 1 J of benzene and 1 g. of paratoluene sulfonic acid were mixed together. The mixture was heated under reflux for 20 hours while removing water distilled as an azeotropic mixture from the top of fractionation column.

After cooling, the reaction mixture was washed with 200 ml. of a aqueous sodium carbonate solution, was dried and was then freed from benzene by distillation to obtain 200 g. of a crude ketal ester. The crude ester was distilled under reduced pressure, whereby 200 g. of an ethylene ketal of ethyl (-phenyl levulinate was obtained, b.p. 125° - 130°C./0.2 mmHg. The thus obtained crude ethylene ketal contained 5% of ethyl ^-phenyl levulinate. The yield of said ethylene ketal of ethyl cf-phenyl-levulinate calculated for 100 purity was 72%.

Example 1 A mixture consisting of 220 g. of ethyl cf-phenyl levulinate, 130 g. of ethylene glycol, 100 ml. of benzene and 1 g. of paratoluenesulfonic acid was heated under reflux while removing water formed and ethanol as an azeotropic mixture from the top of fractionation column. After 9 hours, 150 ml. of anhydrous ethanol and then an ethanol solution of sodium ethylate prepared by dissolving 4 g. of sodium metal in 80 ml. of anhydrous ethanol were added, and the mixture was maintained at 80°C. for 1 hour. After cooling, the mixture was charged with 500 ml. of benzene and was poured into 3 I of cold water. .

Subsequently, the organic layer formed was recovered, and the water layer was further extracted with 200 ml. of benzene and the both organic layers were united therewith.

The organic layer was dried with anhydrous sodium sulfate, and benzene was distilled off, whereby, 255 g. of a crude ethylene ketal of ethyl }f-phenyl levulinate was obtained. Subsequently, the crude ethylene ketal was subjected to reduced pressure distillation to obtain 250 g. of a pure product, b.p. 130°C./0.2 mmHg, yield 95 .

According to gas chromatograph quantitative analysis, the product had a purity of 98-99$ and the content of unreacted keto ester was 1-2$. Accordingly, the yield calculated for 100$ purity was 93-94$.

Example 2 A mixture consisting of 123.8 g. of ethyl levulinate, 106 g. of ethylene glycol, 300 ml. of benzene and 0.5 g. of paratoluenesulfonic acid was heated under reflux for 13 hours while distilling off an azeotropic mixture (water, ethanol and benzene) having a boiling point of 65°C from the top of fractionation column.

Subsequently, a part of the reaction liquid was taken up in benzdne and subjected to gas chromatographic analysis to obtain a benzene solution of a mixture containing the following compounds : (Area $ of ester portion) (I) Ethyl levulinate 4$ (II) Ethylene ketal of ethyl levulinate 29$ (III) Ethylene ketal of ^-hydroxyethyl levulinate 1 40$ (IV) Ethylene ketal of ethylene dilevulinate 26$ The liquid was further reacted, and when unreacted ketone compounds had not been observed any more, an ethanol solution of sodium ethylate prepared by dissolving 2 g. of sodium in 150 ml.- of anhydrous ethariol- was added to the liquid,1 and the mixture was boiled for 1 hour.

Subsequently, the' treatments similar to: those as in Example 1 were' effected to obtain 100 g. of an ethylene ketal of ethyl levulinate, b.-p.- lil.5°C/12 mmHg Example -3 A mixture consisting of 30.7 g* of ethyl - ( 2-thi-enyl)-levulinate,- 20 ml. of ethylene glycol, 15 ml. of benzene and 0.-15 g'. of p-toluenesulfonic acid monohydrate was reacted in similar way as described in Example 1 to yield ethylene ketal of ethyl 29.-1 g. , b.p. .120° - 125°0.-/0.1 mmHg.

Claims (4)

Claims :

1. A process for producing ethylene ketals of ¾"-keto-carboxylic acid esters represented by the formula, R 1-, -CH /-Cχ-GH2-CH2-C00R2o 0 0 / / CH2—CH2 ^furyl or thienyl/ wherein R-j_ is a hydrogen atom, alkyl group or aryJ, [group; and R2 is a lower alkyl group, and a mixture thereof, which comprises reacting in the presence of an acid catalyst a lower alkyl ester of γ-keto-carboxylic acid represented by the formula, R1-CH2-C-CH2-CH2-C00R2 0 ... wherein n and.R are. as defined above, with ethylene glycol -formedJ removing . formod. water and' alcoho f"rom the reaction mixture to yield. a reaction mixture containing as the desired product ethylene ketal of γ-ketocarboxylic acid ester and as byproducts ethylene glycol ester or ethylene glycol diester of ethylene ketal of γ-ketocarboxylic acid, and, reacting the obtained reaction mixture with a monohydric . lower alcohol in the presence of an alkali metal monohydric lower alcoholate catalyst wherein the alcohol and alcoholate have same alkyl moiety as 2

2. A process according to Claim 1, wherein the y-keto-carboxylic acid ester is ethyl ^"-phenyl levulinate, ethyl levulinate, or ethyl ^-(2-thienyl) -levulinate.

3. A process according to Claim 1,. wherein the "^-keto-carboxylic acid ester is ethyl ester, the alkali metal monohydric lower alcoholate is sodium.ethylate-:and the monohydric lower alcohol is ethahol. '.

4. A process according to any of Claims 1 to 3, wherein the amount of the alkali metal lower alcoholate is 0.05 mol or less per mol of the starting ester. I A. E. MULFORD AgeiDit for A^Iicsnt