HU205101B - Process for producing isodehydroacetic acid alkyl esters - Google Patents

Abstract

Intermediates of iso-hydro-acetic-acid-alkyl-esters of general formula (I) (R = low C alkyl gp.) are prepd. by condensation of aceto-acetic-acid-alkyl-esters (II) -w-in the presence of hydrochloric acid. Acid and solvents are removed from the reaction mix which is then mixed with or pref. poured into water. - Cpds. (I) acrystallised and filtered. Alkali metal or ammonium salts are added to the filtrate to approach or reach saturation pt. The soln. is extracted by a water-immiscible solvent for (II). The soln is evaporated and (II) is reused.-a

Description

Our invention relates to the production of valuable intermediates. More particularly, the present invention relates to a process for the preparation of alkyl isodehydroacetic acid esters of formula (I) wherein R is C 1-4 alkyl.

As mentioned above, the compounds of formula (I) are valuable intermediates which can be converted, for example, to alkyl glutaconic acid alkyl esters of formula (III) (wherein R is as defined above). U.S. Pat. Compounds of formula Ο may be used, inter alia, in the preparation of a commercially available pharaoh antacid (11-methoxy-3,7,11-trimethyl-2E, 4E-dodecadienoic acid isopropyl ester).

The compounds of formula (1) are known to be prepared by condensation of alkyl acetic acid esters of formula (Π) (wherein R is as defined above) at various temperatures (0-100 ° C) in the presence of acidic condensing agents. . A2529 917 U.S. Pat. No. 2,607,781. U.S. Pat. No. 4,198,198 discloses sulfur trioxide as an acidic condensing agent. One disadvantage of the process is that the sulfur trioxide used and the oleum produced from it are extremely coirous. Extraction of the reaction mixture with benzene followed by evaporation of the extract gives an oily product (56%) in medium yield of the corresponding isodehydroacetic acid ethyl ester of formula (I) which is subjected to complex multistage distillation and fractional purification. No. 2,675,391. U.S. Pat. The highly corrosive nature of the reaction mixture necessitates the use of costly acid resistant structural materials. The process is carried out in several stages and the reaction time is very long. The resulting compound of formula (I) is purified by expensive and complex fractional vacuum distillation techniques.

It is known in the literature (U.S. Patent No. 2,673,212) that compounds of formula (I) can be converted by base-catalyzed reaction to alkyl-glutaconic acid alkyl esters of formula (wherein R is as defined above). It is disadvantageous for the preparation of the compound of the formula (Μ) of good quality if the used alkyl ester of isodehydroacetic acid (I) contains as an impurity a starting acetic acetic acid alkyl ester of formula (H). The acetic acid alkyl ester content of the compound of formula (Ο) cannot be substantially reduced below the undesirable level by prolonging the reaction time. According to our experiments, the yield of isodehydroacetic acid methyl ester during gas condensation of the methyl acetic acid methyl ester was found to be only 80% after 64 days, and consequently the reaction mixture contained a considerable amount of methyl acetic acid. Thus, the compound of formula (I) of sufficient purity can be obtained only by purification of the product obtained. According to the literature, the purification is carried out using fractional vacuum distillation technology that is complicated, requires many steps and requires expensive equipment. In addition to complicated and expensive equipment, these methods also have the disadvantage that their energy requirements are very high.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the known processes for the production of isodehydroacetic acid alkyl esters of general formula (I) which can be carried out on an industrial scale and can be carried out on a commercial scale without complicated and costly vacuum and fractional purification.

The present invention relates to a process for the preparation of alkyl isodehydroacetic acid esters of formula I (wherein R is C 1 -C 4 alkyl) by condensation of an acetic acid alkyl ester of formula H (wherein R is as defined above) in the presence of hydrogen chloride. by mixing the reaction mixture with water at a temperature of 45-55 ° C, preferably by pouring it in water, to a maximum of 30% of the acetic acid alkyl ester of the formula (ítés) after acidification and solvent removal, The compound of formula (I) is isolated by dissolving the relatively poorly water-soluble alkali metal or ammonium salt, preferably sodium chloride, in an amount of 20% by weight, corresponding to a saturation value, in the filtrate obtained after separation. alkyl ester solvent, vi extraction with a water immiscible organic solvent, the extract is evaporated and the acetic acetic acid alkyl ester (H) thus obtained is recycled to the compound of the formula (t).

The present invention is based on the discovery that when the acid and solvent deprotected reaction mixture obtained by condensation of the acetic acetic acid alkyl ester of formula (Π) with water under the conditions described below, the compound of formula (I) is cooled well after cooling. crystalline form which can be easily separated. The compound of formula (I) thus obtained is of such purity that it can be used directly without further purification, for example, to prepare alkylglutaconic acid alkyl esters of formula (M).

This finding is all the more surprising since it is not necessary to continue the acid-catalyzed condensation of the compounds of formula (H) for several weeks until complete or near complete conversion, but under the conditions of the present invention up to 30-40% of the unreacted Even in the presence of an ester, a crystalline compound of formula I is obtained which is easily separable and of sufficient purity. It has now been found that the aqueous treatment of the present invention can be carried out with the desired result, even if the reaction mixture contains 30-40% of the unreacted acetic acid alkyl ester of formula (Π). Before the reaction2

The progress of - - that is, the reduction in the amount of the compound of formula Π - can be monitored by gas chromatography.

Preferably, the process of the present invention may be carried out as follows:

The acetic acid alkyl ester of formula (II) is dissolved in alkanol and hydrogen chloride, preferably gaseous hydrogen chloride, is introduced into the solution. This operation can be carried out at a temperature of 10-40 ° C, preferably 20-25 ° C. The compound of formula (II) is preferably dissolved in an alkanol corresponding to R. Thus, the methyl acetate may be dissolved in methanol and the ethyl acetate may be dissolved in ethanol. This has the advantage that in this case the compound of formula (I) corresponding to the group R in the compound of formula (II) is obtained in a single substance. When alkanol other than R in the compound of formula (II) is used (e.g., acetic acid methyl ester is dissolved in ethanol), a mixture of compounds of formula (I) wherein R is methyl and ethyl may be obtained, which in some cases may cause difficulties .

As used herein, the term "C 1-4 alkyl" refers to straight or branched C 1-4 alkyl groups (e.g., methyl, ethyl, npropyl, isopropyl, n-butyl, etc.). The starting material of formula (Π) is preferably an acetic acid methyl ester or an ethyl acetate, particularly preferably an acetic acid methyl ester. The reaction was continued until the reaction mixture contained 30% of unreacted compound (II) as determined by gas chromatography. Most of the hydrogen chloride and alkanol is removed from the reaction mixture by evaporation. The resulting residue is then mixed with water, preferably poured into water.

The amount and temperature of the water used for the precipitation is very important in order for the compound of formula (Π) to be precipitated in a crystalline form which is sufficiently pure in the presence of a considerable amount of acetic acid alkyl ester and alkanol. The solvent-deacidified mixture is poured into water so that the acetic acid alkyl ester content is not more than 301%, preferably 5-101%. The process is carried out at a temperature of 45-55 ° C, preferably about 45 ° C. Water at 50 ° C was used. Pouring the mixture into water at a temperature lower than 45 ° C results in a compound of formula I containing impurities which needs to be purified. If the precipitation is carried out in water heated to 55 ° C, the hydrolysis of the product results in losses and the yield deteriorates. The aqueous emulsion was then cooled to 10-15 ° C with vigorous cooling. Under the conditions described above, at 4555 ° C, the compound of Formula I initially precipitates as an oil. This has the advantage that it does not contain impurities in the form of inclusions. Upon cooling, the oily compound of Formula (I) gradually crystallizes and is thus separated in a well-separated, well-separated form of appropriate purity.

The compound of formula (I) may be isolated from the mixture by filtration or centrifugation.

From the filtrate obtained after separation of the compound of formula (I), the present compound of formula (II) can be recovered in a simple manner according to the invention in a suitable purity and recycled to the isodehydroacetic acid alkyl ester of formula (I). The filtrate is dissolved in an amount of alkali metal or ammonium salt which is relatively poorly soluble in water at or near the saturation level. Sodium chloride, potassium chloride, ammonium chloride, sodium sulphate, potassium sulphate or ammonium sulphate are preferably used for this purpose. Sodium chloride is particularly preferred. Preferably the sodium chloride is dissolved in the filtrate to a salt concentration of 20% by weight to a saturation concentration. The aqueous solution is then extracted with an organic solvent which is immiscible with water and capable of solubilizing the acetic acid alkyl ester of formula (II). Chlorinated aliphatic hydrocarbons (e.g., methylene chloride, ethylene chloride, chloroform or carbon tetrachloride), aromatic hydrocarbons (preferably benzene or toluene) or alkyl acetates (preferably ethyl acetate) are preferably used. Preferably, organic solvents having a boiling point substantially different from the boiling point of the acetic acid alkyl esters of formula II are used. For example, when using methyl acetic acid (bp 170 ° C) as the compound of formula II, the extraction is preferably carried out with water-immiscible organic solvents having a boiling point not exceeding 100-105 ° C. In a particularly preferred embodiment of the process, dichloromethane can be used for the extraction. Preferably, a solvent is used which does not form an azeotropic compound of formula II.

The compound (II) obtained after evaporation of the organic solvent extracts is recycled to the isodehydroacetic acid alkyl esters (I). In this manner, the compound of formula (Π) can be converted to the desired compound of formula (I) in greater than 90% yield.

The advantages of the process of the present invention can be summarized as follows:

- reducing reaction time;

- suppression of adverse reactions;

- improving the capacity utilization of equipment;

- elimination of costly high energy vacuum distillation and fractional distillation processes requiring complex equipment;

- Preparation of a compound of formula (I) of high purity;

converting the compounds of formula (Π) by high conversion into the desired compound of formula (I).

The following non-limiting Examples illustrate the invention without further limiting it.

HU 205 101 Β

Example 1

Hydrochloric acid gas was bubbled into a solution of 232 g of methyl acetate in acetic acid and 29 ml of methanol at 20-25 ° C. The reaction is monitored by gas chromatography.

Cbromosorb WHP on 0.149-0.177 mm SE 30%; column length 1.5 m;

N ₂ : 1.6 · 100 kPa

H _2: 30 ml / min 'evaporator; 220 'C'column; 60 ° C to 200 ° C at 20 ° C / min

GC; Chromium 4 with flame ionization detector

When the reaction mixture contains only 30% by weight of unreacted methyl acetate, most of the hydrogen chloride gas and methanol are removed by evaporation. The residue was poured into 800 ml of water at 50 ° C (about 8% by weight of methyl acetic acid in the reaction mixture). The resulting suspension is stirred slowly with vigorous stirring. Cool to 10-15 'C. The resulting crystal suspension is filtered and washed with water. 121.2 g of 95-97% methyl isodehydroacetic acid methyl ester are obtained which can be used directly for the preparation of methyl glutaconic acid methyl ester without further purification.

M.p. 61.4-61.9 'C

Analysis:

calculated found

C-59.0% C-59.62%

H-6.05% H-6.17%

0 to 34.93%

Sodium chloride was dissolved in the combined filtrates to a salt concentration of 20% w / v. The resulting solution was extracted with dichloromethane (3 x 75 mL) and the combined organic phases were evaporated. The resulting residue (62 g) containing acetylacetic acid methyl ester can be recycled to isodehydroacetic acid methyl ester production without further purification.

In successive 3-4 reactions, the methyl acetic acid is converted in a 92% yield into isodehydroacetic acid methyl ester of sufficient purity for use in the production of methyl glutaconic acid methyl ester without further purification.

Example 2 In a 500 ml four-necked flask equipped with a stirrer, a thermometer, was added 91.6 g (0.5 mol) of methyl isodehydroacetic acid prepared as in Example 1 and then 2.3 g of sodium hydroxide was added. 200 mL of methanol. The reaction mixture is refluxed for one hour with stirring. (The pH of the reaction is basic: = 8.)

The reaction is monitored by gas chromatography. Concentration of the reaction mixture once gave gas chromatography 95% pure methyl glutaconic acid (84.3 g, 98% yield).

The completion of the reaction was monitored by gas chromatography as described in Example 1. The reaction mixture contained less than 1% methyl isodehydroacetic acid.

Retention time: methyl glutaconic acid methyl ester: 9.8 minutes.

Example 3

The procedure of Example 1 was performed with the exception that the de-acidified and solvent-free residue was poured into 400 ml of water. 120 g of 93% pure isodehydroacetic acid methyl ester are obtained, m.p. 58.7-59.6 ° C.

Example 4

The procedure described in Example 1 is carried out with the exception that sodium sulfate is dissolved in the mother liquor to a concentration of 25% w / v to regenerate the acetic acid methyl ester. The reaction mixture was extracted with toluene (3 x 75 mL). The combined organic distillates were distilled over a 50 cm column. The residue consists of methyl acetic acid containing 15% toluene.

Claims (10)

PATENT CLAIMS A process for the preparation of isodehydroacetic acid alkyl esters of formula © wherein R is C 1 -C 4 alkyl by condensation of an acetic acid alkyl ester of formula © wherein R is as defined above in the presence of hydrogen chloride, characterized in that the reaction mixture is, after de-acidification and solvent removal, mixed with water at 4555 ° C, preferably poured into water, to give a maximum of 301% of the acetic acid alkyl ester of formula (H); The compound obtained after separation is dissolved in a relatively poorly water-soluble alkali metal or ammonium salt, preferably sodium chloride, in an amount of 20% by weight to a saturation value of the filtrate obtained by dissolving the acetic acid alkyl ester of formula (H). , not with water extraction with a volatile organic solvent, the extract is evaporated and the acetic acid alkyl ester (II) thus obtained is recycled to the compound (©). 2. A process according to claim 1, wherein the acidification and solvent deprotection reaction mixture is poured into water so that the acetic acid alkyl ester content of formula (I) is between 5% and 10% by weight. Process according to claim 1 or 2, characterized in that the reaction mixture obtained after the acid and solvent removal is poured into water at 50 ° C. 4. A process according to any one of claims 1 to 4, wherein the aqueous solution at 45-55'C is added, after the reaction mixture obtained after acid and solvent desulphurisation, to 10-15'C and the crystalline compound © is isolated by centrifugation or filtration. HU 205 101 Β 5. A process according to any one of claims 1 to 3, wherein the relatively poorly water-soluble alkali metal or ammonium salt is sodium, potassium or ammonium chloride or sulfate. 6. A process according to claim 5, wherein sodium chloride is used. 7. Process according to any one of claims 1 to 3, characterized in that the water-immiscible organic solvent for the acetic acid alkyl ester of formula (II) is a chlorinated aliphatic hydrocarbon, aromatic hydrocarbon or alkyl acetate having a boiling point not exceeding 100-105 ° C. 8. A process according to claim 7 wherein the solvent is methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, benzene, toluene or ethyl acetate. A process according to claim 8, wherein the solvent is dichloroethane or dichloromethane. 10. A process according to any one of claims 1 to 3 wherein the compound of formula (Π) is methyl acetic acid.