HU194852B - Improved process for production of izodehydro-aceticacid-alkyl-esthers - Google Patents

Abstract

Improved prepn. of iso-dehydroacetic acid-alkyl estero of formula (I), where R is a 1-4C alkyl gp., comprises condensation of an acetoacetic-ester of formula (II), at 0-50 deg.C, in the presence of hydrogen bromide and an 1-4C alkanol.

Description

The present invention relates to an improved process for the preparation of an alkyl ester of isodehydroacetic acid of formula (I) wherein R is a C 4 4 alk alkyl group; condensation at 0-50 ° C.

The isodehydroacetic acid alkyl esters of formula (I) can be used in the preparation of valuable pharmaceutical and organic chemical intermediates, such as vitamin A.

The commercially available synthesis of the compounds of formula (I) is based on the corresponding acetic acetate ester of formula (II) and is converted to the target compound in the presence of a condensing agent.

which is technically very unmanageable on the one hand and condensation at this temperature is doubtful).

In the latter known process, over 80% production can be achieved in 20-100 hours, although the selectivity is somewhat reduced by increasing the production, so that the side reactions cannot be completely eliminated.

The main disadvantage of the latter known method is that it requires a closed, pressure-resistant device. Given that water is released during the condensation reaction, the presence of aqueous hydrochloric acid vi destroys the apparatus in a relatively short period of time.

The advantages of our procedure are summarized in the following table:

Used materials Pressure selection Yield: alcohol / Weight ratio / hydrochloric acid / M / ' bar % % DOS 3,021,596 JP 80 85580 0.2 2.0 1.5 5.0 30-50 63 98 62 88 According to the present invention 0.05 0.2 1.4 1 98 88 92

Org. Synth., 32, 76, 78 (1952), sulfuric acid is used as a condensing agent and, by reaction at 10-15 ° C in 5 to 6 days, yields 27 to 36%.

In U.S. Patent No. 2,529,917, the condensing agent is hydrochloric acid, and after a two-week reaction, the space is about 50%.

The poor production of the known processes can be explained by the fact that the water liberated upon condensation of the two molecules also produces free isodehydride acetic acid in the presence of water, and in the presence of water and acid the acetone is hydrolyzed to the acetic acid. carbon dioxide.

Adverse side reactions were primarily attempted by reacting under pressure and using ethanol. According to a published publication in the Federal Republic of Germany, condensation is carried out in the presence of 0.2 to 2.0 parts by weight of ethanol acetate per liter by weight of ethanol Given that 1.5 5.0 moles of hydrogen chloride gas are introduced into the mixture, Working at temperatures of 50 ° C, the reaction is estimated to be carried out only at 30 50 bar (29.4 49 x ^{10 5} pascals).

German Patent Publication No. 3,021,596 teaches that the amount of ethyl alcohol used in the known process is critical, 0.2 to 2.0 parts by weight, based on 1 part by weight of acetate; and with less ethyl alcohol, the desired effect cannot be achieved

SUMMARY OF THE INVENTION The present invention is directed to the elimination of laryngeal rings associated with the known processes and to an economically feasible process for the preparation of an alkyl ester of isodehydroacetic acid (I).

It has now been found that the above object is achieved by condensing the acetic acid ester of the general formula (II) in the presence of hydrochloric acid or hydrogen bromide at a temperature of from 1 to 4 ° C with 50 to 20% by weight of alkanol to the acet the reaction mixture is saturated with dry hydrochloric acid gas or hydrobromic acid and the concentration of saturated hydrochloric acid or hydrobromic acid is maintained during the reaction, with up to 1.4 molar equivalents of hydrochloric acid or hydrogen chloride being added to the reaction mixture.

For the process according to the invention, preferably, methanol is preferably used as a C14-C4 alkanol, preferably in an amount of 5 to 12% by weight, based on the acetate.

During the saturated reaction at 0 ° C, preferably 10 ° C to 20 ° C, saturation concentration is maintained by introducing anhydrous hydrochloric acid gas or anhydrous hydrogen bromide;

-2194852 only uses up to 1.4 molar equivalents of hydrochloric acid or hydrobromic acid. In general, the reaction mixture is initially saturated with anhydrous hydrochloric acid or hydrogen bromide and then saturated again every 24 to 48 hours until the reaction is completed, which can be checked by gas chromatography. The hydrochloric acid or hydrobromic acid present is then removed, for example by aeration in vacuo, and the alkanol present and the water formed during the reaction are evaporated in vacuo.

Alternatively, the reaction mixture may be extracted with water-immiscible organic solvent (s), the organic solution of the isodehydroacetic acid alkyl ester washed and finally concentrated.

The process of the present invention can be carried out at atmospheric pressure in conventional chemical equipment without special conditions. Since acid saturation is carried out in several parts, the use of pressure equipment and special cooling conditions are not required.

The process of the invention has a selectivity of about 98% and a yield of 88-92%. Although the reaction time is relatively long when using equipment of appropriate size, very high production / capacity can be achieved. Since by-products are practically non-formed, the resulting product does not need to be subjected to a specific purification operation, but can usually be used directly for subsequent reaction surprises after evaporation.

A further advantage of the process according to the invention is that it requires less alkanol hydrochloric acid hydrobromide than is known in the art.

It will be surprising to those skilled in the art that the process of the present invention suppresses the formation of by-products since the use of a strong acidic acid in the presence of liberated water is expected to result in the formation of by-products, as noted above.

No. 3,021,596. According to the German Federal Publication, the formation of by-products can be suppressed, inter alia, by 20 to 200% by weight of ethanol, and it is therefore not expected that the beneficial effect of the process of the invention will be as much as 5 to 20% by weight of alkanol.

The invention is illustrated in detail by the following examples:

Example 1

To a 1 L four-necked round bottom flask equipped with a reflux condenser, gas inlet, thermometer and stirrer was added 400 g of acetic acid methyl ester and 40 g of methyl alcohol. Dry hydrogen chloride gas was added to the mixture at 10-25 ° C with water cooling and the saturation state was maintained continuously for 3 weeks. The reaction mixture was concentrated under vacuum at 1.33 x 10 Pa to a phenolic temperature of 150 ° C.

282 g (85%) of isodehydroacetic acid methyl ester are obtained, which is 94% pure.

Example 2

Into a 1500 L volume of enameled stirrer bottom enamel duplicator was added 1000 kg of acetic acid methylester and 100 kg of anhydrous methyl alcohol. The mixture was water-cooled at 10-25 ° C, saturated with anhydrous hydrochloric acid gas, and saturated for three weeks. A total of 275 kg of hydrochloric acid is used. The reaction mixture was concentrated under a vacuum of 1.33 x ^{10 4} Pa to 130 ° C.

1486 kg (89%) of methyl isodehydroacetic acid are obtained, which is 94% pure.

Example 3

The procedure described in Example 1 was followed except that 80 g of ethyl alcohol was used instead of methyl alcohol and starting from ethyl acetate. 235 g (73.6%) of ethyl isodehydroacetic acid are obtained with a purity of 94.2%.

Example 4

The same procedure as in Example 1 was followed, except that anhydrous Hydrogen Bromide was used instead of hydrochloric acid gas. 278 g of methyl methyl isodehydroacetic acid are obtained.

Example 5

Anhydrous hydrochloric acid gas was added to a mixture of 400 g of ethyl acetate in ethyl acetate and 40 g of ethyl alcohol at 10-25 ° C until saturation with hydrogen chloride was repeated every 36 hours. After three months, the reaction mixture was poured into 1000 ml of water, 150 ml of n-butanol and 300 ml of toluene, the phases were separated and the aqueous phase was extracted twice more with 150 ml of n-butanol and 300 ml of toluene. The organic phases are combined and washed with 10% aqueous sodium carbonate solution until pH = S (approximately 300 mL of solution is required). The organic phase is washed with water (150 ml) to make it alkaline and then evaporated under vacuum at 1.33 x ^{10 4 to} an internal temperature of 150 ° C.

235 g (73.6%) of ethyl isodehydroacetic acid are obtained, which is 94.2% pure.

Example 6

Starting from 400 g of acetic acid methyl ester and from 40 g of isobutanol, the serine described in Example 1 was used. After evaporation, a total of 278 g (80%) of the product is obtained, which according to gas chromatography is 120 g of isodehydroacetic acid methyl ester and 158 g of isodehydroacetic acid isobutyl

Physical identification data of the prepared isodehydroacetic acid alkyl esters:

Isodehydroacetic acid methyl ester: m.p.

Izodehldroecetsav ethyl ester. fp .:

166 C / 1.6X10 Pa lasodehydroacetic acid n-butyl ester: fp.

167 C'9.3x10 Pa

Claims (2)

A process for the preparation of an isodehydroacetic acid alkyl ester of formula (I) wherein R is a C 1 -C 4 alkyl group, an acetoacetic ester of formula (II) wherein R is in the presence of hydrochloric or hydrobromic acid and proline a -50 ° C, characterized in that the alkanol is calculated acetecetószterre 5 to 20 mass% in an amount of at θ ^1, the condensation is carried out under atmospheric pressure, the reaction mixture was saturated with anhydrous HCl gas or hldrogénbromlddal, Os saturation maintaining the hydrochloric acid or hydrogen bromide concentrate during the reaction such that no more than 1.4 molar equivalents of hydrochloric acid or hydrogen bromide are used. 2. A process according to claim 1 wherein the alkanol is methanol.