DE1156799B - Process for the production of vitamin A acid esters - Google Patents

Description

The invention relates to a process for the preparation of vitamin A acid esters.

For the synthesis of vitamin A from vitamin A acid, one method is currently believed to be the most advantageous viewed, converted to the vitamin Α acid in its lower alkyl ester and the ester obtained under Using an active hydride, such as lithium aluminum hydride, is reduced to vitamin A. In terms of the methods for producing lower alkyl groups of vitamin Α acid are only the following two became known: In one process, vitamin Α acid is treated with diazomethane (cf. O. Schultzkopf, HeIv. Chimica Acta, Vol. 33, 1949, Pp. 443 to 452) and the other is vitamin A acid with an alkyl halide, an alkali carbonate and a ketone as a solvent (see U.S. Pat. No. 2,583,594 and C. D. Robeson, Journal of the American Chemical Society, Vol. 77, 1955, pp. 4111-4119).

In general, when the vitamin Α acid is esterified, the conjugated acid is rearranged Double bond system and thus an isomerization, and it is a by-product in addition to the vitamin A acid esters formed the corresponding retro isomer. Using the procedures mentioned above it is now possible to obtain a vitamin A acid ester which is essentially free of the retro-isomer however, these methods have some disadvantages. In particular the former, the Diazomethane process, is a laboratory process only and cannot be used on a larger scale be carried out as the diazomethane is expensive and explosive. The second process, the alkyl halide process, also has some disadvantages, since the esterification temperature is too high (e.g. reflux temperature of methyl ethyl ketone) and consequently the isomerization from the trans to the cis position is favored.

The invention is therefore a more economical and easier to carry out process for Esterification of the vitamin Α acid without the formation of the retro isomer and the isomerization of the transine the cis position. The process according to the invention for the preparation of vitamin A acid esters is thereby characterized in that one vitamin Α acid with a lower dialkyl sulfate and a hydroxide, Carbonate or bicarbonate of alkali or alkaline earth metals in a hydrocarbon solvent Reacts at room temperature to 60 ° C and the lower alkyl ester of vitamin Α acid formed separated from the hydrocarbon solvent in a conventional manner.

Method of manufacture
of vitamin A acid esters

Applicant:

Sumitomo Chemical Company Ltd.,
Osaka (Japan)

Representative: Dipl.-Ing. H.Leinweber, patent attorney,
Munich 2, Rosental 7

Shigeya Saijo, Hishinomiya-shi,

and Kiyoshi Ohizumi, Asiya-shi (Japan),

have been named as inventors

The method according to the invention is considerably easier to carry out than the known methods, the vitamin A acid esters obtained have remarkably good properties and the yields achieved are very high.

The dialkyl lower sulfates used in the present invention are known esterifying agents. Among these is dimethyl sulfate and diethyl sulfate to be highlighted as particularly advantageous.

Among the hydroxides, carbonates and bicarbonates the alkali and alkaline earth metals are particular to be emphasized sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, Sodium bicarbonate and potassium bicarbonate.

In accordance with the invention, the use of a hydrocarbon solvent is essential. The solvent should dissolve the obtained vitamin A acid ester, but should have a low solubility in with respect to water and dialkyl sulfate. The typical solvents used according to the invention are used are petroleum ether, gasoline, benzene, toluene, xylene, η-hexane and cyclohexane.

When carrying out the method according to the invention, vitamin Α acid is first with a lower one Dialkyl sulfate and an alkaline compound described above in a hydrocarbon solvent treated. The ratio of the amounts of acid, lower dialkyl sulfate and alkaline Compound can vary widely, but it should be mentioned that the lower dialkyl

309 747/420

3 4

sulfate and the alkaline compound in at least the hydrocarbon layer is separated, advantageously equimolar amounts with respect to the vitamin A are washed with water and then acid is used. At the most advantageous, dried. Evaporation of the hydrocarbon layer, method and as best characterizing the invention - preferably in vacuo, leaves the desired end but the lower dialkyl sulfate, preferred vitamin A acid ester. If desired, a considerable excess of lower dialkyl sulfate is added, for example a 2- to 8-fold molar amount of an alkaline compound before the removal excess, in particular a 4 to 8-fold excess. decomposition of the hydrocarbon layer. Correspondingly, the alkaline compound is the layer which corresponds to the excess of the lower part preferably used in an excess containing the io alkyl sulfate of the hydrocarbon layer above, e.g. B. separated in a 1- to 4-fold and reused for the next esterification process molar excess, especially in a 1.5 to.
3 times. In the examples below, the procedure is

The hydrocarbon solvent can be explained in more detail according to the invention,

at least the same volume as that of the present.

esters are used. Appropriate example

wisely, 5 to 10O times the volume of the To a mixture of 9 g of all-trans-vitamin A-

the ester, preferably 5 to 20 times the amount, acid (melting point 180 to 181 ° C with a

used. Ultraviolet absorption maximum at 352.5 ιημ,

The esterification reaction can be carried out by mixing the 2 ° ε = 44,900 [s. Fig. I]) and 90 ecm gasoline are 22.7 g

Vitamin Α acid, the lower dialkyl sulfate, given the dimethyl sulfate. The mixture is increased to 40

alkaline compound and the hydrocarbon ^{heated to 45 0} C and stirred. To this

Solvent are effected. The alkaline mixture will be mixed over a period of 1.5 hours

Binding can advantageously be in the form of an aqueous slowly 25 ecm of an aqueous 20% sodium Solution or suspension can be added. The 25 hydroxide solution is added, with the vitamin A acid

Mixture is dissolved at room temperature or at one. Then another 25 ecm of the water

Temperature up to the boiling point of the added comparable engined 20% strength sodium hydroxide · ^s,

turned solvent well stirred. The to be applied and the mixture is stirred for 1 hour at 20 ° C,

However Dende temperature must not exceed 6O ⁰ C is then separated loading the gasoline layer to carry with, otherwise the formation of the retro isomers washed 3 ° water, over dehydrated sodium sulfate

and the isomerization of the trans to the cis isomer dried and evaporated in vacuo to 9.4 g

occur. So a temperature of 40 to 50 ⁰ C yellow methyl ester of the all-trans-vitamin A acid to-

leaving behind the most favorable temperature for the esterification according to. The ester crystallizes after cooling,

the invention. melts at 69 to 72 ⁰ C and has an ultraviolet

In the most favorable embodiment of the invention 35 absorption maximum of 357.5 ΐημ, ε - 43 800 (s.

a mixture of vitamin A acid, lower Fig. 2).

Dialkyl Sulphate and Hydrocarbon Solvent Example 2
first to one within the aforementioned range

lying temperature heated, stirred and added to a mixture of 9 g of all-trans-vitamin A

alkaline compound, preferably in the form of a 4 ° acid and 90 ecm benzene, 22.7 g of dimethyl

aqueous solution, this fed in portions. sulfate given, and the mixture is under the same

The esterification reaction according to the invention under conditions treated as in Example 1,
runs in a heterogeneous system. The vitamin A acid dissolves and reacts within an hour of the hydrocarbon solvent used to dissolve it. The reaction mixture becomes like that of the vitamin A acid ester as it is formed. 45 Example 1 treated accordingly, according to the invention, the vitamin A acid (ultraviolet absorption maximum nenen vitamin A acid ester essentially free of 357.5 ηιμ, ε - 43,600) is to 9.3 g methyl esters deliver,
the retro isomer and can be pure vitamin A ...
by reduction with lithium aluminum hydride. Example 3
This fact can be seen from the drawings. 50 To a mixture of 3 g of all-trans-vitamin A-If all-trans-vitamin A acid with the ultraviolet acid and 30 ecm of gasoline, 9.3 g of diethyl sulfate absorption spectrum according to FIG. 1 are added after the addition. The mixture is heated to 40 to 45 ° C, esterified according to the invention, is stirred and slowly added dropwise with 8.4 ecm of a trans-vitamin A acid ester with the ultraviolet aqueous 20% sodium hydroxide solution over a sorption spectrum obtained according to Fig. 2, the added ₃ hours after the 55 period of 1 ² /, wherein the Vit reduction is achieved using lithium aluminum hydride in all-trans-amine A acid. Then white vitamin A can be converted, which is added to dissolve 8.4 ecm of the aqueous 20% sodium hydroxide ultraviolet absorption spectrum according to FIG. 3, and the mixture is left for 1 hour. As clearly seen stirred at 20 ⁰ C from these spectra. Then the gasoline layer is drained, no retro-isomers are present. When a 60 is separated, washed with water, dried over dehydrated vitamin A acid with all-cis- or any other sodium sulfate, and used in the vacuum-turned configuration as the starting material, evaporate. 3.3 g of ethyl ester are obtained, of which a vitamin A acid ester is obtained with the corresponding vitamin A acid with an ultraviolet absorption configuration. maximum at 357.5 m μ, ε - 43 500.

After the end of the esterification, which is due to 65

Disappearance of the undissolved vitamin A acid shows, comparison experiment

the ester obtained is made from the hydrocarbon To 10 g all-trans-vitamin A acid (melting point

Solvent recovered. For this purpose be 180 to 181 ⁰ C) 100 ecm of methyl ethyl ketone,

25 g of ethyl bromide, 0.1 g of sodium iodide and 14 g of anhydrous potassium carbonate are added. The mixture is heated for 4 hours with stirring and reflux. Then the solvent is reduced under The pressure is distilled off, and 300 ecm of water are added to the residue.

Benzene is added to extract an oily substance. The extract is washed twice with 4% aqueous sodium hydroxide solution, then with water, and then dried with the aid of anhydrous Glauber's salt. The solvent is completely removed under reduced pressure, and 10.4 g of yellow, oily vitamin A ethyl ester are obtained. The yield is 94.5%. The ultraviolet absorption maximum is 358 m μ, ε = 40 700.

When using the method according to Example 3, an approximately 100% yield is achieved, which according to the Comparative experiment only shows a yield of 94.5%.

The degree of purity is more favorable in the method according to the invention, since an ε value = 43,500 96% purity, the value ε = 40 700 on the other hand with the conventional method only 90% purity is equivalent to.

Example 4

7.6 g of dimethyl sulfate are added to a mixture of 3 g of all-trans-vitamin A acid and 30 ecm of gasoline. The mixture is heated to 40 to 5O ⁰ C with stirring; 28.8 ecm of an aqueous 20% potassium carbonate solution are slowly added dropwise over a period of 2 hours, the vitamin Α acid being dissolved. Then, further 28.8 cc of 20% potassium carbonate solution added, and the mixture is stirred for 1 hour at 2O ⁰ C. The gasoline layer is then separated off, washed with water, dried over dehydrated sodium sulfate and evaporated in vacuo. 3.1 g of yellow methyl ester of all-trans-vitamin Α acid with an ultraviolet absorption maximum at 357.5 ΐημ, ε = 43,600 are obtained.

Example 5

22.7 g of dimethyl sulfate are added to a mixture of 9 g of vitamin Α acid (alltrans vitamin Α acid with 30% 2-cis vitamin A acid) and 90 ecm η-hexane. The mixture is heated to 4O ⁰ C with stirring. Then 25 ecm of an aqueous 20% sodium hydroxide solution are slowly added dropwise over a period of one hour, the vitamin Α acid being dissolved. Subsequently, an additional 25 cc of the aqueous sodium hydroxide solution was added and the mixture is stirred for 1 hour at 20 ⁰ C. The hexane layer is then separated off, washed with water, dried over dehydrated sodium sulfate and evaporated in vacuo. 9.3 g of methyl ester of vitamin acid with an ultraviolet absorption maximum at 359 m μ, ε = 42,800 are obtained.

Example 6

22.7 g of dimethyl sulfate are added to a mixture of 9 g of all-trans vitamin A acid and 90 ecm of η-hexane. The mixture is heated to 40 to 45 ^° C. with stirring. Calcium hydroxide, suspended in 185 ecm of water, is then slowly added dropwise over a period of 3 hours. After stirring for a further 2 hours, the n-hexane layer is separated off, washed with water, dried over dehydrated sodium sulfate and evaporated in vacuo. 9.3 g of methyl ester of vitamin acid with an ultraviolet absorption maximum at 357 ΐημ, ε = 43,000 are obtained.

Claims (4)

PATENT CLAIMS: 1. A process for the preparation of vitamin A acid esters by treating vitamin Α acid with an alkylating agent in the presence of an alkaline compound and a solvent, characterized in that the alkylating agent is a lower dialkyl sulfate and the alkaline compound is a hydroxide, carbonate or bicarbonate an alkali or alkaline earth metal and a hydrocarbon is used as the solvent and the esterification is carried out ^{between room temperature and a maximum of 6O 0 C.} 2. The method according to claim 1, characterized in that the lower dialkyl sulfate is dimethyl sulfate or diethyl sulfate. 3. The method according to claim 1, characterized in that the alkaline compound is in the form an aqueous solution is used. 4. The method according to claim 1 to 3, characterized in that that the lower dialkyl sulfate is in a 2- to 8-fold molar excess, the alkaline one Compound in a 1 to 4 fold molar excess and the hydrocarbon solvent is used in 5 to 100 times the volume of the vitamin A acid ester produced. Considered publications:
German patent specification No. 886 601. For this purpose, 1 sheet of drawings © 309 747/420 10.63