DE1211179B - Process for the preparation of the vitamin A acid ester of vitamin A. - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C 07c

German class: 12 ο-25

Number: 1211179

File number: N 23085 IV b / 12 ο

Filing date: April 24, 1963

Opening day: February 24, 1966

It is known for making compounds with vitamin A that have better potency Have a shelf life as vitamin A, the vitamin A alcohol to esterify. U.S. Patent 2,971,966 is z. B. the production of higher fatty acid esters of vitamin A has been described, in addition to a good Shelf life also have good fat solubility.

According to the invention, an ester of vitamin A is now produced by having vitamin A with Vitamin Α acid is esterified in a manner known per se. This new connection exhibits a very good shelf life, can therefore be stored well, is readily fat-soluble and has a considerably higher biological value Potency than the well-known higher fatty acid esters of vitamin A.

Since the stability of vitamin A compounds is known to increase with increasing melting point (see J. Keith Guillory and Takeru Higuchi, J. Pharm. Sci., Vol. 51, 1962, pp. 100-105) is the better stability of the ao vitamin A acid ester of vitamin A prepared according to the invention clearly after the following comparison with the melting points of others for administration People can find eligible vitamin A esters.

Method of manufacture

of the vitamin A acid ester of vitamin A.

Applicant:

N. V. Philips' GloeÜampenfabrieken, Eindhoven (Netherlands)

Representative:

Dipl.-Ing. H. Zöepke, patent attorney,

Munich 5, Erhardtstr. 11

Named as inventor:

Pieter Henri van Leeuwen, Weesp (Netherlands)

Claimed priority:

Netherlands April 27, 1962 (277 834)

link

Vitamin A acetate ...
Vitamin A palmitate.
Vitamin A stearate ..
Vitamin A myristate.
Vitamin A acid ester

of vitamin A.

Melting point

6O ⁰ C

29 ⁰ C 37 ° C 35 ⁰ C 85 ⁰ C

The esterification reaction according to the invention can e.g. B. be done in that vitamin Α alcohol with Vitamin Α acid or a suitable derivative of vitamin Α acid is reacted. the Reaction of the alcohol with the free acid must be carried out under conditions in which water is removed from the reaction mixture. Of the known dehydrating agents in esterification reactions of this type, dicyclohexylcarbodiimide is preferably used in this case. Suitable derivatives of vitamin Α acid are z. B. the acid anhydride and acid halides, preferably the acid chloride. The esterification reaction takes place according to methods known per se. Vitamin A is preferably added to the reaction mixture and vitamin A acid halide, a suitable acid binder is added, in particular an organic base, like pyridine or collidine.

According to another esterification process known per se, the new ester according to the invention is made obtained in that vitamin A acid halide with a metal alcoholate of vitamin A, e.g. B. with the sodium, potassium or lithium vitamin A alcoholate, is made to react.

It has been found that the esterification according to the invention proceeds particularly well when a so-called Transesterification process is used. A lower alkyl ester is left in this process of vitamin Α acid with vitamin Α alcohol or with a lower alkanoic acid ester of vitamin Α-alcohol react. This transesterification reaction takes place in the presence of a catalyst. As such substances known as transesterification catalysts are suitable, e.g. alkali or alkaline earth alcoholates, oxides or hydroxides, such as sodium ethylate, lithium methylate, potassium ethylate, barium methylate, calcium methylate, Magnesium isopropylate, potassium hydroxide, calcium hydroxide, barium oxide, amides, such as sodium, Calcium or potassium amide, and phenates, such as sodium phenolate or calcium phenolate or compounds, such as phenyllithium or butyllithium. Very good results were achieved with the aid of sodium sodium methylate as a catalyst. The transesterification reaction is preferably carried out in a suitable solution

609 509/402

solution carried out, ζ. Β. aromatic hydrocarbons, such as benzene or toluene, aliphatic hydrocarbons such as petroleum ether or cyclohexane and ethers such as n-butyl ether, diethyl ether of ethylene glycol. Dimethyl ether of diethylene glycol or dioxane. By using an ester of vitamin A acid with a lower one aliphatic alcohol, preferably through the use of the methyl or ethyl ester and either of free vitamin A or a vitamin A ester with a lower aliphatic carboxylic acid During the transesterification, a low-boiling alcohol or ester that passes through the reaction mixture Distillation can be removed. The methyl esters of vitamin A acid are therefore preferred and the free vitamin A alcohol or vitamin A acetate Use.

After the transesterification reaction, which can be carried out according to conventional methods, the reaction product becomes obtained as a light yellow syrup which crystallizes after inoculation.

This new ester of vitamin A, like vitamin A, can be used in pharmaceutical preparations find, optionally as a mixture with other vitamins in conventional liquid or solid carrier materials. This new ester can also be used as a food additive in the usual way for vitamin A. found, optionally in the form of a powder, optionally together with other vitamins and / or minerals and antioxidants, optionally in an enveloping substance, e.g. B. gelatin or pectin or a waxy material.

example 1

35

In a 1-1 round bottom flask fitted with a distillation head was fitted with a downward sloping condenser, 230 mg of sodium metal in 5 ml of absolute Dissolved methanol. The excess of methanol was removed in vacuo. The sodium methylate was covered with a layer of benzene of about 50 ml, after which 32.8 g (0.1 mol) of pure vitamin A acetate and 31.4 g (0.1 mol) of pure vitamin Α-acid methyl ester, which are dissolved together in 400 ml of dry benzene were added. The mixture was heated slowly, taking methyl acetate at about 55 ° C distilled off. The transesterification reaction was carried out by distilling off 200 ml of the solvent in 1.5 hours completed. After the reaction mixture was cooled to room temperature, was the liquid successively with 300 ml of 0.1 N sulfuric acid, 300 ml of dilute sodium bicarbonate solution and washed 300 ml of distilled water. Thereafter, the organic liquid with the help of magnesium sulfate dried and the solvent removed under reduced pressure. The residue, a light yellow syrup, slowly becoming crystalline.

Yield: 56 g of a product with a melting point of about 25 ° C. E ^ _m = 1120 at λ _ηαχ = 342πΐμ.

After repeated recrystallization from a mixture of benzene and methanol, a product was obtained obtained with a melting point of 85 ° C.

Example 2

In the same way as described in Example 1, the vitamin Α-acid methyl ester was transesterified with the free vitamin Α-alcohol. The yield was 98 ⁰ Io of theory; .a light orange-colored product with a melting point of about 25 ° C. Egg? " = HOO at X _max = 342 ηΐμ.

After recrystallization from benzene and methanol, it became a product with a melting point of 85 ° C obtained.

Example 3

To a solution of 0.1 mol of vitamin A in 150 ml of ethylene chloride and 30 ml of pyridine, a solution of 0.1 mol of vitamin A acid chloride, dissolved in 150 ml of ethylene chloride, was added at 10 ° C. over the course of one hour. After standing for 2 hours at 25 ° C., the reaction mixture was added to a mixture of 150 ml of water and 30 ml of diethyl ether. The ether layer was separated and the liquid was washed successively with 0.5 η-sulfuric acid, water, 5% sodium bicarbonate solution and water. The organic solvent was removed under reduced pressure. A crystalline compound was obtained from the oily residue after seeding. Melting point after recrystallization from a mixture of benzene and methanol 85 ° C. EJf _n 344 = 1350 (in cyclohexane).

Example 4

In the manner described in Example 3, the vitamin A acid ester of vitamin A was obtained from the Sodium compound obtained from vitamin A and vitamin A acid chloride.

Claims (3)

Patent claims: 1. A process for the preparation of the vitamin A acid ester of vitamin A, characterized in that that in a known manner vitamin Α-alcohol or its metal derivatives with vitamin Α acid or its reactive derivatives, such as anhydrides or Halides, optionally in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, converts or a lower vitamin A acid alkyl ester with vitamin A or its lower alkanoic acid esters in the presence of a basic transesterification catalyst transesterified. 2. The method according to claim 1, characterized in that sodium methylate is used as the transesterification catalyst Is used. 3. Process according to Claims 1 and 2, characterized in that vitamin A acetate is transesterified with the methyl ester of vitamin Α acid. Considered publications:
German exposition No. 1122 061,
1122062;
U.S. Patent Nos. 2,971,966, 2,758,924. 609 509/402 2.66 © Bundesdruckerei Berlin