DE1003726B - Process for the production of ª ‡, ª ‰ -unsaturated acid halides of the vitamin A series - Google Patents

Description

GERMAN

kl. 12 ο 25

INTERNAT. KL. C 07 C

PATENT OFFICE

EDITORIAL 1003 726

N8103IVb / 12o ON M E L DE DAY: NOVEMBER 28, 1953

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: MARCH 7, 1957

It is known that the elimination of water from oxy compounds of the vitamin A series, which conjugated Have double bonds, forms a mixture of isomers with allyl rearrangement. These isomeric compounds The vitamin A series have the same number of carbon atoms, but they are different by the arrangement of the double bonds in the basic hydrocarbon skeleton. These isomers are called as "normal" and "iso" compounds. Sometimes the "iso" compounds are also called "retro" compounds designated. Only the term "Iso" is used in the description of the invention. Under "normal" connections are to be understood as substances that can be represented by a structural formula in which the arrangement of the system of conjugated double bonds is similar to that in vitamin A (cf. FIGS. 1 and 2). Under »Iso« - Compounds are to be understood as substances whose structural formula relates to the arrangement of the double bonds which is illustrated in Figs. These have practically no vitamin A effectiveness. In this Formation of iso-compounds is probably the explanation for the relatively low yield of effective "normal" To look for compounds in some syntheses of vitamin A. According to the invention it has now been established that it is possible to manage the elimination of water from certain oxyacids of the vitamin A series in such a way that that practically exclusively reaction products with "normal" structure are obtained and practically no "iso" compounds are formed when the oxyacids are treated with halogenating agents, which a carboxyl group to a carboxylic acid halide group

H ₃ C.

, CH ₈ method of manufacture

of α, / 9-unsaturated acid halides

the vitamin A range

Applicant:

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

Representative: Dipl.-Ing. H. Zoepke, patent attorney, Munich 5, Erhardtstr. 11

Claimed priority:
Netherlands 22 January 1953

Henderikus Obias Huisman and Anne Smit,

Weesp (Netherlands),
have been named as inventors

able to transfer, z. B. with the help of phosphorus halogen compounds or thionyl chloride, whereby at the same time the hydroxyl group with formation of water is split off.

According to the invention, the oxyacids of the formulas are used as starting materials

OH

H ₃ C

V-CH = CH-C-CH ₂ -COOH

pn I

OJbL ₃ OH

= CH-C = CH-CH = CH-C-CH ₂ -COOH

CH, CHo

used, and there are compounds of the general formula according to the invention

H ₃ C _x XH ₃

[XH = CH-C = CH

CH ₃ -CO shark

«09 838/417

3 4

in which η = 1 or 2 and Hai is a halogen atom. U.S. Patent 2,591,110 suggests a method

means. As already stated above, the excess is present in order to reduce the

surprising the method according to the invention in that compounds of the general formula

that the a, /? formed as reaction products - un-

saturated acid halides practically no "iso" -ver- 5 H ₃ C. .CH ₃

contain bonds, but practically exclusively ^ χ

! —CH

= CH - C = CHl-C:

CH ₃

"Normal" unsaturated acid halides are, although possibly as an intermediate stage, a mixture of isomers can arise.

The conversion of the above-mentioned oxy-10
acids of the α , / ^ - unsaturated acid halides, the resulting mixture of isomers is broken down into their components, for example with phosphorus trichloride, phosphorus penta-. According to this procedure the mixture becomes chloride, phosphorus tribromide or thionyl chloride. of isomers of an alkaline saponification in such a way The preparation of acid halides with the help of these is subject to saponification of the "iso" ester of the above-mentioned halogenating agent or sulfonyl chloride is generally 15, but not the ester of the known (cf. for example P. Karrer, "Organic Che- Acid of the indicated formula. From the Saponificationmistry", 1938 [English edition], p. 196). The saponified "iso" isomer is also isolated and it is known that under the action of phosphorus acid or its salt is converted into an ester of ß-oxy- Esters produce unsaturated acid halides under carboxylic acids 20 Influence of catalysts such as phosphoric acid, chlorine release, hydrogen, sulfuric acid, formic acid, phosphorus-Acid chlorides of the formula mentioned are also oxychloride, iodine, zinc chloride, oxalyl chloride, and phosphorus (cf. Karr er, HeIv. Chim Acta, Vol. 17, 1934, trichloride or the hydrogen iodide salt of dimethyl-S. 3). The heraniline described in these publications, however, is isomerized to an ester with the correct system of positional processes than that according to the 25 conjugated double bonds. In the present invention. A cycle would proceed according to that patent-Next it can be pointed out that in writing, a yield of over 90% has been proposed in several patents, from esters with the desired system of double bonds, hydroxypolyene compounds of the vitamin A series to obtain. However, these results could not be reproduced in Verdenen a terminal carbon atom an esterified 30 similar tests. It is true that a carboxyl group or an esterified or etherified one, the partial saponification of the isomer mixture that carries the hydroxyl group, was able to split off water by replacing the hydroxyl group by boiling a solution of ionolacetic acid for 4 hours with a halogen atom and producing ethyl acetate in benzene with iodine, either simultaneously or subsequently Halogen water- to be confirmed; the isolated "iso" acid could be cleaved off. The general process only partially esterifies, while in the case of this reaction, German Patent 837 240 interprets an isomerization of the "iso" acid or ester into the, while details in the following "normal" acid or ester are not to any noticeable extent Patent specifications for the following substances communicated took place. In this comparative experiment, after the saponification of the isomer mixture, the normal ß- Jon-Hereinafter, R denotes the 1- [2 ', 6', 6'-trimethyl- 40 ylideneacetic acid ethyl ester in 95% purity and in cyclohexanol ') - yl] -3,7-dimethyl radical. In the USA.- a yield of 50.2%, calculated from Jonolessig patent specification 2369168: R-3,7-dioxy-9-acyloxy-nonadienoic acid ethyl ester obtained. The maxima in the UV-Ab- {1, 5) and R-4, 7-dioxy-9-acyloxynonadiene- (1.5); in the sorption spectrum were 260 and 301 ταμ; U.S. Patent 2,382,085: R ^ -oxy ^ -acyloxynonatri- the corresponding E} * _m values were 428 and 510, respectively. En- (1,3,5); in US Pat. No. 2,424,994: R-5-45 The "iso" acid was calculated in a yield of 40.5%, ethyl oxyoctatriene (1,3,7) carboxylate (8) and inferior to ethyl ionolacetate , generated. This US Pat. No. 2,540,118: R-3-oxy-9-alkoxynonatri- showed a maximum in the UV absorption spectrum at en- (1,5,7). In none of these reactions are acid 283 ταμ; the Ei * _m value was 1045. This acid halide formed because the terminal groups could be converted into the ethyl ester either esterified or etherified hydroxyl groups in only 63.5% yield. The UV absorption spectrum or an esterified carboxyl group are. In addition, this substance only showed a maximum, namely in these known methods an undesired 284 ταμ; E}? _m = 1015. These data, however, are characteristic of the allyl rearrangement during the cleavage of the hydroxyl group for the so-called "iso" ionylidene acetic or the halogen atom, resulting in an isomeric acid ester.

mixture is created. From the Swiss patent 55 last it can be pointed out that in document 262 796 a process for the preparation of the USA.-patent specification 2,576,104 a process so-called C ₁₈ ketone is known, according to which ß- is written to isomers of compounds the all-Jonylidencrotonsäure converted into an acid halide common formula
and this intermediate product then with the dimethyl H ₃ C CH
compound of a metal of the II. subgroup of the Peri- 60

pp

odic system is treated. Although this process temporarily creates an acid halide from the Vitamin A series, but this acid halide does not belong to the group of compounds lh

CH

CH = CH-C = CH

CH ₃

COOR

which are produced according to the invention. In addition, 65 in which R is hydrogen or an alkyl group, in sales according to the previously known method, no isobonds with the correct system of double merization take place because bonds are converted in the starting product. Following this procedure will namely the / J-Jonylidencrotonsäure, allegedly already the isomer mixture with catalytic amounts of one correct system of conjugated double bonds before proton-attracting compound treated, e.g. B. with hand is. 70 phosphorus trichloride, iodine, p-toluenesulfonic acid, zinc chloride

or formic acid. According to this method, however, are not the same as according to the method according to the invention Acid halides are formed because the carboxyl group is esterified. Furthermore, the known method works less favorably than the process of the present invention because the isomerization has to be repeated several times in order to obtain a satisfactory yield of the compound with the correct system of double bonds. If a solution of the so-called "Iso" -ionylideneacetic acid ethyl ester is divided into three parts and

H ₃ C,

.CH _H

a different amount of phosphorus trichloride is added to each portion (namely 0.1 mol, 0.5 mol or 1 mol per ester), then it was found that the yield of the normal / S-ionylideneacetic acid ethyl ester is very low in all three cases. A shift in the maximum in the UV absorption spectrum could not be determined. [X _max = 284 m / *).

Compared to these known methods, the invention

the advantage of being in a simple manner, in high yield and

ίο in one operation from the hydroxy acids of the formula

OH

i-CH ₀ = CH-C-CH, -COOH

I,

CH,

H ₃ C.

CH,

OH

CH = CH-C = CH-CH = CH-C-Ch ₉ -COOH

\ / CH ₃

to produce the corresponding acid halides with simultaneous elimination of water, which already have the desired system of conjugated double bonds. Separation of isomers, which was necessary in almost all known processes, is thus unnecessary, because when water is split off in the vitamin A series, an undesired allyl rearrangement often takes place at the same time. In carrying out the invention, it should be noted that / when using phosphorus trihalides as the halogenating agent to complete the reaction of 1 mol of a hydroxycarboxylic acid in α ^ - unsaturated acid halide is at least _^2/3 mol of phosphorus trihalide are required. When phosphorus pentachloride is used, the starting material at least _^2/5 mol of phosphorus pentachloride is to be used to 1 mole. It is also possible to use larger amounts of the halogenating agent per mole of the starting product than those mentioned here.

It is advisable to carry out the halogenation in a solvent that is compatible with the reaction components does not react, for example benzene, toluene or xylene. In these solvents the reaction takes place preferably carried out at a temperature between 50 and 70 °.

Chloroform is particularly suitable as a solvent. In this case, halogenation becomes preferable carried out at a temperature between -50 and 0 °, at the same time the elimination of water occurs.

The invention enables intermediate products for the synthesis of vitamin A to be obtained in good yield without forming large amounts of undesired isomers.

example 1

Ethyl ionolacetate, prepared from /? -Ionone and ethyl monobromoacetate according to the Reformatzki method was saponified with an excess of a 2η-methanolic potassium hydroxide solution by boiling for 2 hours over the course of 2 hours. The potassium salt of the oxyacid was formed during this process. After cooling, the reaction solution was diluted with three times the amount of water. The aqueous solution was extracted with diethyl ether to remove non-acidic components and acidified with a dilute acid. This was followed by a second ether extraction. The ethereal solution was made with water CH ₃

washed, then dried with sodium sulfate and finally the ether was distilled off. The oxy acid (/? - ionole acetic acid, cf. Fig. 5) remained in a yield of 96% of theory, calculated on the corresponding Ethyl ester.

A _maiC = 237m _{/ M} ; E}? _m = 227

12.6 g of this oxy acid was dissolved in 100 ml of anhydrous benzene. This solution became a solution of 6.5 g of phosphorus trichloride in 30 ml of benzene were added dropwise.

The reaction mixture was heated to 60 ° for 2 hours.

The acid chloride obtained in this way was converted directly into the methyl ester without further purification by the cooled benzene solution carefully in a continuously stirred, cooled to 0 ° solution of 360 ml Sodium ethylate was poured into methanol.

This solution was diluted with half a liter of water and then extracted with diethyl ether. The essential extract was washed with a cold aqueous 1η sodium hydroxide solution and then with water. The ethereal solution was dried and then concentrated. The yield of methyl ester was 11.8 g, that is 98% of theory, calculated on the oxyacid used. The UV absorption spectrum showed two maxima at 258 and at 299 ταμ. The EÜ values were 427 and 495.

These data are for the methyl / 9-ionylideneacetate characteristic (the content of /? -ionylideneacetic acid methyl ester in these 11.8 g was about 90%).

In contrast to the method of US Pat. No. 2,591,110, practically no undesirable results arise Isomer.

Example 2

A mixture of 96 g / J-Jonon, 45 g zinc and 300 ml Benzene was heated to the boil with stirring on the reflux condenser. Within 20 minutes, 84 g Ethyl monobromoacetate was added dropwise. When the ethyl ester was added the mixture became a half Cooked hour. After cooling to 0 °, this solution was mixed with 500 ml of a 10% strength aqueous acetic acid solution Stirred for half an hour, then the benzene layer separated and washed dried with water with sodium sulfate. The solvent was distilled off in vacuo.

133 g (95%, calculated on /? - ionone) of ethyl ionolacetate were obtained obtain.

These were saponified by boiling for 2 hours with 350 ml of 2η potassium hydroxide solution in methanol. the The cooled solution was diluted with 1 liter of water and extracted three times with diethyl ether to remove undesired by-products.

The aqueous solution was acidified with dilute sulfuric acid and the ionolacetic acid with diethyl ether moved out. This extract was washed with water, dried with sodium sulfate and in vacuo constricted. 118 g of pure ionoleic acid remained as a residue. The calculated yield was 90% on / J-Jonon.

The obtained 118g oxyacid were in 11 dry Dissolved benzene and the resulting solution with a solution of 61 g of phosphorus trichloride in 300 ml of dry benzene offset. This solution was left to stand for 2 hours and then stored at 0 ° for 1 hour. the Solution was decanted and the solvent removed in vacuo. There remained almost 118 g pure jÖ-Jonylidenessigsäurechlorid.

The yield based on / I-ionone was 90%.

Dissolved in cyclohexane, the acid chloride shows two maxima in the UV absorption spectrum, namely a maximum at 270 τημ; Eif _m = 423 and a second at 325 ηιμ; E IiL = 519.

Example 3

The C ₁₈ ketone was reacted with ethyl bromoacetate and zinc under the conditions as described by Schwarzkopf in Helvetica Chimica Acta, Vol. 32, 1949, p. 443, to _{give the ethyl oxy-C 20} ester (FIG. 6). The ester obtained was converted into the corresponding acid with alcoholic potassium hydroxide solution. 0.1 mol of this acid was, as described in Example 1, dissolved in 100 ecm anhydrous benzene and treated with 8 g of phosphorus trichloride in 25 ecm benzene at 50 °.

Approximately 0.092 gram moles of crude vitamin A acid chloride was obtained as a viscous orange-red colored oil. The UV absorption spectrum of the acid chloride, dissolved in cyclohexane, showed a maximum at 372 ταμ; Έ \ * = 1075.

Claims (4)

PATENT CLAIMS: 1. Process for the preparation of acid halides of the vitamin A series of the formula CH = CH-C = CH CH, - CO - Shark in which η = 1 or 2 and Hal represents a halogen atom, characterized in that compounds of the formehi H ₃ C CH ₃ OH CH = CH-C-CH ₂ -COOH CH, respectively H ₃ C, CH ₃ CH ₃ in an inert solvent such as benzene, toluene or xylene, expediently at temperatures up to 70 ° treated with halogenating agents which convert a carboxyl group into a carboxylic acid halide group be able to convict. 2. The method according to claim 1, characterized in that the halogenating agent is phosphorus trichloride, Find phosphorus pentachloride, phosphorus tribromide or thionyl chloride use. 3. The method according to claim 1 and 2, characterized in that the reaction in benzene at a CH _S OH = CH-C-CH ₂ -COOH
CH ₃ Temperature between 50 and 70 ° is carried out. 4. The method according to claim 1 and 2, characterized in that the reaction in chloroform at carried out at a temperature between -50 and 0 ° will. Considered publications: German Patent Specifications Nos. 886 601, 873 240; U.S. Patents No. 2,540,118,2,382,085,2369,168, 2,591,110; 2,576,104; Swiss patent specification No. 262 796. 1 sheet of drawings © 509 838 / 41T 2.57