DE1050763B - Synthesis of vitamin A acid and its esters - Google Patents

Description

um » d- u us,

FEDERAL REPUBLIC OF GERMANY

GERMAN

INTERNAT. KL. C 07 C

PATENT OFFICE

EXPLAINING PAPER 1050 763

B44931IVb / 12o

β (si, im-

ENTRY DAY: JUNE 8, 1957

NOTICE
DEK REGISTRATION
AND ISSUE DEB
EDITORIAL: FEBRUARY 19, BR U AR 19 59

In the case of the older processes for the production of vitamin Α acid and its esters (cf. e.g. summary reports by O. Isler, Chimia, Vol. 4, 1950, p. 116 ff., By J. G. Baxter, progress of chemistry org. Natural substances, Springer-Verlag, "Vienna, Vol. 9, 1952, p. 78, and by H. O. Huisman et al., Recueil des Travaux Chim. of the Pays-Bas, Vol. 71, 1952, p. 911, Vol. 75, 1956, p. 977) are called Starting materials almost without exception the / J-ionon or der, ß-Ionylidenacetaldehyd used and the still missing carbon atoms of the side chain condensed with the help of organometallic syntheses. Bigger ones So far, these processes have not achieved any technical importance. In patent specification 950 551 a method described, which is simpler than the previously known, but also an organometallic Contains condensation stage. Recently, some processes have become known in which the technical often difficult to control reaction stages with organometallic compounds are avoided; the The last step in this process is a condensation of aldehydes or ketones with an ylide of phosphorus (cf. German patents 950 552, 951 212 and 1 001 256).

It has now been found that the crystalline vitamin A acid or, if desired, its Esters can be obtained if 4- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (r)] - buten- (2) (I), expediently in the presence of polar solvents, with a hydrohalide of a triarylphosphine, preferably with Triphenylphosphine hydrochloride or hydrobromide, the equivalent amount of 4 - methylhexadiene - (2,4) - al - (1) acid- (6) (II) or their esters and at least the equivalent amount of an alkali or alkaline earth alcoholate implements.

A particularly suitable solvent is dimethylformamide. But you can also do the reaction in the presence run other polar and non-polar solvents or their mixtures, e.g. B. in methanol, Ethanol, ether, dioxane, tetrahydrofuran, 2,5-dimethyltetrahydrofuran, Acetonitrile, chloroform, N-methylpyrrolidone, benzene, toluene, xylene, nitrobenzene. in the in general, the reaction rate in more polar solvents is much greater than in the weak or not polar. If solvents other than dimethylformamide, N-methylpyrrolidone or tetrahydrofuran are used, it is often useful before adding the alkali or alkaline earth metal Completely distill off the solvent and replace it with one that is used with the alcoholate Temperature does not react automatically. It is expedient to work at temperatures below 0 ° C., preferably between 0 and -10 ° C, but the reaction still proceeds satisfactorily at -70 and at -1-100 ° C.

10

Synthesis of Vitamin A Acid
and their esters

Applicant:

Aniline & Soda Factory in Baden

Corporation,

Ludwigshafen / Rhine

Dr. Horst Pommer and Dr. Wilhelm Sarnecki,

Ludwigshafen / Rhine,
have been named as inventors

20th

The starting material for the claimed process, the 4- [2 ', 6', 6'-trimethylcyclohexen- (2 ') -ylidene- (1')] - butene (2) (I), is obtained by reduction of / S-ionone, e.g. B. with Lithium alanate or aluminum isopropylate according to the

Meerwein and Ponndorf's method for ß-Ionol and treating it with dehydrating agents, e.g. B. p-Toluenesulfonic acid, in excellent yields easily accessible.

According to previous attempts, the emerging one appears

Vitamin A acid in an alkali-dependent equilibrium with the starting components or one out to stand this intermediate product formed and not previously isolated in pure form.

Compared to the older process, including the

Patent specification 1001256 offers the new method Advantages. The laborious and lossy conversion of the / 3-ionol into / 3-ionyl halide and the Isolation of the ß-ionyl-aryl-phosphonium balogenide. at the implementation does not produce any disruptive water of reaction,

which can often only be removed with great difficulty and often only inadequately. The reaction products, in particular the free vitamin A acid is obtained in high purity. You can in a simple way to be isolated.

The yields of crystalline vitamin A acid and also of its esters are very good; one receives, however always a mixture of the stereoisomers first (a cis bond lies between the carbon atoms 9 and 10).

The vitamin A acid is a physiologically highly effective compound. You can either without further ado used as a pharmaceutical or converted into vitamin A alcohol in a manner known per se will.

OoU ϋόό

The parts mentioned in the examples are parts by weight.

example 1

200 parts / Wonon are dissolved in 400 parts of absolute ether and at - 15 ^C C with stirring and passing nitrogen to a suspension of 20 parts Lithiumalumimumhydrid in 500 parts of absolute ether was added dropwise. The mixture is stirred for a further 1 hour at 0 ° C., a solution of 20 parts of ethyl acetate in 50 parts of absolute ether is carefully added and, after stirring for 15 minutes, the reaction mixture is decomposed with 200 parts of an aqueous, cold-saturated ammonium chloride solution. The voluminous precipitate is nitrated, the filtrate is dried over sodium sulfate and the solvent is distilled off. The residue is dissolved in 500 parts of benzene and, after the addition of 0.5 part of p-toluenesulfonic acid, heated in a circulating apparatus until no more water separates out. The benzene solution is cooled to +5 ⁰ C, nitrated, and the filtrate was freed from the solvent and distilled. 160 parts of 4- [2 ', 6', 6'-trimethycyclohexen- (2 ') - ylidene] ~ butene (2) are obtained at b.p. _{13 115 to 118 ° C.} In methanolic solution, this C ₁₃ retro-colalen hydrogen <shows a light absorption maximum at 273 ηαμ (ε = 30,000) and inflections at 263 ΐημ (ε = 24,800) and 285 ΐημ (ε = 23,200). 90 parts of 4- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene] -butene- (2) (I) and 165 parts of triphenylphosphine hydrobromide are suspended in 200 parts of dimethylformamide and stirred for 12 hours at room temperature. 70 parts of 4-methyll-alhexadiene (2,4) acid (6), mp 177 ° C., white needles of water, λ _{ηακ, are added} to the clear solution. (in methanol) = 274 ΐημ (e = 28,000), dissolved in 150 parts of isopropanol, added dropwise. The mixture is cooled to -40 ° C. while stirring. Then one leaves rapidly with stirring 190 parts of a 30 °; Run in a solution of sodium methylate in methanol; Here, the temperature rises up to - 10 ^c C. The mixture is stirred nor S minutes at this temperature and then neutralized it with 10 ° / _o sulfuric acid (Congo red). After stirring for 60 minutes at room temperature, the vitamin A acid has crystallized out. They are sucked off sharply and washed with a little ice-cold isopropanol. When water is added, a small amount, mainly all-trans vitamin A acid, crystallizes out of the filtrate. The filter cake is suspended in 500 parts of water and stirred for 5 hours at room temperature, then it is filtered off with suction and washed with water. After drying over calcium chloride in vacuo at 40 to 50 ° C., 110 parts of vitamin A acid are obtained as a mixture of the all-trans and 9,10-cis isomers; the melting point is between 146 and 158 ° C. The isomer mixture shows X _maa . (in methanol) 347 to 349 πιμ (ε about 40,000). The stereoisomeric vitamin Α acids can be separated by fractional crystallization from alcohol or methanol. The all-trans-vitamin A acid is obtained with a temperature of 180 to 182 ° C, k _max , (in methanol) 351 to 352 πιμ (ε = 45000), in the form of bright yellow, broad needles and the 9.10 -cis-vitamin-A-acid with a temperature of 189 to 190 ° C, X _max . (in methanol) 343 πιμ (ε = 36500), in the form of pale yellow, fine needles united to form S tufts. The ratio of the stereoisomers varies between 20 and 40 ° / ₀ of the all-trans form and is to some extent dependent on the reaction temperature.

Example 2

90 parts of 4- [2 ^/ , 6 ^/ _> 6 ^/ -trimethylcyclohexen- (2 ^/ ) -ylidene] -butene ~ (2) and 150 parts of triphenylphosphomic hydrochloride are stirred in 150 parts of dimethylformamide for 36 hours and, after adding a solution of 70 parts of 4 -Methyl-l-alhexadiene- (2,4) -. Acid- (6) in 150 parts of isopropanol in the same way as indicated in Example 1, processed further. The yield of vitamin A acid as a mixture of the stereoisomers is 115 parts; the proportion of the all-trans isomer does not exceed 25 ° / _0th

Example 3

90 parts of 4- [2 ', 6', 6'-trimethylcyclohexen- (2) ^/ -ylidene] -butene- (2) and 200 parts of triphenylphosphine hydrobromide are stirred in 200 parts of dimethylformamide for 12 hours. Then 80 parts of 4-methyl-1-alhexadiene (2,4) acid (6) ethyl ester, F. 58 "C, 1 _mgx . (In methanol) 272 πιμ (= 31000), when dissolved in 50 parts of dimethylformamide is added the mixture is cooled with stirring to -. 40 ^c C, are at this temperature dropwise 90 parts of a 30 ° / _o solution of sodium methylate in methanol and allowing the temperature of the mixture in the course of one hour slowly to 0 ° C increase. Now overlaid the mixture with petroleum ether, adding 70 parts of 10 ° / ₀ sulfuric acid and stirred for 30 minutes. the petroleum ether layer is separated and washed several times with water. After drying over sodium sulfate, nitrided through a short column (eg. B. about 20 cm long, 2.5 cm diameter, aluminum oxide according to Brockmann, activity III) and the filtrate is distilled. At boiling point _{0> 005} 159 to 164 ° C 90 parts of vitamin A ethyl ester are obtained as a mixture of the stereoisomers ( X _max . 346 to 349 ηιμ, e = 38000), Schut z

not claimed within the scope of the present invention.

Claims (1)

Claim; Process for the production of vitamin A acid and its esters, characterized in that 4- [2 ', 6', 6'-Trimethylcyclohexen- (2 ') - yliden- (1')] - butene (2) in the presence of solvents, preferably Dimethylformamide, with a hydrohalide of an arylphosphine, preferably triphenylphosphine, with 4-methyl-1-alhexadiene (2,4) acid (6) or their esters and with at least one equivalent of an alkali or alkaline earth alcoholate.