DE1001256C2 - Process for the preparation of compounds of the vitamin A series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT 1 001 REGISTRATION DAY:

NOTICE THE REGISTRATION AND ISSUE OF EDITORIAL:

ISSUE OF PATENT LETTERING:

kl. 12 ο 25

INTERNAT. KL. C 07 C

AUGUST 3, 1955

JANUARY 24, 1957 JULY 4, 1957

agrees with the exposition

1 001 256 (B 36729 IV b / 12 o)

It has been found that compounds of the vitamin Α series are obtained if a ß-ionyl halide is used with a phosphine, e.g. B. triphenylphosphine, converts to the quaternary phosphonium halide, this, expedient in dimethylformamide solution, with an equivalent amount of an alkali or alkaline earth alcoholate or an alkali acetylide into the / monylidenephosphinylide converts to this one aldehyde of the general formula

IO

O = CH - CH = CH - C (CH ₃ ) = CH - R

can act, where R is an alkyl, a carboxylic acid ester or an optionally etherified or esterified CH ₂ OH group, and separates the phosphine oxide formed as a by-product.

The reaction can be in the case of the use of / S-ionyl bromide, triphenylphosphine, sodium acetylide and Formulate 4-methylhexadiene (2, 4) -al- (l) -ic acid- (6) -ethyl ester as starting materials as follows:

Process for the preparation of compounds of the vitamin A series

Patented for:

Badische Anilin- & Soda-Fabrik Aktiengesellschaft, Ludwigshafen / Rhein

Dr. Horst Pommer, Ludwigshafen / Rhein, and Dr. Georg Wittig, Tübingen, have been named as inventors

H ₃ C

CH,

H ₂ C
H ₂ C

C-CH = CH-CH-Br + P 1 -C ₆ H ₅

C ₆ H ₅

\ / V
CH2 C H3

CH,

HoC

CH,

H ₂ C C-

H ₂ CC

-CH = CH-CH-P - ^ - C ₆ H ₅

C ₆ H ₅ CH, ^β

Br NaC = CH

H ₃ C CH ₃

\ / '· - ■■ + / ^C 6 ^H ^

C CH = CH-CP ^ CH, + CHO-CH = CH-C = CH-COOc ₂ H ₅

H ₂ CC

H ₂ CC

CH,

CH ₃

CH,

X _B H, CH ₃

709 573/428

C ₆ H _5x
C ₆ H ₅ - ^ PO

H ₃ C CH ₃

H ₂ CC

H, C C

COOC, H-

CH,

The new process allows the construction of compounds of the vitamin Α series in a simple manner and delivers pure end products in good yields; it is simpler than the previously known procedures (cf.e.g. "Advances in the chemistry of organic natural products", Springer-Verlag, Vienna 1952, vol. IX, p. 56 ff). The after Products available with the process, such as vitamin A, vitamin Α acid, vitamin A ether and axerophten, are known to be valuable pharmaceutical products.

The parts mentioned in the examples are parts by weight.

example 1

In a solution of 20 parts of pure /? - ionol (cf. HH Inhoffen, F. Bohlmann and M. Bohlmann, Lieb. Ann. D. Chem., Vol. 565, 1949, p. 35) in 150 parts of absolute ether at +15 to + 20 ° a solution of 18 parts of phosphorus tribromide in 80 parts of absolute ether gradually entered with stirring. After stirring for 12 hours at room temperature, the mixture is poured onto ice and the ethereal layer is lifted off and washed well with water. The ether solution is dried with calcium chloride for 2 hours and then concentrated a little under reduced pressure. After adding 22 parts of triphenylphosphine, the mixture is stirred at room temperature for 5 hours. The solvent is then distilled off and the residue is heated to 80 to 90 ° for 30 minutes in a water jet vacuum. The partially crystalline phosphonium bromide is dissolved in 150 parts of dimethylformamide, and 4.5 parts of finely powdered sodium acetylide are added while stirring at room temperature. Ylid formation occurs immediately, which can be recognized by the reddish-brown discoloration. After stirring for 1 hour at about 20 °, a solution of 5 parts of 4-methylhexadiene (2,4) -al- (l) -acid (6) -ethyl ester in 15 parts of dimethylformamide is added. There is a slight increase in temperature; the mixture is stirred for a further 2 hours, it is poured onto a mixture of ice and 10 ° / ₀ hydrochloric acid and extracted it with petroleum ether. The light yellow petroleum ether solution is washed with water, dried over sodium sulfate and stored at -5 ° for 10 hours. Then the precipitated triphenylphosphine oxide is filtered off. From the filtrate is distilled off under a pressure of 0.001 mm Hg, all parts passing below .100 °. The residue (about 8 parts) consists of vitamin A-acid ethyl ester (X _max = 351 to 353 ηιμ, ε = 28 500 [in methanol]), from which 4.8 parts of vitamin Α-acid as yellow needles from by alkaline saponification F. = 181 to 182 °.

Example 2

A solution of 6 parts of γ-methylsorbinaldehyde in 20 parts of dimethylformamide is added to a solution of / J-ionylidene triphenylphosphinylide in dimethylformamide, prepared as in Example 1 from 20 parts of / 3-ionol. With an increase in temperature, a reaction occurs which is ended after stirring for 2 hours without external heat input. Now, the reaction product is poured onto a mixture of ice and 10 ° / ₀ hydrochloric acid and extracted with petroleum ether. The petroleum ether solution is washed neutral with water, dried over sodium sulfate and stored at -5 ° for 12 hours. It is then filtered through a short alumina column and the filtrate was distilled to obtain 4.3 parts Axerophten from Kp. _{0, 01} = 140 as a yellow viscous oil to 143 ° ß _max = 322-324 ΐημ), ε = 38 000 [in Hexane]). A red-violet color reaction is obtained with antimony trichloride.

Example 3

In a solution of 40 parts / mono! in 250 parts absolute ether, a solution of 40 parts of phosphorus tribromide in 60 parts is carried at + 10 ° with stirring absolute ether gradually. After stirring for 6 hours, the reaction product is poured onto ice and washed well with water. The washed ethereal solution of / S-ionyl bromide is mixed with 20 parts of calcium chloride Shaken for 20 minutes, filtered and dated at reduced pressure at a maximum of 35 ° bath temperature Freed solvent. The crude / 3-ionyl bromide thus obtained is stirred into 45 parts of molten triphenylphosphine, with self-heating to about 90 ° the / monyltriphenylphosphonium bromide is formed. The yield is about 100 parts.

The solution of this phosphonium salt in 200 parts of dimethylformamide is added gradually ₀ methanolic sodium methylate solution with einör 10 ° /, is reached to a _pH value of 7.9. A solution of 30 parts of 4-methylhexadiene (2,4) -al- (1) -acid- (6) -ethyiester in 30 parts of dimethylformamide is gradually added to the resulting dark purple solution of / S-ionylidene triphenylphosphine. After 60 minutes, after heating to 70 °, the methanol is distilled off in vacuo and poured the dimethylformamide solution with stirring to a mixture of ice and 10 ° / ₀ sulfuric acid. Then it is extracted with petroleum ether; the extracts, washed neutral with water, are dried with sodium sulfate for 5 hours at -5 °. After the solvent has been driven off, 50 parts of residue remain, which essentially consist of ice-vitamin A-ethyl ester.

For the isolation of cis-vitamin Α-acid or conversion into trans-vitamin A-acid ester one can like proceed as follows:

cis-vitamin A acid: 25 parts of the resulting cis-vitamin A acid ethyl ester are dissolved in 150 parts of alcohol and refluxed with 5 parts of potassium hydroxide in 10 parts of water for 30 minutes. The alcohol and unsaponifiable low molecular weight fractions are driven off with steam. After acidification with 10 ° / ₀ hydrochloric acid, receiving the precipitating acid with ether and evaporation of the ether 11 parts of pale yellow crystals are obtained which πιμ after recrystallization from methanol at 146 ° melt (A _{m 'a.} = 330, ε = 42,000 [in methanol]); They therefore consist of cis-vitamin A acid.

trans-vitamin A-acid ethyl ester: 25 parts of the crude cis-vitamin A-acid ethyl ester are in the high-

vacuum distilled, with the trans-vitamin A acid ethyl ester {X _max = 3Si ηιμ, ε = 38,000 [in methanol]) passing over in a yield of 13 parts under a pressure of 0.005 mm Hg at 145 to 150 °. The trans-vitamin Α-acid with a melting point of 181 to 182 ° can be obtained therefrom in the usual way by saponification.

Claims (1)

Claim: Process for the preparation of compounds of Vitamin Α series, characterized in that one / 3-ionyl halide with a phosphine, for. B. triphenylphosphine, to the quaternary phosphonium halo- .genid converts this, expediently in dimethylformamide solution, with an equivalent amount of an alkali or alkaline earth alcoholate or an alkali acetylide converts into the / 3-ionylidene phosphinylid, on this one aldehyde of the general formula O = CH-CH = CH-C (CH ₃ ) = CH-R can act, where R denotes an alkyl, a carboxylic acid ester or an optionally etherified or esterified CH ₂ OH group, separates the phosphine oxide formed as a by-product and optionally saponifies, esterifies or rearranges the reaction products in the customary manner in stereoisomeric forms. © 609 767/427 1.57 709 573/428 6.