DE957942C - Process for the preparation of compounds of the vitamin A series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED FEBRUARY 14, 1957

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12 0 GROUP 25
INTERNAT. CLASS C 07c

B 35789 IVb112 0

Dr. Georg Wittig, Tübingen, Dr. Horst Pommer, Ludwigshafen / Rhine,
and Dr. Ernst Hartwig, Heidelberg

have been named as inventors

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

Process for the preparation of compounds of the vitamin A series

Patented in the territory of the Federal Republic of Germany from May 18, 1955

Patent application announced on August 16, 1956

Patent issued on January 24, 1957

It has been found that compounds of the vitamin A series can be produced by one Compound of the general formula

CH,

or

_: = C-C = CH-CH ₂ OR

CH ₃
XCH ₉ CH = CH-C = CH-CH ₂ OR

in which X = halogen and R = alkyl, aryl or

Acyl means with. a phosphine, in particular

Triphenylphosphine, to the quaternary phosphonium

balogenid converts this with the equivalent amount of an organic alkali compound or of an alkali amide or alkoxide converted into the corresponding phosphomium ylide, this. reacts with / Honon, separates the phosphine oxide formed and, if desired, the triple bond partially hydrogenated to the double bond by methods known per se.

As phosphonium ylide one calls after a proposal by G. Wittig (Angew. Chemie, Vol. 63, 1951, p. 15) compounds that mesomer between, 'the general formulas

R, P = CR,

-CR,

react.

The synthesis can be in the case of the use of triphenylphosphine (I), ι-bromo-4-methyl-

CH,

6-methoxyhexen- (4) -in- (2) (II) and / 3-ionone (V) formulate as starting materials as follows:

CH,

5 I + ■ I

BrCH ₂ -C = CC = CH - CH ₂ -OCH ₃ + (C ₆ H ₅ ) ₃ P- »(C ₆ H ₅ ) _S P -CH ₂ C = C- C == CH-CH ₂ - OCH ₃ Br

(II) (I) (III) 70

t (-HBr)

• \ / CH ₃ CH ₃ U = CH = CH-CO + (V)

CH,

CH ₅

CH,

'-CHC = CC = CH-CH ₂ OCH ₃

(IV) _

CH _S

CH = CH-C = CH-C = CC = CH-CH ₂ OCH ₃

CH,

H ₃ C

CH,

(VI) partial
φ hydrogenation

CH ₃ CH ₃

1-CH = CH-C = CH-CH = CH-C = CH-CH ₂ OCH,

CH,

In this way, from / Monon (V) and the phosphonium salt (III) via its ylide (IV) the dehydrovitamin A methyl ether (VI) _5, which can be partially hydrogenated to the vitamin A methyl ether; Vitamin A acetate is obtained in a corresponding manner from the corresponding acetyl derivative (R = CH _{3 CO).}

The starting compounds can, for. B. Newman, J. Organic Chem., Vol. Ϊ́γ, 1952, S. 962, bzw.iiach be prepared 2,555,599, 2,555,600 and ^2,555,601 the process of the USA.-Patenitschriften 2,555,598.

The connections that are easily accessible in this way The vitamin A series are biologically highly effective substances, including pharmaceutical Find use.

The parts mentioned in the examples are parts by weight.

example 1

20 parts ^ methyl-o-methöxyhexeni- (4) -ini- (2) -yl- (i) -triphcnylphosphonium bromide (F. = 155 with decomposition), which is obtained by reacting i-bromo-4-methyli '-6-methoxyhexen- (4) -in- (2) was obtained with the equivalent amount of triphenylpihosphine ¹ , are suspended in 200 parts of absolute ether and treated with the equivalent ^ amount of an ethereal solution of phenylüthiiim under nitrogen and cooling in an ice bath . The solution is stirred for about 10 minutes at temperatures below

2O °. A solution of 8 parts of γ-ionone in 10 parts of absolute ether is then allowed to run into the dark-colored reaction mixture, with cooling being used to ensure that the temperature does not rise above 20 ° . The mixture brightens sieve, and it separates from triphenylphosphine oxide. After about 10 minutes this is suctioned off under nitrogen, the ethereal solution is washed with 5% phosphoric acid, dried and freed from the solvent. After the not unreleased ionone has been separated off by distillation under reduced pressure, the residue is taken up in petroleum ether, some triphenylphosphine oxide still separating out. The solution is ¹ to an alumina column - optionally, wherein the crude product initially rearing in a deep yellow colored zone at the upper part of the column · .The development with petroleum ether leads to the formation of two zones, of (activity "o after B'rockmann II). which the lower one contains the dehydrovitamin A methyl ether. By eluting the lower zone with ether and driving off the solvent, about 2 parts of dehydrovitamin A methyl ether are obtained as a yellow oil with an absorption maximum at 316 ταμ (in> hexane).

Partial hydrogenation with the Lindlar catalyst (cf. HeIv. Obim. Acta, Vol. 35, 1952, p. 446) gives the vitamin A methyl ether, which is a yellow oil with an absorption maximum of 327 to 328 ταμ (in hexane ) is obtained. From-

booty in this partial hydrogenation comes in handy quantitatively.

Example 2

50 parts of the by reacting i-bromo-6-acetoxy-4-methylhexent- (4) -yne <- (2) Phosphonium salts obtained with the equivalent amount of triphenylphosphine are in 250 parts, anhydrous Dissolved dimethylformamide and quickly converted into a solution of at ordinary temperature 2.3 parts of sodium iti entered 75 parts of absolute alcohol, with a red-brown Solution of the ylid forms. One then adds 20 parts / Monon, noting the "temperature"

can rise above 30 ^0. After stirring for five hours, the reaction mixture is poured into water and extracted with petroleum ether. The extract is washed with water and dried over sodium sulfate and the solvent is distilled off under reduced pressure. After separation of the unconsumed / Monons d'by distillation under reduced. Pressure is chromatographed on aluminum oxide (activity II-III according to Brockmann!). The petroleum ether eluate becomes 11.12-

«5 Dehydro Vitamin A Acetate as a viscous, pale yellow oil · obtained. In hexane it shows an absorption maximum at X _max = 31 Sm ^ a, ε = 30,000. Its partial hydrogenation with the Lindlar catalyst in thiophene-free benzene leads to vitamin Α acetate, which in hexane has an absorption maximum at X _max = 2> ² Z to 324 ταμ, ε = 4θθοο shows.

Claims (1)

PATENT CLAIM: Process for the production of connective tissue. the vitamin Α series, characterized by that one can combine the general formulas CH ₃ I. XCH ₂ C = CC = CH-CH ₂ -OR or CH, XCH ₉ CH = CH-C = CH-CH ₅ OR in which X = halogen and R = alkyl, aryl or acyl, reacts with a phosphine, especially triphenylphosphine, to form the quaternary phosphonium halide, which is converted into the corresponding YHd with the equivalent amount of an organic alkali compound or an alkali amide or alcoholate, this reacts with β- ionone, the phosphine oxide formed is separated off and, if desired, the triple bond is partially hydrogenated to the double bond by methods known per se. © 609 579/515 ».58 (609 797 2.57)