DE2513999A1 - Methylbutene dial 1-acetals prepn. - from crotonaldehyde, acetals useful as inters for carotenoids - Google Patents

Abstract

Process for prepg. trans-3-methyl-2-butene-1,4-diol-1-acetals of formula (I) comprises (a) ozonolysis of crotonaldehyde acetals (II) in an org. solvent at 0 degree C then reductive elimination to give glyoxal monoacetals which (b) are vinylated in a Grignard reaction then acetylated to give cpds. (III), then (c) (III) are hydroformylated using conventional Rh catalysts at 60-140 degrees C and 20-1500 atm. excess, with CO and H2 and (d) the prod. is subjected to conventional elimination of acetic acid. (R1 and r2 = 1-4C aliphatic hydrocarbyl or together form ethylene or propylene, opt. substd. by 1-4C alkyl, pref. CH3). (I) are inters. in synthesis of carotenoids e.g. reaction with the ylid from beta-ionylideneethyltriphenylphos-phonium salts and subsequent hydrolysis, gives retinal. Process provides (I) in relatively few stages.

Description

Process for the preparation of trans -3-methyl-2-butene-1,4-dial-1-acetals The invention relates to a very advantageous process for the preparation of trans-3-methyl-2-butene-1, 4-dial-1-acetals (3-methyl-rumardialdehyde-1-acetals), starting from crotonaldehyde acetals, by ozonolysis with subsequent reductive work-up, Grignard vinylation and acetylation of the glyoxal monoacetals obtained and hydroformylation of the obtained new 2-acetoxy-but-3-en-1-al-acetals and elimination of acetic acid.

The trans-3-methyl-2-butene-1,4-dial-1-acetals are as intermediates of extraordinary interest in the synthesis of carotenoids. For example can be obtained by reacting trans-3-methyl-2-butene-1,4-dial-1-acetals with the ylid of ß-Ionylidenäthyltriphenylphosphoniumsalzen and subsequent hydrolysis to simple Way to get the coveted and previously only in a complex way to produce retinal. Retinal has the same effectiveness as vitamin A. You can also use retinal by simple Wittig reaction with the retinyltriphenylphosphonium salt, which is readily available from retinol produce B-carotene in a very economical way.

A previously known process, according to which trans-3-methyl-2-butene-1,4-dial-1-acetals can be obtained in good yields, requires ten operations in each case, as can be seen from the following scheme: It was therefore the spirit of the invention to develop a process that would make it possible to obtain the coveted trans-3-methyl-2-butene-1,4-dial-1-acetals in a simpler way, i. E. with a lower working wall.

There has now been a process for the preparation of trans -3-methyl-2-butene-1,4-dial-1-acetal found, according to which the desired products, starting from acetals of crotonaldehyde, obtained in just a few technically relatively easy synthesis steps will.

The invention thus relates to a process for the preparation of trans-3-methyl-2-butene-1, 4-dial-1-acetals of the formula I. in which R1 and -R2 denote an aliphatic hydrocarbon radical with 1 to 4 carbon atoms or R1 and R2 together denote an ethylene radical or a propylene radical, which can be substituted by alkyl groups with 1 to 4 carbon atoms, preferably methyl groups, which thereby is characterized in that a) a crotonaldehyde acetal of the formula II in which R1 and R2 have the meaning given above, subjected to ozonolysis in organic solvents at temperatures below OoC, preferably at temperatures from -20 to -40 ° C with subsequent reductive work-up, b) vinylated the glyoxal monoacetal obtained in a Grignard reaction and then acetylated and c) the new compounds of the formula III obtained in which R1 and R2 have the meaning given above, reacted with CO and H2 in the presence of common rhodium-containing hydroformylation catalysts at temperatures from 60 to 140 ° C. and pressures from 20 to 1500 atmospheres and then acetic acid is eliminated from the hydroformylation product in a manner known per se.

The crotonaldehyde acetals required as starting materials are known Compounds made, for example, from crotonaldehyde and alcohols or diols Circulation of water with suitable solvents, such as benzene or Chlorororm, can be produced.

The conversion of crotonaldehyde acetal with ozone takes place in organic Solvents, Inert solvents such as pure solvents can be used as organic solvents or chlorinated hydrocarbons, e.g. pentane, hexane, carbon tetrachloride, trichloroethane, Methylene chloride or acetic acid ester, but also proton-active solvents such as Methanol and ethanol, or mixtures of these solvents can be used. With special It is advantageous to use a solvent for the reaction with ozone, which is the subsequent reductive splitting does not interfere, so that a solvent exchange due to the unstable nature of ozonization products would be problematic, can be omitted It is particularly advantageous to use methanol, methanol, methyl acetate and ethyl acetate as solvent. The solvents are generally used in amounts of 200 to 1500 g, preferably 400 to 600 g, per mole of crotonaldehyde acetal To carry out the reaction, the crotonaldehyde acetal is generally dissolved in the solvent and passes into this solution at the reaction temperature 0 2 and 03 existing gas flow until no more ozone is absorbed, what, for example, by browning an acidic potassium iodide solution in a downstream Wash bottle can be displayed The reaction temperature at the ozonolysis is generally at temperatures from -78 to OOC, preferably -40 to -200C.

The response time depends on the amount of available standing ozonizer supplies. A powerful ozone generator is for example described by G Wagner in J. Prakt. Chem. (4), 13, 99 (1961) The work-up the reaction mixture obtained in the ozonolysis takes place in a manner known per se Way by reductive cleavage.

The reductive cleavage of the ozonolysis products can have different effects Way, for example with trialkyl or triaryl phosphites, such as trimethyl Triethyl or triphenyl phosphite with the systems NaI / Thiosulfate, Zînk / Eisessign Zinl </ 50 goat acetic acid, with H2S, HJ, metal hydrides, triphenylphosphine, Dimethyl sulfide, Na2S03 or by catalytic hydrogenation With particular advantage with regard to the yields and purity of the products as well as the workload takes place - especially on an industrial scale - the reductive splitting by catalytic hydrogenation. We therefore describe the work-up of the ozonolysis product obtained by catalytic hydrogenation as an example of reductive splitting.

In addition to nickel, metals are particularly important for catalytic hydrogenation of the platinum group, in particular palladium, are suitable as hydrogenation catalysts. The active metal can either be in a finely divided state alone or on one inert carrier material, such as aluminum oxide, silica, calcium carbonate or activated carbon, be used dejected.

The hydrogenation is generally carried out at temperatures from -20 to + 400C, preferably 10 to 400C.

To carry out the reductive cleavage, one generally adds the reaction mixture obtained in the ozonolysis, the hydrogenation contact (about 1 to 3 g / 100 ml) and passes in H2 at the reaction temperature until the reaction mixture is removed no more H2 is absorbed.

In the case of a continuous configuration of the process, one uses In the hydrogenation tower, it is best to have a contact column with catalytically active packing.

The reaction mixture is generally worked up by fractional distillation.

It was surprising to be able to work in the simple way described can produce glyoxal monoacetals in good yields, since Advances in Org. Chem., Vol. 3 (1963), page 263, it is known that acetals are not resistant to ozone and since Can, J. Chem. 49 (1972), 14> 2465 - 67 a method is also known, according to the effect of ozone at low temperatures cyclic Acetals of saturated aldehydes, the corresponding carboxylic acid esters can be obtained. Also information in the chemical reports ffi (1903), page 1935, that with action glyoxal monoacetal formed from ozone on acroleindiethylacetal in aqueous emulsion did not encourage an advantageous process for the preparation of glyoxal monoacetal to look for by means of ozonization, since a reworking of the specified experiments showed that the reaction mixture can explode with no apparent cause.

The vinylation of the glyoxal monoacetals obtained in a Grignard reaction and subsequent ae-tylation takes place with particular advantage in such a way that the glyoial monoacetal obtained with a solution of a vinyl magnesium halide of the general formula CH2 ~ CH-MgX, in which X stands for C1, Br or J, and then with about molar amounts of acetic anhydride and the reaction mixture in the usual Way worked up hydrolytically.

The implementation of glyoxal monoacetals with a solution of a vinyl magnesium halide is generally carried out in the manner customary for Grignard reactions and at temperatures from -50 to OOC, preferably from -30 to -5 0C.

Vinylmagnesium halides are vinylmagnesium chlorides and bromides and iodides, especially vinyl magnesium chloride, into consideration. The manufacture of the Vinyl magnesium halide solutions are produced in a known manner by reacting vinyl chloride, bromide or iodide with magnesium in ethereal solvents such as methylql, tetrahydrofuran or diethylene glycol dimethyl ether, preferably in tetrahydrofuran. 0.5 to 5, preferably about 1 to 2, molar solutions are used. To get one as possible To achieve full implementation of the ketone, it is advisable to take about 10 indicate molar excess of the vinyl Grignard compound to use.

In the preferred embodiment of the method according to the invention before working up the Grignardation approach, in the Usually by pouring the reaction mixture into water or adding dilute Acids, such as sulfuric acid, under ice-cooling and extraction with an organic Solvents such as diethyl ether, benzene or methylene chloride, and then Fractionation can errolgen, the reaction mixture an at least molar amount, preferably an approximately molar amount of acetic anhydride and thus isolates the directly 2-acetoxy -) - buten-1-al-acetal of the formula III instead of the corresponding alcohol. The acetal of the formula III can be used directly for the hydroformylation.

However, the reaction mixture occurring during the Grignard vinylation can also be used Work up in the usual way and then the 2-hydroxy -) - buten-1-al-acetal obtained in the usual manner with acetic anhydride or an acetyl halide in the presence of one tertiary amine or H3P04 as a catalyst in the corresponding 2-acetoxy compound the formula III convert (see example 2).

The yields are both for the acetal and for the alcohol at about 90% of theory. Both the acetal of the formula III and the corresponding one Alcohol are new compounds.

It was surprising that the new compounds of the formula III are obtained in excellent yield by reacting glyoxal monoacetals with the solution of a vinyl magnesium halide, since carbonyl compounds in which the proton on the aC atom is acidic, often with Grignard compounds with enolate formation according to the following equation react (cf. Houben-Weyl, Vol. 13 / 2a, 296 to 297) and in the glyoxal monoacetals the M proton is additionally inductively activated by the two alkoxy groups.

For example, the formation of enolates is favored when the carbonyl compound can develop a keto-enol tautomerism, i.e. when the protons are in the "position to the Carbonyl group are additionally acidified. In the present case, such occurs Activation by the two alkoxy radicals.

When reacting carbonyl compounds with Grignard reagents A second side reaction also comes to the fore if the i-C atom is electronegative Substituents are: the hydrogenation of the carbonyl group by the Grignard reagent (see Houben-Weyl, Vol. 12/20, p. 296 ff.).

Finally, the action of both basic reagents such as R-Mg-R and Lewis acids such as MgCl2, both of which occur in Grignard's solution, would result in an intramolecular disproportionation of> -oxo-acetals to α-oxy-esters expect.

(See U.S. Patent 3,492,325 and J.E. Thompson J. Org. Chem. 52, 3947 (1967) up to 3950).

The hydroformylation of the new compounds of the formula obtained III is generally carried out in the presence of customary rhodium-containing hydroformylation catalysts, because only this a preferred entry of the formyl group in the i-position to the acetoxy group cause.

The cobalt catalysts otherwise also used for hydroformylation are not suitable because they cause hydrolytic cleavage under the reaction conditions of the acetal group and preferential entry of the formyl group cause in ß-position to the acetoxy group.

The usual rhodium-containing hydroformylation catalysts come finely divided metallic rhodium, rhodium carbonyls, rhodium chlored3 rhodium nitrate Rhodium sulfate and complex compounds' which by reacting rhodium salts or rhodium carbonyl compounds with triphenylphosphine, olefins, diolefins or Acetylacetone can be obtained considering square planar rhodium complexes are preferred, wle dimaric rhodium carbonyl chloride, dimeric cyclooctadiene- (1,5) -yl-rhodium chloride jRh-Cl-CODg2 and rhodium carbonyl acetylacetonate.

The catalyst is generally used in one concentration from about 1 to 500 ppm, preferably 1 to 150 ppm, calculated as metal on the compound of the formula III The reaction temperature is generally 60 to 140 ° C, preferably 70 to 1100 ° C.

The reaction is generally carried out at a pressure of 20 to 1500 atü, preferably 200 to 700 atmospheres, in particular 500 to 700 atmospheres.

The reaction can be solvent-free or in inert organic Solvents are carried out. In particular, aliphatic, cycloaliphatic or aromatic hydrocarbons into consideration. Be mentioned for example petroleum ether, gasoline mixtures, hexane, cyclohexane, benzene, toluene, xylene mixtures, Cumene and p-DiisopropylbenzolO The hydroformylation of the new compound of the formula III is generally stirred first to form a mixture of 3-formyl-2-acetoxy-butanaaceta1 and the 4-formyl-2-acetoxy-butanal acetal.

The use of the highest possible pressure and the lowest possible temperatures favors the formation of the desired 3-formyl compound.

It already occurs under the hydroformylation reaction conditions to split off acetic acid from the hydrorormylated product, it comes through Hydrogenation of the now unsaturated compound to form 3-formyl-butanal acetal as an undesirable by-product. This undesirable side reaction becomes largely prevented if you a) only work with partial conversion (which of course only with continuous operation makes sense), b) at the lowest possible temperatures works, c) uses the lowest possible rhodium concentrations, d) no polar ones Solvent used and e) the presence of bases in the reaction mixture as possible prevented.

The elimination of acetic acid from the hydroformylation product takes place analogously to the elimination of acetic acid from 1,2-diacetoxy-3-methyl-butan-4-al according to U.S. Patent 3,840,589 by heating the hydroformylation product to temperatures from about 60 to 1800C, preferably by heating the hydroformylation product in the presence of a salt-like catalyst of the general formula Q + Y, in which Q + is an ammonium cation or an alkali metal cation or an equivalent of an alkaline earth metal cation or a polyvalent anion exchanger and Y for a nucieophile Anion or, if this is polyvalent, the equivalent thereof.

Examples of suitable cations Q + are the cations of the general Formula Nu4 +, in which the radicals R can be identical or different and are hydrogen or alkyl radicals, as in the cations Nu4 +, tetramethylammonium, trimethylammonium, Dimethylammonium, methylammonium, methylethylammonium and the like. In these The anion exchangers, which are mostly networked, also belong to the series insoluble macromolecular compounds, which contain a large number of primary, carry secondary, tertiary or mostly quaternary ammonium groups. Among the metallic Cations Q + are preferred to sodium, potassium and barium.

Nucleophilic (basic) anions are e.g. chloride, bromide, iodide, hydroxyl, Cyanide, carbonate, hydrogen carbonate, phosphate, acetate, propionate, butyrate, methylate, Ethylate, propylate, butylate and phenolate.

The elimination of acetic acid takes place with particular advantage by heating in the presence of ammonium, alkali or alkaline earth metal acetates or in the presence of Compounds which convert into the acetates mentioned under the reaction conditions. As compounds that under the reaction conditions in ammonium, alkali or alkaline earth acetates pass over, for example, the corresponding salts with acids, which have a lower value Have acidic strength than acetic acid, such as hydroxides, cyanides, carbonates, hydrogen carbonates, Propionates butyrates, methylates, alkylates, propylates, butylates and phenates.

The preferred amounts of the catalyst & + Q + Y are between 0, oil and 1%, and the preferred temperatures are in the range from 70 to 130 C.

Usually the reaction is carried out without a solvent, however you can also work in the presence of an inert solvent or diluent. Hydrocarbons such as benzene, toluene, petroleum ether and ligroin are suitable for this and substituted hydrocarbons such as anisole.

The laurel and end of the reaction are based on the acetic acid split off easy to determine. After removing the acetic acid, optionally the solvent and the catalyst can be the remaining mixture of I and III due to the Separate different physical properties easily, e.g. extract iv or preferably by distillation under reduced pressure.

With the aid of the process according to the invention, the can be used as intermediates extremely interesting trans-3-methyl-2-buten-1 in the synthesis of carotenoids, 4-dial-1-acetals in a much simpler way and with much less effort are produced than by the already known processes. The for the invention Process required starting materials are relatively easily accessible.

Example 1 a) Preparation of glyoxalneopentylglycol monoacetal In a bubble column, i.e. a column to be filled with liquid into which the gas is introduced through a frit, the solution of 34.3 g of crotonaldehyde neopentyl glycol acetal cooled to -300C in 290 g of methanol. A current is passed through this solution of 90 1 oxygen per hour containing 2.5% (0.1 mol / hour) ozone. Initiation is continued until ozone in a noticeable amount of the reaction mixture again leaves (this is indicated by the dark color of an acidic potassium iodide solution in a downstream Washing bottle displayed), which is the case after about 2 1/2 hours.

The reaction solution is then placed in a reaction vessel with a Gassing stirrer brought, flushed with N2 and mixed with 5 g of a contact, the consists of calcium carbonate with 5% palladium. The hydrogenation with hydrogen begins at -15QC and finishes at around OOC. Ss9 normal liters of hydrogen are absorbed0 When the hydrogenation has ended, the contact is filtered off and the glyoxal monoacetal is isolated by fractional distillation. At a boiling point of 96 0C under pressure from 35 torr, 25 g of glyoxalneopentylglycol monoacetal are obtained; this corresponds to a Yield of 82 ß of theory.

b) Preparation of 2-acetoxy-3-buten-1-al-neopentylglycol acetal In a 500 ml four-necked flask (stirrer, thermometer, dropping funnel) are placed under a nitrogen atmosphere 110 ml of a 1.09 molar solution of vinyl magnesium chloride in tetrahydrofuran (THF) cooled to -200C. At this temperature, 14.4 g (0.1 mol) of the according to a) glyoxalneopentylglycol monoacetal obtained, dissolved in 20 ml of THFj, was added dropwise. In 9 g (0.15 mol) of glacial acetic acid dissolved in a little THF are added dropwise to this solution at -200C and allows the mixture to come to room temperature with stirring. After adding 150 ml of water separates an upper phase. The water phase is separated and twice extracted with 60 ml of ether. The combined organic phases are in a rotary evaporator concentrated and the residue is distilled under reduced pressure. 18.8 is obtained g of a fraction with a boiling point Kp0> 2 = 72 to 76 ° C, which according to gas chromatography and NMR spectroscopic analysis to 97 ffi from 2-acetoxy-3-buten-1-al-neopentyl glycol acetal. This corresponds to a yield of 88 ffi of theory.

c) Preparation of trans-D-methyl-2-butene-1,4-dial-1-neopentylglycol acetal 100 g of 2-acetoxy-3-buten-1-al-neopentylglycol acetal are placed in a high-pressure vessel with a capacity of 0.8 liters and 50 ppm Rh as -Rh-Cl-CODg2 in 300 ml of cyclohexane as solvent heated to 80 ° C and under a pressure of 650 atmospheres carbon monoxide and hydrogen by volume implemented by 1: 1. By Pressing the gas mixture is the Pressure kept constant.

After 4 hours, the mixture is cooled under pressure and then relaxed. The gas chromatographic analysis of the reaction mixture shows the following composition: 10% unreacted 2-acetoxy-3-buten-1-al-neopentyl glycol acetal, less than 2% 3-formyl-butanal neopentyl glycol acetal, 88% of a mixture of 3-formyl and 4-formyl-2-acetoxybutanal neopentyl glycol acetal in a ratio of 68:32 parts.

The reaction mixture obtained is mixed with 0.3 g of sodium acetate, Heated to boiling under reflux for 3 hours and then by distillation worked up. 38 g of trans-3-methyl-2-butene-1,4-dial-neopentylglycol acetal are obtained from the boiling point Kpg = 67 to 690C.

Example 2 Preparation of 2-acetoxy-3-butene-1-al-neopentyl glycol acetal via 2-hydroxy-3-buten-l-al-ne opentylglycol acetal in a 500 ml four-necked flask 110 ml of a 1.09 molar solution of vinyl magnesium chloride are added under a nitrogen atmosphere cooled to -20 ° C in THF. At this temperature, 14.4 g (0.1 mol) are analogous Example 1 a) Glyoxalneopentylglycol monoacetal produced - dissolved in 20 ml of THF - added dropwise. For work-up, 100 ml of a 15 are allowed to show without further cooling to acidic aqueous acetic acid and the organic upper phase is separated off. The watery one Phase is extracted twice with 60 ml of ether each time.

The combined organic phases are washed twice with 100 ml of water each time and washed once with saturated sodium chloride solution and concentrated on a rotary evaporator. The residue (21.2 g) gives 15.8 g of a upon distillation under reduced pressure uniform fraction from boiling point Ko 1 = 70 to 740C. The yield of 2-hydroxy-3-buten-1-al-neopentyl glycol acetal is 92% of theory.

17.2 g (0.1 mol) of the 2-hydroxy-3-buten-1-al-neopentylglycol acetal obtained analogously to the above procedure are at room temperature to a solution of 16.0 g (0.2 mol) of pyridine and 15.3 G (0.15 mol) of acetic anhydride in 30 ml of methylene chloride. Man lets stand for about 24 hours and then decomposes the excess acetylating agent cooling by adding 2 ml of water under an ice bath. After adding 100 ml of methylene chloride extract one after the other with 90 ml of water, saturated copper sulfate solution and saturated saline. The organic phase is then concentrated and the residue (25> 5 g) is distilled under greatly reduced pressure. You get 17 g of a fraction with a boiling point Ko 05 = 64 to 720C, which according to gas chromatography consists of 2-acetoxy -) - buten-1-al-neopentylglycol acetal in a purity of 94%. The yield of 2-acetoxy-3-buten-1-al-neopentylglycol acetal is 79.5 ff Theory, based on the hydroxy compound used.

Claims (2)

Claims 1. Process for the preparation of trans-3-methyl-2-butene-1,4-dial-1-acetals of the formula I. in which R1 and R2 denote an aliphatic hydrocarbon radical with 1 to 4 carbon atoms or R1 and R2 together denote an ethylene radical or a propylene radical which can be substituted by alkyl groups with 1 to 4 carbon atoms, preferably methyl groups, characterized in that that a) a crotonaldehyde acetal of the formula II in which R1 and R2 have the meaning given above, subjected to ozonolysis in organic solvents at temperatures below OOC with subsequent reductive splitting, b) vinylating the glyoxal monoacetal obtained in a Grignard reaction and then acetylating and c) the new compounds of the formula obtained III in which R1 and R2 have the meaning given above, in the presence of customary rhodium-containing hydrorormylation catalysts at temperatures from 60 to 140 ° C. and pressures from 20 to 1500 atmospheres with CO and H2 and then eliminated from the hydroformylation product in a manner known per se acetic acid. 2. Verrahren according to claim 1, characterized in that in Reaction step b) the glyoxal monoacetal obtained with the solution of a vinyl magnesium halide of the general formula CH2 = CH-MgX in which X stands for C1, Br or J, and then with about molar amounts of acetic anhydride and then the reaction mixture worked up hydrolytically in the usual way.