GB2028330A

GB2028330A - Ethylenic hydroxyacetals, a process for their preparation and their use

Info

Publication number: GB2028330A
Application number: GB7928939A
Authority: GB
Original assignee: AEC Societe de Chimie Organique and Biologique SA
Current assignee: Adisseo France SAS
Priority date: 1978-08-22
Filing date: 1979-08-20
Publication date: 1980-03-05
Also published as: CH640494A5; DE2934017A1; FR2434135B1; JPS5528993A; GB2028330B; FR2434135A1; JPS631942B2; SU1011047A3; DE2934017C2

Abstract

Ethylenic hydroxyacetals of the general formula: <IMAGE> wherein R represents a 2,6,6- trimethylcyclohex-1-enyl or a 2,6- dimethylhepta-1,5-dienyl radical and R1 is a straight- or branched-chain alkyl group containing 1 to 4 carbon atoms, are useful in the synthesis of vitamin A and lycopene.

Description

SPECIFICATION New ethylenic hydroxyacetals, a process for their preparation and their use This invention relates to ethylenic hydroxyacetals, useful in the synthesis of vitamin Aand lycopene, and to a process for their preparation.

The present invention provides ethylenic hydroxyacetals of the general formula:

wherein R represents a 2, 6, 6 - trimethylcyclohex - 1 - enyl radical or a 2,6 - dimethylhepta - 1,5 - dienyl radical and R1 represents a straight- or branchedchain alkyl radical containing 1 to 4 carbon atoms, preferably an ethyl radical.

French Patent No. 1,243,824 describes a process for the preparation of carotenoid compounds of the general formula: P-(ls)n-CHO 11 wherein P represents the 2, 6, 6 - trimethylcyclohex 1 - enyl radical, Is represents an isoprene radical

and n is 1,2 or 3, by a Claisen reaction between an alkyl formate of the general formula H-COOR2, wherein R2 represents an alkyl radical containing 1 to 4 carbon atoms, and a methyl ketone of the general formula: P-(ls)n~1-CH=CH-CO-CH3 Ill wherein P, Is and n are as hereinbefore defined, to give a p-ketoacetal of the general formula: P-(ls)n~1-CH=CH-CO-CH2-CH(OR2)2 IV wherein P, Is, n and R2 are as hereinbefore defined.

By treatment with an organometallic compound, the product of general formula IV is converted to a methyl - P - hydroxyacetal of the general formula:

wherein P, Is, n and R2 are as hereinbefore defined.

The conversion of the product of general formula V to the product of general formula 11 is effected by dehydration of the tertiary alcohol and hydrolysis of the acetal group, via the intermediate retra-acetal of the general formula:

wherein n and R2 are as hereinbefore defined. The dehydration and the hydrolysis are generally carried out in acetone in the presence of aqueous hydrochloric acid.

Using the process of French Patent No. 1,243,824, it is necessary, in order to prepare the aldehyde of vitamin A (retinene), to start from a compound of general formula III wherein n is 2. This compound is itself obtained by the process described in French Patent No. 1,167,007, from a compound of general formula II wherein n is 1.

The compounds of the present invention are par tics marly valuable intermediates for preparing aldehydes of the general formula:

wherein R is as hereinbefore defined, which are themselves known as intermediates for preparing vitamin A or lycopene, depending on the meaning of R.

According to a feature of the present invention, the ethylenic hydroxyacetals of general formula I are prepared by a Gngnard reaction which comprises reacting a compound of the general formula: CH3-Z VIII wherein Z represents a lithium atom, a halogenomagnesium radical MgX or a halogeno-zinc radical ZnX, in which X represents a halogen atom, with an ethylenic ketone of the general formula:

wherein R and R1 are as hereinbefore defined and hydrolysing in an acid medium the organometallic compound thus obtained.

The ethylenic ketones of general formula IX are described and claimed in our copending Application No. 7928937.

The reaction is generally carried out by adding the ketone of general formula IX to an excess of the reactant CH3-Z (which is preferably methylmagnesium chloride) in a suitable organic solvent e.g. diethyl ether, at a temperature of from -50" to +30"C. The product of general formula I is liberated from the organometallic complex product obtained by treatment, e.g. with an iced dilute acid or by treatment with a buffered solution of acetic acid, and may be extracted with a suitable solvent, e.g. hexane or diethyl ether.

The ethylenic ketone of general formula IX can be obtained by condensing a ketone of the general formula:

wherein R is as hereinbefore defined, with an acetalaldehyde of the general formula:

wherein Ri is as hereinbefore defined.

The condensation is carried out in the presence of an anionisation agent, in an appropriate solvent and at a suitable temperature. The anionisation agent is a basic agent which is sufficiently active to anionise the ketone of general formula X. The anionisation agent used is generally a hydride, amide, alcoholate or hydroxide of an alkali metal, preferably of sodium.

Sodium methylate is particularly suitable. It is advantageous to use from 0.05 to 1.5 mols of anionisation agent per moi of the ketone of general formula X employed.

The nature of the solvent is immaterial, provided, however, that the solvent chosen is inert towards the reactants employed. In general, the less polar a solvent, the more suitable it is. Liquid aliphatic hydrocarbons, e.g. hexane, cycloaliphatic hydrocarbons, e.g. cyclohexane, aromatic hydrocarbons, e.g. benzene, halogenated hydrocarbons, e.g. 1,2 - dichloroethane, ethers, e.g. diethyl ether, tetrahydrofuran or dioxan, alcohols, e.g. methanol or ethanol, nitriles, e.g. acetonitrile and amides, e.g. dimethylformamide or N - methylpyrrolidone, are of particularvalue. If an alkali metal hydroxide is used, it is possible to carry out the reaction in water, or preferably in a mixture of water and a water-miscible or -immiscible organic solvent, optionally in the presence of a quaternary ammonium hydroxide (e.g. tetrabutylammonium hydroxide).In all cases it is preferableto stirthe reaction mixture vigorously. In general, 3 to 10 volumes of solvent are used per volume of the ketone of general formula X.

For a given solvent, the anionisation agent is chosen so that, in the presence of the ketone of general formula X, the reaction mixture assumes a redbrown to deep brown coloration.

The acetal-aldehyde of general formula XI is used at the rate of 1 to 1.7 mols per mol of the ketone of general formula X employed.

The reaction temperature is not critical and it is possible to carry out the reaction at from -50 C to the reflux temperature of the reaction mixture and preferably from -30" to +60"C.

The reaction time can vary within rather wide limits and depends essentially on the reactants used.

In general, a duration of from 1/4 of an hour to 4 hours is suitable to obtain a good yield of the product of general formula IX.

The product of formula IX obtained can be isolated by known methods. In general, the reaction mixture is poured - if necessary, after having been cooled into water which may contain an acid such as acetic acid, and the product of general formula IX is extracted by means of an organic solvent, e.g. hexane. The crude product obtained can be purified by physical methods, e.g. molecular distillation.

The ketone of general formula X wherein R represents the 2,6,6 - trimethylcyclohex - 1 - enyl radical is ss - ionone and that wherein R represents the 2, 6 - dimethylhepta - 5 - dienyl radical is pseudo ionone.

The acetal - aldehyde of general formula XI can be obtained by reacting an alkyl orthoformate of the general formula H-C(ORt)3, in which R1 is as hereinbefore defined, with a 1,3 - dienoxysilane of the general formula:

wherein R4 represents a hydrocarbon radical and more particularly a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms, a cycloalkyl radical, e.g. cyclopentyl or cyclohexyl, a phenyl radical or an aralkyl radical, e.g. benzyl orp- phenylethyl, and p is 1,2 or 3, in the presence of a Lewis acid.

The condensation of the alkyl orthoformate with the dienoxysilane can be carried out equally well in an organic solvent which is inert towards the reactants used, or in the absence of any solvent. Iri the former case, it is possible to employ aliphatic hydrocarbons (e.g. hexane or heptane), cycloaliphatic hydrocarbons (e.g. cyclohexane), aromatic hydrocarbons (e.g. benzene), ethers (e.g. diethyl ether or tetrahydrofuran), halogenated hydrocarbons (e.g.

methylene chloride or chloroform), nitriles (e.g.

acetonitrile or propionitrile) or amides (e.g.

dimethylformamide, dimethylacetamide or N methylpyrrolidone).

The temperature at which the reaction is carried out can vary within wide limits in accordance with the reactants employed and the nature and amount of catalyst. In general, the reaction is carried out at from -40" to +150"C and preferably from 0" to 100"C.

A temperature of from + 100 to +70 C is very suitable. However, it is possible to work outside these limits. The pressure can be equal to, greater than or less than atmospheric pressure.

Lewis acids which can be used as catalysts, include the boron halides and their complexes with ethers, and the halides of transition metals (metals of groups 1 b to 7b and 8 of the periodic classification of the elements: Handbook of Chemistry and Physics, 53rd edition, published by The Chemical Rubber Co.). The zinc and tin halide, zinc chloride, zinc bromide, stannous chloride, stannous bromide, stannic chloride and stannic bromide are particularly suitable and are preferably used.

The amount of catalyst, expressed as the number of mols of Lewis acid per dienoxy group present in the dienoxysilane, can vary within wide limits. In general, 1 x 10-4 to 0.5 mol of Lewis acid, and in particular of zinc halide or of tin halide, per dienoxy group suffices for carrying out the reaction successfully. This amount is preferably between 1 x 10-3 mol and 0.2 mol per dienoxy group.

The duration of the reaction depends on the conditions chosen and on the nature of the reactants and can vary from a few minutes to a few hours.

The products of general formula XII generally are known products which can easily be prepared by reacting a mono-, di- ortri-halogenosilane of the general formula: (R4)-Si(HaI)4, XIII wherein R4 and p are as hereinbefore defined and Hal represents a halogen (chlorine or bromine) atom, with an a,ss- orss,y-ethylenic enolisable aldehyde or ketone, in the presence of zinc chloride and of a hydracid acceptor, in accordance with the process described in Belgian Patent No. 670,769.

The conversion of the hydroxy-acetal of general formula I to the aldehyde of general formula VII, which comprises dehydration of a tertiary alcohol and hydrolysis of an acetal group, via the intermediate retroacetal, can be carried out in one or several steps. Conventionally, the dehydration of a tertiary alcohol is carried out with a mineral acid.

The hydrolysis of an acetal can be carried out with an aqueous hydrogen halide acid in a water-miscible organic solvent in which the product to be treated, and the acid, are soluble. Acetone is particularly suitable for this purpose. The conversion of the hydroxyacetal of general formula I to the aldehyde of general formula VII is preferably carried out in acetone, by means of aqueous hydrochloric acid or hydrobromic acid. The conversion is preferably carried out in the presence of an anti-oxidant, e.g. ionol.

If the radical R represents the 2,6,6- trimethyl - cyclohex - 1 - enyl radical, the aldehyde of general formula VII can be reduced by known methods to vitamin A; if R represents the 2,6 - dimethylhepta 1,5 - dienyl radical, the aldehyde of general formula VII can be converted to lycopene by dimerisation by known methods.

By the expression "known methods" as used in this specification is meant methods heretofore used or described in the chemical literature.

The following Examples illustrate the present invention.

EXAMPLE 1 A solution of methyl-magnesium chloride (prepared from 1.34 g of magnesium) in 17 ml of anhydrous diethyl ether is added in the course of 40 minutes, at -30 C, to a solution of 5.88 g of purified 9 -(2', 6', 6'- trimethylcyclohex-l '-enyl)-l, 1- diethoxy - 3 - methyinona - 3, 5,8 - trien - 7- one (referred to hereinafter as C19 diethyl acetal), of 89% purity, in 20 ml of anhydrous diethyl ether. The reaction is allowed to continue for a further 15 minutes and the reaction mixture is then poured into a solution of 0.59 g of sodium acetate and 3.54 g of glacial acetic acid in 47.2 ml of water. After allowing the phases to settle out, and separating them, the aqueous phase is extracted with 60 ml of diethyl ether.

The combined organic phases are washed with 15 ml of water and then twice with 15 m I of a 3% w/v aqueous solution of sodium bicarbonate. 5.81 g of 9 (2', 6', 6' - trimethylcyclohex - 1' - enyl) - 1, 1 - dieth oxy - 3,7 - dimethylnona - 3, 5,8 - trien - 7 - ol (referred to hereinafter as C20 diethyl hydroxyacetal) are thus isolated, having the following characteristics: ultraviolet spectrum: AmaX = 241 nm; E1%,= 531 (isopropanol).

The C19 diethyl acetal used as starting material in the procedure described above can be prepared as follows: A mixture of g (161 millimols) of 1, 1 - diethoxy 3 - methylpent - 3 - en - 5 - al and 28.14 g (147 millimols) of p-ionone is added to a suspension, cooled to 0 C, of 2.10 g (38.9 millimols) of sodium methylate in 150 ml of anhydrous hexane. After stirring for 30 minutes at a temperature of about 0 C, the reaction mixture is poured into about 300 ml of water containing 2% v/v of glacial acetic acid. The aqueous phase, the pH of which is between 4 and 5, is extracted with 300 ml of hexane. The organic layer is washed with 150 ml of an aqueous sodium bicarbonate solution and then with water until neutral.

The combined organic phases are dried over anhydrous sodium sulphate and then concentrated to dryness under reduced pressure (12 mm Hg) until constant weight is reached. 54.1 g of an orange oil are thus obtained; according to determination by high-pressure liquid chromatography with an internal standard, this oil contains 63.3% wiw of C19 diethyl acetal and 8% wlw ofp-ionone.

The degree of conversion is 84% and the yield relative to p-ionone consumed is 80.5%.

After purification by high-pressure liquid chromatography, C19 diethyl acetal having the following characteristics is obtained: ultraviolet spectrum: AmaX = 330 nm; Ei17m= 683 (isopropanol), determination of the ethoxy radicals (OC2H5) by the Zeisel method: calculated: 25%; found: 23.37%.

1,1 - Diethoxy-3- methylpent-3- en - 5- al can be prepared as follows: 22.2 g of ethyl orthoformate (1.5 x 10-1 mol),0.37 g of molten zinc chloride (2.76 x 10-3 mol) and 50 ml of anhydrous acetonitrile are introduced, under an argon atmosphere, into a 250 ml three-necked flask equipped with a stirrer, a condenser and a dropping funnel. The mixture is stirred and 23.4 g of 1 trimethylsilyloxy - 3 - methyl - 1,3 - butadiene (1.5 x 10-t mol) dissolved in 15 ml of anhydrous acetonitrile are then added overthe course of 5 minutes. The mixture is heated, and boils under reflux at76 C.

After heating for 45 minutes, the mixture is cooled to 50"C and the volatile products and the solvent are distilled off at 20 mm Hg pressure, using a trap.

Using vapour phase chromatography, 10.9 g of trimethylsilyloxyethane are identified, and measured, in the distillate and the trap.

The residue is dissolved in 50 ml of diethyl ether and the solution is neutralised by adding 25 ml of a saturated aqueous sodium bicarbonate solution. The organic phases are decanted, washed with 25 ml of distilled water and dried over potassium carbonate.

After filtering the solution and concentrating it to dryness, 199 of 1, 1 - diethoxy - 3 - methylpent - 3 en - 5 - al are identified and measured by infrared spectrography, vapour phase chromatography and nuclear magnetic resonance in a fraction distilling at between 75 and 80"C/0.3 mm Hg. After rectification, the 1,1 -diethoxy-3-methylpent-3-en-5-aI is obtained in the form of a pale yellow liquid boiling at 73"C/0.2 mm Hg and having a refractive index n2,0 = 1.4602.

EXAMPLE2 A solution of methyl-magnesium chloride (prepared from 2.58 g of magnesium) in 33 ml of anhydrous diethyl ether is added in the course of 1 hour, at-25 C, to a solution of 17 g of 9 - (2', 6', 6' trimethylcyclohex - 1' - enyl) - 1, 1 - diethoxy - 3 - methylnona - 3, 5,8 - trien - 7 - one (C19 diethyl acetal), purified by molecular distillation and of 81% purity, in 55 ml of anhydrous diethyl ether.The reac tion mixture is allowed to react four a further 15 minutes and is then poured, over the course of 10 minutes, into a solution consisting of 83 ml of water, 9.43 ml of concentrated hydrochloric acid (d = 1.19) and 10 ml of diethyl ether, whilst maintaining the temperature at between 0" and 5"C. After the phases have settled out and been separated, the organic phase is washed with 30 ml of water, twice with 30 ml of water containing 0.85 g of sodium bicarbonate, and then with 30 ml of water containing 0.12 g of sodium bicarbonate. The ethereal solution is dried over sodium sulphate.After filtering the solution and concentrating it to dryness under reduced pressure at a temperature of between 35 and 40"C, 17.72 g of 9 - (2', 6', 6' - trimethylcyclohex - 1' - enyl) - 1, 1 - diethoxy - 3,7 - dimethylnona - 3,5,8 - trien - 7 - ol (referred to hereinafter as C20 diethyl hydroxyacetal), are obtained, having the following characteristics: ultraviolet spectrum: A,, = 241 nm; E1Cm % = about 530.

EXAMPLE 3 [Use of a product according to the invention for the preparation ofretinene (vitamin A aldehyde)] A solution, kept under a nitrogen atmosphere, of 2.0 g of C20 diethyl hydroxyacetal in a mixture of 48.0 ml of acetone containing 0.25% v/v of water and of 0.68 ml of water containing 0.020 g of ionol is heated to the reflux temperature. 0.6 ml of a hydrobromic acid solution (obtained by adding 1 cm3 of aqueous 48% w/v hydrobromic acid to 47 ml of acetone) is then added rapidly. After cooling, the reaction mixture is poured into 150 ml of water. After two extractions with 50 ml of hexane, the combined organic phases are washed with 50 ml of a 5% w/v aqueous sodium bicarbonate solution and thereafter with 25 ml of water until neutral, and are then dried over sodium sulphate. After filtration and concentration to dryness under reduced pressure (12 mm Hg followed by 1 mm Hg) 1.69 g of retinene, having the following characteristics, are obtained: ultraviolet spectrum: AmaX = 380 nm; E CMm = 853 (isopropanol).

Claims

1. An ethylenic hydroxyacetal of the general formula:

wherein R represents a 2,6, 6 - trimethylcyclohex - 1 - enyl radical or a 2,6 - dimethylhepta - 1,5 - dienyl radical and R1 represents a straight- or branchedchain alkyl radical containing 1 to 4 carbon atoms.

2. An ethylenic hydroxyacetal according to claim 1 wherein R1 represents an ethyl radical.

3. 9 - (2', 6', 6' - Trimethylcyclohex - 1' - enyl) - 1, 1 - diethoxy - 3,7 - dimethylnona - 3, 5,8 - trien - 7 - ol.

4. Processforthe preparation of an ethylenic hydroxyacetal of the general formula specified in claim 1 which comprises reacting a compound of the general formula CH, wherein Z represents a lithium atom, a halogenomagnesium radical MgX or a halogeno-zinc radical ZnX, in which X represents a halogen atom, with an ethylenic ketone of the general formula:

wherein R and R1 are as defined in claim 1, and hydrolysing in an acid medium the organometallic compound thus obtained.

5. Process according to claim 4, in which the reaction is carried out in an organic solvent at a temperature of from -50" to +30"C.

6. Process according to claim 5 in which the solvent is diethyl ether.

7. Process according to claim 4, 5 or 6 in which the compound of general formula CH3Z is methylmagnesium chloride.

8. Process for the preparation of an ethylenic hydroxyacetal of the general formula specified in claim 1 substantially as hereinbefore described.

9. Process for the preparation of an ethylenic hydroxyacetal of the general formula specified in claim 1 substantially as hereinbefore described with especial reference to Example 1 or 2.

10. An ethylenic hydroxyacetal as claimed in claim 1 when prepared by a process as claimed in any one of claims 1 to 9.

11. Process for the preparation of an aldehyde of the general formula:

wherein R is as defined in claim 1, which comprises the dehydration and hydrolysis of a hydroxyacetal as claimed in claim 1.

12. Process according to claim 11, in which the dehydration and hydrolysis are carried out in acetone by means of aqueous hydrochloric acid or hydrobromic acid.

13. Process according to claim 11 substantially as hereinbefore described.

14. Process according to claim 11 substantially as hereinbefore described with especial reference to Example 3.