GB2028818A - New ethylenic ketones and a process for their preparation - Google Patents

New ethylenic ketones and a process for their preparation Download PDF

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GB2028818A
GB2028818A GB7928937A GB7928937A GB2028818A GB 2028818 A GB2028818 A GB 2028818A GB 7928937 A GB7928937 A GB 7928937A GB 7928937 A GB7928937 A GB 7928937A GB 2028818 A GB2028818 A GB 2028818A
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/10—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • C07C403/16—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms not being part of —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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Abstract

New ethylenic ketones of the general formula <IMAGE> 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 branched-chain alkyl group containing from 1 to 4 carbon atoms are useful in the synthesis of vitamin A and lycopene.

Description

SPECIFICATION New ethylenic ketones and a process for their preparation This invention relates to ethylenic ketones, useful in the syntheses of vitamin A and lycopene, and to a process for their preparation.
The present invention provides ethylenic ketones 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 R, represents a straight- or branchedchain alkyl radical containing 1 to 4 carbon atoms, preferably a methyl or ethyl radical.
French Patent No. 1,243,824 describes a process for the preparation of carotenoid compounds of the general formula: P-(ls),-CHO II wherein P represents the 2, 6, 6 - trimethylcyclohex 1 - enyl radical, Is represents an isoprene radical
and n is 1,2 or3, 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(1s)n~1Cl I = CHCOCH3 Ill wherein P, Is and n are as hereinbefore defined, to give a p-ketoacetal ofthe general formula: P(Is)n~1CH = CHCOCH2CH (OR2)2 IV wherein P, Is, n and R2 are as hereinbefore defined.
By treatment with an organo-metallic compound, the product of general formula IV is converted to a ss - 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 II is effected by dehydration of the tertiary alcohol and hydrolysis of the acetal group, via the intermediate retroacetal 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 Ill wherein n is 2. This compound is itself obtained, by the process which is described in French Patent No. 1,167,007, from a compound of general formula 11 wherein n is 1.
It is also known, from French Patent Specification No.71/36,598, published as Specification No.
2,113,010, to prepare enamine-ketones of the gen
eral formula: R' R 0 R3 VII wherein A represents, inter alia, a 2, 6, 6 - trimethylcyclohex - 1 - enyl radical, R' and R" represent, inter alia, methyl, ethyl or phenyl radicals, m represents an integer from 1 to 5, and Y represents an olefinic hydrocarbon group of the general formula:
wherein the symbols R3, which may be identical or different, represent a hydrogen atom or a methyl or ethyl radical. This patent specification does not, however, give an example of the preparation of a compound of general formula VII wherein X represents a group
,wherein R3 represents a methyl or ethyl radical.
The compounds of the present invention are useful as intermediates which are particularly valuable for the preparation of aldehydes of the general formula:
wherein R is as hereinbefore defined, which are themselves known as intermediates for the preparation of vitamin A or of lycopene, depending on the meaning of R.
According to a feature of the present invention, the ethylenic ketones of general formula I are prepared by reacting a ketone of the general formula:
wherein R is as herein before defined, with an acetal-aldehyde of the general formula:
wherein R1 is as hereinbefore defined, in the pres enceofan anionisation agent for the ketone of general formula IX, in a solvent.
The anionisation agent is a basic agent possessing sufficient activity to anitonise the ketone of general formula IX. 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 mol of the ketone of general formula IX.
The nature of the solvent is immaterial, provided, however, that the solvent 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 particular value. If an alkali metal hydroxide is used as the anionisation agent, it is possible to carry out the reaction in water or preferably in a mixture of water and a watermiscible or -immiscible organic solvent, optionally in the presence of a quaternary ammonium hydroxide, (e.g. tetrabutylammonium hydroxide). In all cases it is preferable to stir the reaction mixture vigorously.
In general, 3 to 10 volumes of solvent are used per volume of the ketone of general formula IX.
For a given solvent, the anionisation agent is chosen so that, in the presence of the ketone of general formula IX, the reaction mixture assumes a redbrown to deep brown coloration.
The acetal-aldehyde of general formula X is generally used at the rate of 1 to 1.7 mols per mol of the ketone of general formula IX 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 pref erablyfrom--30to +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 hourto 4 hours is suitable to obtain a good yield of the product of general formula I.
The product of general formula I obtained by the process of the present invention 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 I is extracted by means of an organic solvent, e.g. hexane. The crude product obtained can then be purified, for example by molecular distillation.
The product of general formula I can be determined in the crude product or in the purified product by analytical methods such as high pressure liquid chromatography using an internal standard.
The ketone of general formula IX wherein R represents the 2, 6, 6 - trimethylcyclohex - 1 - enyl radical isp-ionone and that wherein R represents the 2, 6, dimethylhepta - 1 - 5- dienyl radical is pseudoionone.
The acetal-aldehyde of general formula X can be obtained by reacting an alkyl orthoformate of the general formula: H-C(OR1)s Xl wherein R is as hereinbefore defined, with a 1,3dienoxysilane 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 orcyclohexyl, a phenyl radical or an aralkyl radical, e.g. benzyl or p-phenylethyl, and p is 1, 2 or 3 in the presence of a Lewis acid.
The condensation of the 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. In 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 ortetrahydrofuran), 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 400 to + 1 500C and preferably from 0 to 1 00 C.
A temperature of from + 1 to +700C 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 halides, zinc chloride, zinc bromide, stannous chloride, stannous bromide, stannic chloride and stannic bromide, are particu larly 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 condi tions 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: (R)-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 accor dance with the process described in Belgian Patent No. 670,769.
The conversion of a compound of general formula I to an aldehyde of general formula VIII can be car ried out by a Grignard reaction between a compound of the general formula: CHZ XIV wherein Z represents a lithium atom, a halogenomagnesium radical Mg-X or a halogeno-zinc radical Zn-X, in which X represents a halogen atom and an ethylenic ketone of general formula land liberation of the hydroxyacetal of the general formula:
wherein R and R1 are as hereinbefore defined, from the organometallic complex formed, followed by dehydration and hydrolysis of the hydroxyacetal of general formula XV to yield an aldehyde of general formula Vlil.
The hydroxyacetals of general formula XV are described and claimed in our copending Application No. 79 . The Grignard reaction is carried out by adding the ethylenic ketone of general formula I to an excess of the reactant of general formula XIV in a suitable solvent, e.g. diethyl ether, at a temperature of from -50" to +30 C. The product of general formula XV is liberated from the organometallic complex product obtained by treatment with, e.g. an iced dilute acid or by treatment with a buffered solution of acetic acid, and is extracted with a suitable solvent, e.g. hexane or diethyl ether.
The conversion of the hydroxyacetal of general formula XV to the aldehyde of general formula VIII which comprises dehydration of a tertiary alcohol and hydrolysis of an acetal group, via the intermediate retro-acetal, 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 XV to the aldehyde of general formula VIII 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 R represents the 2, 6, 6 - trimethylcyclohex - 1 enyl radical, the aldehyde of general formula VIII 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 VIII 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 mixture of 30 g (161 millimols) of 1, 1 - diethoxy 3 - methylpent- 3 - en - 5 - al and 28.149 (147 millimols) of eionone is added to a suspension, cooled to OOC, of 2.10 g (38.9 millimols) of sodium methylate in 150 ml of anhydrous hexane.
After stirring for 30 minutes art 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 a 5% w/v 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 mmHg followed by 1 mmHg) 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 oii contains 63.3% w/w of 9 - (2', 6', 6' - trimethylcyclohex - 1' - enyl) - 1, 1 - diethoxy - 3 - methyinona - 3, 5, 8 - trien - 7 - one (referred to hereinafter as C19 diethyl acetal) and 8% w/w of p-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: uitraviolet spectrum: AmaX = 330 nm; E1 /cm = 683 1 cm (isopropanol), determination of the ethoxy radicals (0C2H5) by the Zeisel method: calculated: 25.00%; found: 23.37%.
1,1 - Diethoxy-3- methylpent-3- en- 5- al used as starting material in the procedure described above can be prepared as follows: 22.2 g of ethyl orthoformate (1.5 x 10-t mol), 0.37 g of molten zinc chloride (2.76 x 10-3 mol) and 50 ml of anydrous 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-' mol) dissolved in 15 ml of anhydrous acetonitrile are then added over the course of 5 minutes. The mixture is heated, and boils under reflux at 760C.After heating for 45 minutes, the mixture is cooled to 50"C and the volatile products formed and the solvent are distilled off under reduced pressure (20 mm Hg) using a trap.
Using vapour phase chromatography,10.9 g of trimethylsilyloxyethane are identified, and measured, in the distiliate and the trap.
The residue is dissoived 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 off, washed with 25 ml of distilled water and dried over potassium carbo nate. After filtering the solution and concentrating it to dryness, 19 g 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 between 75 and 80"C/0.3 mm Hg. After rectification, 1,1 - diethoxy-3-methylpent-3-en-5-al is obtained in the form of a pale yellow liquid boiling at 20 73 C/0.2 mm Hg and having a refractive index nD = 1.4602.
EXAMPLE2 0.171 g (3.16 millimols) of sodium methylate is added to a solution, cooled to 0 C, of 1.105 g (5,755 millimols) of ,B-ionone and 1 g (6.33 millimois) of 1, 1 - dimethoxy - 3 - methylpent - 3 - en - 5 - al in 6.5 ml of cyclohexane. The mixture is stirred for 1 hour at 0 C.
Following the procedure described in Example 1, 1.99 g of an orange-brown oily product, containing 67.4% w/w of 9 - (2', 6', 6' - trimethylcyclohex - 1' enyl) - 1, 1 - dimethoxy - 3 - methyinona - 3, 5, 8 - trien - 7 - one (hereinafter referred to as C19 dimethyl acetal) and about 4% w/w of pionone, are isolated.
1,1 - Dimethoxy-3- methylpent-3-en- 5-al can be prepared as follows: 13.25 g of methyl orthoformate (1.25 x 10-1 mol), 0.312 g of zinc chloride (2.3 x 10--2 mol) and 40 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 a solution of 19.5 g of trimethylsilyloxyisoprene (1.25 x 10-' mol) in 15 ml of anydrous acetonitrile is then added over the course of 5 minutes. The mixture is heated to the reflux temperature. After 1 hour 10 minutes, thin layer chromatography shows that all the trimethylsilyloxyisoprene has disappeared.The reaction mixture is cooled and the acetonitrile is removed by distillation under reduced pressure (20 mm Hg). The residue is neutralised by adding 50 ml of a saturated sodium bicarbonate solution, and 25 ml of diethyl ether are then added. The organic phase is separated off, dried over potassium carbonate and then concentrated to dryness. Distillation of the residue gives 12.5 g of 1,1 - dimethoxy-3- methylpent- 3 - en - 5 al (boiling point70-75 C/0.4 mm Hg).
EXAMPLE 3 A mixture of 5.0 g (26.9 millimols) of 1, 1 - diethoxy - 3 - methylpent - 3 - en - 5 - al and 4.69 9 (24.4 millimols) of p-ionone is added to a suspension, cooled to 0 C, of 0.65 g (9.56 millimols) of sodium ethylate in 25 ml of hexane. After having been stirred for 30 minutes at OOC, the reaction mixture is treated as in Example 1. 9.04 g of a crude product, containing 63.1 % w/w of C19 diethyl acetal, are thus obtained.
EXAMPLE 4 Following the procedure of Example 3, but replacing the sodium ethylate by 0.65 g (9.3 millimols) of potassium methylate, 9.05 g of a product containing 49% wlw of C19 diethyl acetal are obtained.
EXAMPLES 0.550 g (2.957 millimols) of 1, 1 - diethoxy - 3 methylpent- 3 - en - 5 - al is added to a mixture of 0.516 g (2.687 millimols) ofp-ionone and 0.140 g (1.458 millimols) of sodium tertiary-butylate in 3 ml of hexane, kept at OOC. The reaction mixture is stirred for3 hours at 0 C and is then treated as described in Example 1. 1.02 g of crude C19 diethyl acetal are thus obtained.
EXAMPLE 6 0.166g (1.482 millimols) of potassium tertiary butylate is added to a mixture of 0.516 g (2.687 mil limols) of p-ionone and 0.550 g of 1, 1 - diethoxy - 3 methylpent - 3 - en - 5 - al in 1.5 ml of hexane, kept at 0"C. The reaction mixture is stirred for 1 hour at 0 C and is then treated as described in Example 1. 1.03 g of a crude product, which contains 57.6% w/w of C19 diethyi acetal, are thus obtained.
EXAMPLE 7 A solution of 0.1 g of tetrabutylammonium hydrox ide in 5.0 ml of 49% w/v aqueous sodium carbonate is added to a mixture, kept at 0"C, of 1.032 g (5.39 millimols) ofp-ionone and 1.500 g (18.06 millimols) of 1,1 -diethoxy-3-methylpent-3-en-5-al in 10.0 ml of hexane. After 30 minutes at 0 C 2.39 g of a product which contains about 34% w/w of Cl 9 diethyl acetal are isolated from the reaction mixture.
EXAMPLE 8 A mixture of 5 g (26.88 millimols) of 1, 1 - diethoxy - 3 - methylpent - 3 - en - 5 - al and 4.709 (24.48 millimols) of pseudoionone is added, over the course of 10 minutes, to a suspension of 0.5 g (9.26 millimols) of sodium methylate in 20.0 ml of hexane, kept at 0 C. After having been stirred for 30 minutes at 0"C, the reaction mixture is treated as described in Example 1. 9.19 g of an orange oily product are thus obtained, and the product is purified by liquid phase chromatography on a silica column to give 5.55 g of 1, 1 - diethoxy - 3, 11, 15 - trimethylhexadeca - 3, 5, 8, 10, 14 - pentaen - 7 - one, which has the following characteristics: ultraviolet spectrum:Amax = 340 nm; E1 /cm = 987 1 cm (isopropanol), determination of the ethoxy radicals (OC2HS) by the Zeisel method: calculated: 25.00%; found: 22.8% EXAMPLE 9 [Use ofa product according to the invention forpre paring retinene (vitamin A aldehyde)] A solution of methyl-magnesium chloride (pre pared from 1.34 g of magnesium) in 17 ml of anhydrous diethyl ether is added over the course of 40 minutes, at-30"C,to a solution of 5.88 g of purified C19 diethyl acetal (of 89% purity) in 20 ml of anhydrous diethyl ether. The reaction mixture is allowed to react for a further 15 minutes and is then poured into a solution of 0.59 g of sodium acetate 5 and 3.54 g of acetic acid in 47.2 ml of water.
After the phases have settled out and been sepa rated, 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 ml of a 3% w/v aqueous solution of sodium bicarbo nate. 5.81 g of 9 - (2', 6', 6' - trimethylcyclohex - 1' enyl) - 1,1 - diethoxy - 3,7 - dimethylnona - 3,5,8 trien - 7 - ol (hereinafter referred to as C20 diethyl hydroxyacetal) are thus isolated, having the foliow ing characteristics: ultraviolet spectrum: Ama, = 241 nm; E1 - 531 1cm (isopropanol).
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 and of 0.020 g of ionol is heated to the reflux temperature.0.6 ml of a hydrob romic acid solution (obtained by adding 1 ml 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; 51% = 853 1cm (isopropanol).
EXAMPLE 10 A solution of methyl-magnesium chloride (prepared from 2.58 g of magnesium) in 33 ml of an hydrous 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 reaction mixture is allowed to react for 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 400C, 17.72 g of 9 - (2', 6,6' trimethylcyclohex - 1' - enyl) - 1,1 - diethoxy - 3,7 - dimethylnona - 3, 5, 8 - trien - 7 - ol), (C20 diethyi hydroxyacetal) are obtained, having the following characteristics: ultraviolet spectrum: Amax = 241 nm; E1 /c m= about 530.
1 cm A solution, kept under a nitrogen atmosphere, of 6 g of C20 diethyl hydroxyacetal in a mixture of 144 ml of acetone containing 0.25% v/v of water, of 2.04 ml of water and of 0.06 g of ionol is heated to the reflux temperature. 1.8 ml of a hydrobromic acid solution (obtained by adding 1 ml of 48% w/v aqueous hydrobromic acid to 47 ml of acetone) are then added.
The reaction mixture is stirred under reflux, in a nitrogen atmosphere, for 22 minutes. After it has cooled, the reaction mixture is poured rapidly into 600 ml of distilled water. After stirring, followed by phase separation, the aqueous phase is extracted twice with 150 ml of hexane and then once with 75 ml of hexane, and the combined organic extracts are washed with 90 ml of a 5% w/v aqueous sodium bicarbonate solution and then twice with 90 ml of water. After drying over sodium sulphate, filtering and concentrating to dryness under reduced pressure, 4.63 g of retinene, having the following characteristics, are obtained: ultraviolet spectrum: Amax = 380 nm; 1 cm

Claims (16)

1. An ethylenic ketone 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 ketone according to claim 1 wherein R1 represents a methyl or ethyl radical.
3. 9 - (2', 6', 6' - Trimethylcyclohex - 1' - enyl) - 1, 1 - diethoxy - 3 - methyinona - 3, 5, 8 - trien - 7 - one.
4. 9-(2', 6', 6' -Trisnethylcyclohex -l'-enyl)-l,l - dimethoxy - 3 - methyinona - 3, 5,8 - trien - 7 - one.
5. 1,1 -Diethoxy-3, 41, 15-trimethylhexadeca- 3,5,8,10, 14-pentaen-7-one.
6. Process for the preparation of an ethylenic ketone of the general formula specified in claim 1 which comprises reacting a ketone of the general formula:
wherein R is as defined in claim 1 with an acetalaldehyde of the general formula:
wherein R, is as defined in claim 1, in the presence of an anionisation agentforthe ketone of general formula lX, in a solvent.
7. Process according to claim 6, in which the anionisation agent is a hydride, amide, alcoholate or hydroxide of an alkali metal.
8. Process according to claim 7 in which the alkali metal is sodium.
9. Process according to claim 6,7 or8 in which the anionisation agent is sodium methylate.
10. Process according to any one of claims 6 to 9 in which 0.05 to 1.5 mole of anionisation agent per mol of the ketone of general formula IX are used.
11. Process according to any one of claims 6 to 10 in which the anionisation agent is an alkali metal hydride, amide or alcoholate and the solvent is an aliphatic, cycloaliphatic or aromatic hydrocarbon, an ether, an alcohol, an amide, a nitrile or a halogenated hydrocarbon.
12. Process according to any one of claims 6,7,8 or 10 in which the anionisation agent is an alkali metal hydroxide and the reaction is carried out in water or a mixture of water and a water-miscible or -immiscible organic solvent.
13. Process according to any one of claims 6 to 12 in which the reaction is carried out at a temperature from -50 C to the boiling point of the reaction mixture.
14. Process for the preparation of an ethylenic ketone of the general formula specified in claim 1 substantially as herein before described.
15. Process for the preparation of an ethylenic ketone of the general formula specified in claim 1 substantially as hereinbefore described with especial reference to any one of Examples 1 to 8.
16. An ethylenic ketone as claimed in claim 1 when prepared by a process as claimed in any one of claims 6 to 15.
GB7928937A 1978-08-22 1979-08-20 Ethylenic ketones and a process for their preparation Expired GB2028818B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518722A1 (en) * 1991-06-14 1992-12-16 L'oreal Dithiane substituted retinoides, their use, process of their preparation, cosmetic and pharmaceutical compositions containing them and their use in therapeutics

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JPH0537521Y2 (en) * 1986-10-23 1993-09-22
JPS6429903U (en) * 1987-08-15 1989-02-22

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US2676988A (en) * 1951-09-11 1954-04-27 Eastman Kodak Co Method of making vitamin a and intermediates formed thereby
US2744142A (en) * 1952-08-08 1956-05-01 Ortho Pharma Corp Reduction process
FR1167007A (en) * 1954-02-04 1958-11-19 Alimentation Equilibree L Process for the preparation of an intermediate ketone compound in the synthesis of vitamin a and carotene
FR1243824A (en) * 1959-07-06 1960-10-21 Aec Chim Organ Biolog Process for the preparation of isoprenic compounds of the carotenoid family and novel intermediates resulting therefrom
NL128386C (en) * 1964-10-12
DE2053737A1 (en) * 1970-11-02 1972-05-10

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518722A1 (en) * 1991-06-14 1992-12-16 L'oreal Dithiane substituted retinoides, their use, process of their preparation, cosmetic and pharmaceutical compositions containing them and their use in therapeutics
FR2677650A1 (en) * 1991-06-14 1992-12-18 Oreal DITHIANE CYCLE SUBSTITUTED RETINOUIDS AND THEIR USE, PROCESS FOR THE PREPARATION OF SAID COMPOUNDS, COSMETIC AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, AND THERAPEUTIC USE OF THE SAME.
US5296505A (en) * 1991-06-14 1994-03-22 L'oreal Compositions of retinoids substituted with a dithiane ring, their use, and process for preparing the compounds

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DE2933996C2 (en) 1988-02-18
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CH639931A5 (en) 1983-12-15
JPS6411625B2 (en) 1989-02-27
JPS6326106B2 (en) 1988-05-27
GB2028818B (en) 1982-12-22
FR2434136A1 (en) 1980-03-21
FR2434136B1 (en) 1981-01-09
SU1068031A3 (en) 1984-01-15
DE2933996A1 (en) 1980-03-06

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