CH639931A5 - ETHYLENIC KETONES AND THEIR PREPARATION. - Google Patents

Description

The present invention relates to new ethylenic ketones of general formula:

Q

50

r

// \ //

CH (OR1> 2 (I)

in which R3 represents a methyl or ethyl radical.

The products which are the subject of the present invention are particularly advantageous intermediates for preparing the aldehydes of general formula:

and their preparation process.

In the general formula I, R represents a 2,6,6,6-trimethyl cyclohexen-1 yl or 2,6-dimethyl heptadien-1,5 yl radical and Rt represents a linear or branched alkyl radical containing 1 to 4 carbon atoms.

In French patent No. 1243824, a process has been described for the preparation of substances from the carotenoid family of general formula:

(VI)

CHO

R X ^ VVV

in which R is defined as above, which are themselves known as intermediates for preparing, according to the significations of R, vitamin A or lycopene.

According to the present invention, the ethylenic ketones of general formula I can be prepared by reacting a ketone of general formula:

P— (Is) n — CHO

(II)

r-ZX / ^ N.

(VII)

in which P is the 2,6,6-trimethyl cyclohexen-1 yl radical, Is is an isoprene residue in which R is defined as above, on an acetalaldehyde of general formula:

3

639,931

0CH \ / \ /

ch (or1) 2

(VIII)

in which Rj is defined as above.

The condensation takes place in the presence of a ketone anionizing agent of general formula VII in an appropriate solvent and at a suitable temperature.

The anionization agent is a basic agent having sufficient activity to anionize the ketone of general formula VIII. As an anionization agent, a hydride, amide, alcoholate or hydroxide of an alkali metal, preferably sodium, is generally used. Sodium methylate is particularly suitable. It is advantageous to use from 0.05 to 1.5 mol of anionization agent per mole of ketone of general formula VII.

The nature of the solvent is indifferent, provided however that the solvent is inert with respect to the reagents used.

In general, such a solvent will be all the better if it is less polar. Of very particular interest are liquid aliphatic hydrocarbons such as hexane, cycloaliphatics such as cyclohexane, aromatics such as benzene, halogenated derivatives such as 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran or dioxane, alcohols such as ethanol, nitriles such as acetonitrile, amides such as dimethylformamide or N-methylpyrrolidone. When an alkali hydroxide is used, it is possible to operate in water or, preferably, in a mixture of water with a miscible or immiscible organic solvent optionally in the presence of a quaternary ammonium hydroxide ( tetrabutylammonium hydroxide). In all cases, it is preferable to vigorously stir the reaction mixture. Generally, 3 to 10 volumes of solvent are used relative to the ketone of general formula VII.

For a given solvent, the anionization agent is chosen such that, in the presence of the ketone of general formula VII, the reaction mixture takes on a brown-red to dark brown coloration.

Acetalaldehyde of general formula VIII is used in an amount of 1 to 1.7 mol of ketone of general formula VII used.

The reaction temperature is not critical, and it is possible to operate between -50 ° C and the reflux temperature of the reaction mixture, and preferably between -30 and + 60 ° C.

The duration of the reaction can vary within fairly wide limits and depends essentially on the reagents used. Generally, a time between% and 4 h is suitable for obtaining a good yield of product of general formula I.

The product of general formula I obtained according to the process of the present invention can be isolated according to the usual methods. Generally, the reaction mixture, if necessary after cooling, is poured into water optionally containing an acid such as acetic acid, and the product of general formula I is extracted using an organic solvent such as hexane .

The crude product obtained can then be purified, for example by molecular distillation.

The product of general formula I can be assayed in the crude product or in the purified product according to analytical methods such as high pressure liquid chromatography with internal standard.

The ketone of general formula VII, in which R represents the 2,6,6,6-trimethyl cyclohexen-1 yl radical, is β-ionone, and that in which R represents the 2,6-dimethyl heptadien-1,5 yl radical is pseudo-ionone.

Acetalaldehyde of general formula VIII can be obtained by reacting, in the presence of a Lewis acid, an alkyl orthoformate of general formula:

H-QOR ^ (IX)

with a dith-1,3 oxysilane of general formula:

in which R4 represents a hydrocarbon radical and more particularly a linear or branched alkyl radical containing 1 to 4 carbon atoms, cycloalkyl such as cyclopentyl or cyclo-hexyl, phenyl or aralkyl such as benzyl or P-phenylethyl, and n 5 is a number integer from 1 to 3.

The condensation of orthoformate with dienoxysilane can be carried out indifferently within an organic solvent inert with respect to the reagents used or in the absence of any solvent. In the first case, we can use aliphatic hydrocarbons io (hexane, heptane), cycloaliphatic (cyclohexane), aromatic (benzene), ethers (ethyl oxide, tetrahydrofuran), halogenated derivatives (methylene chloride, chloroform ), nitriles (acetonitrile, propionitrile), carboxamides (dimethylformamide, dimethylacetamide, N-methylpyrrolidone).

The temperature at which the reaction is carried out can vary within wide limits depending on the reagents used, the nature and the amount of catalyst. In general, one operates between -40 and 4-150 ° C and preferably between 0 and 100 ° C. A temperature between +10 and + 70 ° C is fine. However, one can operate outside these limits. The pressure can be equal, higher or lower than atmospheric pressure.

As Lewis acids which can be used as catalysts, mention may be made of boron halides and their complexes with ethers, and the halides of transition metals (metals from groups lb to 7b 25 and 8 of the periodic table of elements: "Handbook of Chemistry and Physics ”, 53rd edition, published by The Chemical Rubber Co). Zinc and tin halides are particularly suitable and are used preferentially. This is the case with zinc chloride and bromide, stannous and stannous chlorides and bromides.

The amount of catalyst, expressed in number of moles 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 zinc and tin halide, per dienoxy group is sufficient to complete the reaction. This amount is preferably between 1 × 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 between a few minutes and some 40 hours.

The products of general formula X are generally known products which can be easily prepared by reaction of a monodi- or trihalosilane of general formula:

45

(R4) n-Si (X) 4.

(XI)

in which R4 and n are defined as above and X represents a halogen atom (chlorine or bromine) with an aldehyde or an enolizable ketone a, ß- or p, y-ethylenic, in the presence of zinc chloride and a hydracid acceptor according to the process described 50 in Belgian patent N ° 670769.

The transformation of a product of general formula I into an aldehyde of general formula VI can be carried out by Gri-gnard reaction between a compound of formula:

d5 CH3-Z (XII)

in which Z is lithium, a halogenomagnesium residue Mg — X or a halozinc residue Zn — X and an ethylenic ketone of general formula I, followed by dehydration and hydrolysis of the product obtained after release of the hydroxyacetal of general formula - »line:

R

CH (OR1) 2

(XIII)

OH

O.

If (R.) 4 n

Pq 65 in which R and Rj are defined as above, of the organometallic complex formed.

To correctly carry out the Grignard reaction, it is essential to add the ethylenic ketone of general formula I to a

639,931

4

excess of reagent of general formula XII in a suitable solvent such as diethyl ether at a temperature between -50 ° and + 30 C. The product of general formula XIII is released from its form. organometallic complex by the action of a diluted ice-cold acid or by the action of a buffered solution of acetic acid and is extracted with an appropriate solvent such as hexane or diethyl ether.

The transition from the hydroacetal of general formula XIII to the aldehyde of general formula VI, which comprises the dehydration of a tertiary alcohol and the hydrolysis of an acetal group by passing through the retroacetal in-term, can take place in one or more steps. It is conventional to carry out the dehydration of a tertiary alcohol with a mineral acid. The hydrolysis of an acetal can be carried out by an aqueous hydrochloric acid in an organic solvent miscible with water where the product to be treated and the acid are soluble. For this purpose, acetone is particularly suitable. The transition from the hydroxyacetal of general formula XIII to the aldehyde of general formula VI is preferably carried out in acetone with aqueous hydrochloric or hydrobromic acid.

When R represents the 2,6,6-trimethyl cyclohexen-1 yl radical, the aldehyde of general formula VI can be reduced to vitamin A according to the usual known methods and, when R represents the 2,6-dimethyl heptadien-1 radical , 5 yl, the aldehyde of general formula VI can be transformed into lycopene after duplication according to known methods.

The following examples, given without limitation, show how the invention can be put into practice.

Example 1

To a suspension cooled to 0 ° C. of 2.10 g (38.9 mmol) of sodium methylate in 150 cm3 of anhydrous hexane, a mixture of 30 g (161 mmol) of 1,1 diethoxy is added. 3-methyl-penten-3 al-5 and 28.14 g (147 mmol) of ß-ionone.

After 30 min of stirring at a temperature close to 0 ° C, the reaction mixture is poured into about 300 cm3 of water containing 2% acetic acid. The aqueous phase, whose pH is between 4 and 5, is extracted with 300 cm3 of hexane. The organic layer is washed with 150 cm3 of an aqueous solution of sodium bicarbonate 5% (w / v), then with water until neutral. The combined organic phases are dried over anhydrous sodium sulphate, then concentrated to dryness under reduced pressure (12, then 1 mm of mercury) to a constant weight. 54.1 g of an orange oil are thus obtained which contains, according to the determination by high pressure liquid chromatography with internal standard, 63.3% of (trimethyl-2 ', 6', 6 'cyclohexen-1' yl) -9 diethoxy-1,1 methyl-3 nonatrién-3,5,8 one-7 (or diethyl C19 acetal) and 8% of ß-ionone.

The conversion rate is 84% and the yield relative to the β-ionone consumed is 80.5%.

After purification by high pressure liquid chromatography, diethyl acetal C19 is obtained, the characteristics of which are as follows:

- ultraviolet spectrum: Xmax = 330 nm, E} "^ = 683 (isopropanol)

- determination of ethoxy radicals (OC2H5) by the Zeisel method:

calculated: 25.00% found: 23.37%.

Diethoxy-1,1-methyl-3-penten-3 al-5 can be prepared as follows:

22.2 g of ethyl orthoformate (1.5 x 10) are placed in a 250 cm3 three-necked flask fitted with a stirrer, a condenser and a dropping funnel. -1 mol), 0.37 g of molten zinc chloride (2.76 x 10-3 mol) and 50 cm3 of anhydrous acetonitrile. Stirred and then added, in 5 min, 23.4 g of trimethylsilyloxy-1 methyl-3-butadiene-1,3 (1.5 x 10 ~ 1 mol) dissolved in 15 cm3 of anhydrous acetonitrile. We heat. The reflux is established at 76 ° C. After 45 min of heating, the mixture is cooled to 50 ° C. and distilled, trapping, under 20 mm of mercury, the light products formed and the solvent. 10.9 g of trimethylsilyl-oxyethane are measured and identified by vapor phase chromatography in the distillate and the trap.

The residue is dissolved in 50 cm3 of diethyl ether and neutralized by the addition of 25 cm3 of a saturated aqueous solution of sodium bicarbonate. The organic phases are decanted, washed with 25 cm3 of distilled water and dried over potassium carbonate. After filtration and concentration to dryness, the quantity is determined and identified by infrared spectrography, vapor chromatography and nuclear magnetic resonance 19 g of diethoxy-1,1-methyl-3-penten-3 al-5 in a distilling fraction between 75 and 80 ° C under 0.3 mm of mercury.

After rectification, 1,1-diethoxy-3-methyl-penten-3 al-5 is in the form of a pale yellow liquid, boiling at 73 ° C under 0.2 mm of mercury and having a refractive index n2 ^ = 1.4602.

Example 2

To a solution, cooled to 0 ° C., of 1.105 g (5.755 mmol) of ß-ionone and of 1 g (6.33 mmol) of 1,1-dimethoxy-3-methyl-penten-3 al-5 in 6.5 cm3 of cyclohexane, 0.171 g (3.16 mmol) of sodium methylate is added. The mixture is stirred for 1 hour at 0 ° C. By operating in the same manner as in Example 1, 1.99 g of an orange-brown oily product is isolated which contains 67.4% of (trimethyl-2 ', 6', 6 'cyclohexen-1' yl ) -9 dimethoxy-1,1 methyl-3atriatrien-3,5,8 one-7 (or dimethyl C19 acetal) and about 4% of ß-ionone.

Dimethoxy-1,1-methyl-3-penten-3 al-5 can be prepared as follows:

13.25 g of methyl orthoformate (1.25 x 10) are placed in a 250 cm3 three-necked flask fitted with a stirrer, a condenser and a dropping funnel. ~ 1 mol), 0.312 g of zinc chloride (2.3 x 10 ~ 2 mol) and 40 cm3 of anhydrous acetonitrile. To the mixture, kept stirring, a solution of 19.5 g of trimethylsilyloxyisoprene (1.25 × 10 −1 mol) in 15 cm 3 of anhydrous acetonitrile is added over 5 min. The mixture is heated to reflux. After 1 h 10 min, it is checked by thin layer chromatography that all the trimethylsilyloxyisoprene has disappeared. The reaction mixture is cooled and the acetonitrile is removed by distillation under reduced pressure (20 mm of mercury). The residue is neutralized by adding 50 cm3 of a saturated sodium bicarbonate solution, then 25 cm3 of diethyl ether are added. The organic phase is separated, dried over potassium carbonate, then concentrated to dryness. By distillation of the residue, 12.5 g of dimethoxy-

1.1 3-methyl-penten-3 al-5 (m.p. 0 4 = 70-75 ° C).

Example 3

To a suspension, cooled to 0 ° C., of 0.65 g (9.56 mmol) of sodium ethyl acetate in 25 cm 3 of hexane, a mixture of 5.0 g (26.0 mmol) is added diethoxy-1,1-methyl-3-penten-3 al-5 and 4.69 g (24.4 mmol) of ß-ionone. After having stirred for 30 min at 0 ° C., the reaction mixture is treated as in Example 1. This gives 9.04 g of a crude product which contains 63.1% of diethyl C19 acetal.

Example 4

By operating as in Example 3, but replacing the sodium ethylate with 0.65 g (9.3 mmol) of potassium methylate, we obtain 9.05 g of a product containing 49% C19 acetal diethyl.

Example 5

To a mixture of 0.516 g (2.687 mmol) of ß-ionone and 0.140 g (1.458 mmol) of sodium tert-butoxide in 3 cm 3 of hexane, kept at 0 ° C., 0.550 g (2.957 mmol) of diethoxy is added. 1.1 methyl 3-penten-3 al-5. The mixture is stirred for 3 h at 0 ° C., then the reaction mixture is treated as described in Example 1. This gives

1.02 g of crude diethyl Cl9 acetal.

Example 6

To a mixture of 0.516 g (2.687 mmol) of ß-ionone and 0.550 g of diethoxy-1,1-methyl-3-penten-3 al-5 in 1.5 cm3 of hexane, kept at 0 ° C, is added 0.166 g (1.482 mmol) of potassium tert-butoxide. The mixture is stirred for 1 hour at 0 ° C., then the reaction mixture is treated as described in Example 1. This gives 1.03 g of crude product which contains 57.6% diethyl C19 acetal.

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Example 7

At a mixture, maintained at 0 ° C, of 1.032 g (5.39 mmol) of ß-ionone and of 1.500 g (18.06 mmol) of 1,1-diethoxy-3-methyl-penten-3 al-5 in 10 , 0 cm3 of hexane, a solution of 0.1 g of tetrabutylammonium hydroxide in 5.0 cm3 of 49% aqueous sodium hydroxide is added. After maintaining the reaction mixture for 30 min at 0 C, 2.39 g of a product is isolated which contains about 34% of diethyl C19 acetal.

Example 8

To a suspension of 0.5 g (9.26 mmol) of sodium methylate in 20.0 cm3 of hexane maintained at 0 ° C., a mixture of 5 g (26.88 mmol) of diethoxy is added over 10 min. -1.1 methyl-3 penten-3 al-5 and 4.70 g (24.48 mmol) of pseudo-ionone. After 30 min of stirring at 0 ° C, the reaction mixture is treated as described in Example 1. This gives 9.19 g of an orange oily product which is purified by liquid chromatography on a silica column. 5.55 g of diethoxy-1,1 trimethyl-3,11,15 hexa-decapenten-3,5,8,10,14 one-7 are thus obtained, the characteristics of which are as follows:

- ultraviolet spectrum: Xrnax = 340 nm, = 987 (isopropanol)

- determination of ethoxy radicals (OC2H5) by the Zeisel method:

calculated: 25.00% found: 22.8%.

Use of a product according to the invention for preparing the retinene or aldehyde of vitamin A:

Example 9

To a solution of 5.88 g of purified diethyl C19 acetal (titrating 89%) in 20 cm3 of anhydrous ether, a solution of methylmagnesium chloride (prepared from 1.34 g magnesium) in 17 cm3 of anhydrous ether. The reaction medium is left to react for another 15 min and then the reaction mixture is poured into a solution of 0.59 g of sodium acetate and 3.54 g of acetic acid in 47.2 cm 3 of water.

After decantation and separation, the aqueous phase is extracted with 60 cm3 of ethyl ether. The combined organic phases are washed with 15 cm3 of water, then twice with 15 cm3 of an aqueous solution of sodium bicarbonate at 3% (w / v). 5.81 g of (trimethyl-2 ', 6', 6 'cyclohexen-1' yl) -9 diethoxy-1,1 dimethyl-3,7 nonatrién-3,5,8 ol-7 or (hydroxyacetal) are thus isolated. C20 diethyl), the characteristics of which are as follows:

- ultraviolet spectrum: Xmax = 241 mm, Ej "^ ,, = 531 (isopropanol).

A solution, maintained under a nitrogen atmosphere, of 2.0 g of diethyl hydroxyacetal C20 in a mixture of 48.0 cm3 of acetone with 0.25% water, of 0.68 is heated to reflux. cm3 of water and 0.020 g of ionol. 0.6 cm3 of a hydrobromic acid solution is then quickly added (obtained by adding 1 cm3 of 48% aqueous hydrobromic acid to 47 cm3 of acetone).

639,931

After cooling, the reaction mixture is poured into 150 cm3 of water. After two extractions with 50 cm3 of hexane, the combined organic phases are washed with 50 cm3 of an aqueous solution of sodium bicarbonate at 5% (w / v) then until neutral with 25 cm3 of water, then dried on sodium sulfate. After filtration and concentration to dryness under reduced pressure (12 then 1 mm of mercury), 1.69 g of retinene are obtained, the characteristics of which are as follows:

- ultraviolet spectrum: Xmax = 380 nm, Ej ° ç ° m = 853 (isopropanol). Example 10

To a solution of 17 g of (trimethyl-2 ', 6', 6 'cyclohexen-1' yl) -9 diethoxy-1,1 methyl-3 nonatrien-3,5-8 one-7 (or diethyl C19 acetal) purified by molecular distillation and titrating 81% in 55 cm3 of anhydrous diethyl ether, a solution of methylmagnesium chloride (prepared from 2.58 g of magnesium) in 33 cm3 is added at -25 ° C in 1 h anhydrous diethyl ether. The reaction is left to react for a further 15 min, then the reaction mixture is poured over 10 min into a solution consisting of 83 cm 3 of water, 9.43 cm 3 of concentrated hydrochloric acid (d = 1.19) and 10 cm 3 diethyl ether, maintaining the temperature between 0 and 5 ° C. After decantation and separation, the organic phase is washed with 30 cm3 of water, twice with 30 cm3 of water containing 0.85 g of sodium bicarbonate, then with 30 cm3 of water containing 0.12 g of sodium bicarbonate sodium. The ethereal solution is dried over sodium sulfate.

After filtration and concentration to dryness under reduced pressure at a temperature between 35 and 40 ° C., 17.72 g of (trimethyl-2,6 ', 6'-cyclohexen-1' yl) -9 diethoxy-1 are obtained, 1 dimethyl-3,7 nonatrién-3,5,8 ol-7) or hydroxyacetal C20 diethyl whose characteristics are the following:

- ultraviolet spectrum: Xmax = 241 nm, Ej = close to 530.

A solution, maintained under a nitrogen atmosphere, of 6 g of diethyl hydroxyacetal C20 is heated until reflux in a mixture of 144 cm3 of acetone at 0.25% water, of 2.04 cm3 of water and 0.06 g of ionol. 1.8 cm3 of a hydrobromic acid solution are then quickly added (obtained by adding 1 cm3 of 48% aqueous hydrobromic acid to 47 cm3 of acetone). The reaction mixture is stirred at reflux under a nitrogen atmosphere for 22 min. After cooling, the reaction mixture is poured quickly into 600 cm3 of distilled water. After stirring followed by decantation, the aqueous phase is extracted twice with 150 cm3 of hexane, then once with 75 cm3 of hexane, the combined organic extracts are washed with 90 cm3 of an aqueous solution of sodium bicarbonate at 5 %, then twice per 90 cm3 of water. After drying over sodium sulfate, filtration and concentration to dryness under reduced pressure, 4.63 g of retinene are obtained, the characteristics of which are as follows:

- ultraviolet spectrum: Â, max = 380 nm, Ej ° çm = 956.

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Claims (8)

639,931 1. Ethylene ketone, characterized in that it corresponds to the general formula: 0 r V \ // CH (OR) in which R represents a 2,6,6,6-trimethyl cyclohexen-1 yl or 2,6-dimethyl heptadien-1,5 yl radical and Rj represents a linear or branched alkyl radical containing 1 to 4 carbon atoms. 2. Process for the preparation of an ethylenic ketone according to claim 1, characterized in that a ketone of general formula is reacted: r // N / ^ \ in which R is defined as in claim 1 on an acetaldehyde of general formula: OCH ch (or1) 2 ch3 and n is an integer equal to 1,2 or 3, by Claisen 5 reaction between an alkyl formate of general formula H-COOR2 in which R2 represents an alkyl radical containing 1 to 4 carbon atoms on a methyl ketone of formula general: P- (Is) n_1-CH = CH-CO-CH3 (III) 10 in which P, Is and n are defined as above, to give a P-ketoacetal of general formula: P - (Is) n-1 - CH = CH - CO - CH2 - CH (OR2) 2 (IV) in which R! is defined as in claim 1, in the presence of an anionizing agent in a suitable solvent. 2 (—CH = CH —C = CH—) 3. Method according to claim 2, characterized in that the anionization agent is chosen from hydrides, amides, alcoholates or hydroxides of alkali metals. 4. Method according to claim 3, characterized in that the alkali metal is sodium. 5. Method according to claim 3, characterized in that the anionization agent is sodium methylate. 6. Method according to claim 2, characterized in that one uses a solvent chosen from aliphatic, cy-cloaliphatic, aromatic hydrocarbons, ethers, alcohols, amides, nitriles, or halogenated derivatives when the agent anionization is a hydride, an amide, or an alkali metal alcoholate. 7. Method according to claim 2, characterized in that a homogeneous or heterogeneous mixture containing water and an organic solvent is used as solvent when the anionizing agent is an alkali hydroxide. 8. Method according to claim 2, characterized in that the reaction is carried out at a temperature between - 50 ° C and the boiling temperature of the reaction mixture. in which P, Is, n and R2 are defined as above, which is transformed into a product of general formula II by passing intermediarily through a P-methyl-P-hydroxyacetal obtained by the action of an organometallic compound. According to this process, it is necessary, to prepare the aldehyde of vitamin A or retinene, from a product of general formula III in which n is equal to 2. This itself is obtained according to the process which is described in French patent N ° 1167007 starting from the compound of general formula II in which n is equal to 1. It is also known, from French patent No. 71.36598 published under the number 2113010, to prepare enamine ketones of general formula: X- N (V) in which A represents, inter alia, a 2,6,6,6-trimethylcyclohexen-1 yl radical and X represents an olefinic hydrocarbon group of formula: in which the symbols R3, which are identical or different, represent a hydrogen atom or a methyl or ethyl radical. This patent does not give an example of preparation of a product of gene-45 formula IV line in which X represents a group.