CH640494A5 - ETHYLENIC HYDROXY-ACETALS AND THEIR PREPARATION. - Google Patents

Description

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

r

A / W

ch (or1) 2

oh which R2 is an alkyl radical containing 1 to 4 carbon atoms, and a methyl ketone of general formula:

P— (Is) n _, - CH = CH — CO — CH3 (III)

5 in which P, Is and n are defined as above, to give a P-ketoacetal of general formula:

P - (Is) n_! - CH = CH - CO - CH2 - CH (OR2) 2 (IV)

in which P, Is, n and R2 are defined as above.

io By the action of an organometallic, the product of general formula (IV) is transformed into p-methyl-p-hydroxyacetal of general formula:

P - (Is) n _ [- CH = CH - C (CH3) - CH2 - CH (OR2) 2 (V) OH

In which P, Is, n and R2 are defined as above.

The transition from 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, passing through the retroacetal of general formula:

CH,

in which R and Rt are defined as in claim 1, and hydrolysis in an acid medium the organometallic complex thus obtained into the product according to claim 1.

3. Method according to claim 2, characterized in that the reaction is carried out in an organic solvent at a temperature between -50 and + 30 ° C.

4. Method according to claim 2, characterized in that the solvent is ethyl ether.

5. Use of a product according to claim 1 for the preparation of an aldehyde of general formula:

cho or, i

<CH-CH = C-Cll) = CH-CH = C-CH, -CH (OR) n-1 1 22

(VI)

in which n and R2 are defined as above.

Generally, dehydration and hydrolysis are carried out in acetone in the presence of aqueous hydrochloric acid.

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 a compound of general formula (II) in which n is equal to 1.

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

r v \

cho

(seen)

40

(I)

50

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

According to the present invention, the ethylenic hydroxyacetals of general formula (I) can be prepared by Grignard reaction between a compound of formula:

CH3-Z (VIII)

in which Z is lithium, a halogenomagnesium residue MgX or a halogenozinc residue ZnX, and an ethylenic ketone of general formula:

0

and their preparation process.

In the general formula (I), R represents a trimethyl-2,6,6-cyclohexen-1 -yl or dimethyl-2> 6-heptadien-1,5-yl radical, and Rt represents a linear or branched alkyl radical containing there 55 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:

P— (Is) n — CHO (11) 60

in which P is the trimethyl-2,6,6-cyclohexen-1-yl radical, Is is an isoprene residue

(—CH = CH — C = CH—)

ch3 65

and n is an integer equal to 1, 2 or 3, by Claisen reaction between an alkyl formate of general formula H-COOR2, in

R

ch

(»1» 2

(ix)

in which R and R! are defined as above.

To carry out the reaction correctly, it is essential to add the ketone of general formula (IX) to an excess of reagent CH3 —Z, in a suitable solvent such as diethyl ether, at a temperature between - 50 and + 30 ° C. The product of general formula (I) is released from its organometallic complex form by the action of a diluted ice-cold acid or by the action of a buffered solution of acetic acid, and is extracted by a suitable solvent such as hexane or diethyl ether.

The ethylenic ketone of general formula (IX) can be obtained by reacting a ketone of general formula:

r

/ V *

(x)

3

640,494

in which R is defined as above, on an acetalaldehyde of general formula:

oc h v 1 • ch (or.)

\ / \ / 1 2 (XI)

in which R! is defined as above.

Condensation takes place in the presence of an anionizing agent, 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 (X). 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 (X) used.

The nature of the solvent is indifferent, provided, however, that the solvent chosen is inert with respect to the reagents used. In general, such a solvent will be all the better if it is less polar. Of particular interest are liquid aliphatic hydrocarbons such as hexane, cycloaliphatic hydrocarbons such as cyclohexane, aromatics such as benzene, halogen derivatives such as dichloro-1,2-ethane, ethers such as ether diethyl, tetrahydrofuran or dioxane, alcohols such as me-thanol, nitriles such as acetonitrile, amides such as dime-thylformamide or N-methylpyrrolidone. When an alkali hydroxide is used, it is possible to operate in water, preferably in a water / organic solvent mixture, 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 (X).

For a given solvent, the anionization agent is chosen such that, in the presence of the ketone of general formula (X), the reaction mixture takes on a reddish brown to dark brown coloration.

Acetalaldehyde of general formula (XI) is used at a rate of 1 to 1.7 mol per mole of ketone of general formula (X) used.

The reaction temperature is not critical, 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 period of between A h and 4 h is suitable for obtaining a good yield of product of general formula (IX).

The product of general formula (IX) obtained 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 (IX) is extracted using an organic solvent such as l 'hexane.

The crude product obtained can be purified by physical methods such as molecular distillation.

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

Acetalaldehyde of general formula (XI) can be obtained by reacting, in the presence of a Lewis acid, an alcoyl orthoformate of general formula H — QOR ^, in which Rt is defined as above, with a dien- 1,3-oxysilane of general formula:

4-n 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 is an integer from 1 to 3.

The condensation of the alkyl orthoformate with the dienoxysilane can be carried out either in 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 (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 + 150 ° C., and preferably between 0 and 100 ° C. A temperature of between +10 and + 70 ° C. is very suitable. 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 halides of transition metals (metals from groups lb to 7b and 8 of the periodic table of elements: "Handbook of Che -mistry 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 × 10 -4 to 0.5 mol of Lewis acid, and in particular zinc or tin halide, per dienoxy group is sufficient to carry out the reaction. This amount is preferably between 1 x 10 "" 3 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 a few hours.

The products of general formula (XII) are generally known products which can be easily prepared by reaction of a mono-, di- or trihalosilane of general formula:

(R4) n-Si (X) 4_n (XIII)

in which R4 and n are defined as above and X represents a halogen atom (chlorine or bromine), with an aldehyde or an enolisable ketone a, ß- or ß.y ^ thytenique, in the presence of zinc chloride and a hydroacid acceptor, according to the process described in Belgian patent N ° 670,769.

The transition from the hydroxyacetal of general formula (I) to the aldehyde of general formula (VII), which comprises the dehydration of a tertiary alcohol and the hydrolysis of an acetal group via the retroacetal, can perform 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 halohydric 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 (I) to the aldehyde of general formula (VII) is preferably carried out in acetone with aqueous hydrochloric or hydrobromic acid.

When the radical R represents the trimethyl-2,6,6-cyclo-hexen-1-yl radical, the aldehyde of general formula (VII) can be reduced to vitamin A according to the usual known methods and, when R represents the radical 2,6-dimethyl-heptadien-1,5-yl, aldehyde

5

10

15

20

25

30

35

40

45

50

55

60

65

640,494

general formula (VII) can be transformed into lycopene by duplication according to known methods.

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

Example 1:

To a solution of 5.88 g of (trimethyl-2 ', 6', 6'-cyclohexen-r-yl) -9-diethoxy-1,1-methyl-3-nonatrién-3,5,8-one- 7 (or purified C19 diethyl acetal) titrating 89% in 20 cm3 of anhydrous diethyl ether, a solution of methylmagnesium chloride (prepared from 1.34 g of magnesium) is added at -30 ° C. in 40 min. in 17 cm3 of anhydrous ether. Let react for another 15 min,

then pour the reaction mixture into a solution of 0.59 g of sodium acetate and 3.54 g of acetic acid in 47.2 cm3 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 (tri-methyl-2 ', 6', 6'-cyclohexen-r-yl) -9-diethoxy-1,1,1-dimethyl-3,7-nona-trien-3,5 are thus isolated. , 8-ol-7 (or hydroxyethyl C20 diethyl), the characteristics of which are as follows:

Ultraviolet spectrum: Xmax = 241 nm E} 0 ^ = 531 (isopropanol).

Diethyl C19 acetal, used as a starting material, can be prepared as follows:

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 diethoxy-1.1 is added. -methyl-3-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, then with water until neutral.

The combined organic phases are dried over anhydrous sodium sulphate, then concentrated to dryness under reduced pressure (12 mm Hg) to a constant weight. 54.1 g of an orange oil are thus obtained which contains, according to the assay by high pressure liquid chromatography with internal standard, 63.3% of diethyl Cl 9 acetal and 8% of β-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 Ej ^ = 683 (isopropanol).

Determination of ethoxy radicals (OC2H5) by the Zeisel method:

Calculated: 25%. 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

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 Hg, the light products and the solvent. 10.9 g of trimethylsilyloxyethane 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 dose 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 Hg. After rectification, the diethoxy-1,1-methyl-3-penten-3-al-5 is in the form of a pale yellow liquid, boiling at 73 ° C. under 0.2 mm Hg and having a refractive index n2 ^ = 1.4602.

Example 2:

To a solution of 17 g of (trimethyl-2 ', 6', 6'-cyclohexen-ryl) -9 diethoxy-1,1-methyl-3-nonatrién-3,5,8-one-7 (or acetal C19 -diethyli-que), purified by molecular distillation and titrating 81% in 55 cm3 of anhydrous diethyl ether, a solution of methylmagnesium chloride (prepared from 2.58 g) is added at -25 ° C over 1 hour. magnesium) in 33 cm3 of 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 cm3 of water, 9.43 cm3 of concentrated hydrochloric acid (d = 1.19) and 10 cm3 of diethyl ether, keeping 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'-cyclohexên-r-yl) -9-diethoxy are obtained -1.1-dimethyl-3,7-nonatrién-3,5,8-ol-7 (or diethyl C20 hydroxyacetal), the characteristics of which are as follows:

Ultraviolet spectrum: Xmax = 241 nm E) "^ = close to 530.

Example 3:

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

A solution, maintained under a nitrogen atmosphere, of 2.0 g of diethyl hydroxyacetal C20 is heated to reflux in a mixture of 48.0 cm3 of acetone with 0.25% water and 0.68 cm3 of water containing 0.025 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). 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 a 5% aqueous sodium bicarbonate solution, then until neutral with 25 cm3 of water, then dried over sodium sulfate . After filtration and concentration to dryness under reduced pressure (12 then 1 mm Hg), 1.69 g of retinene are obtained, the characteristics of which are as follows:

Ultraviolet spectrum: Xmax = 380 nm E} "^ = 853 (isopropanol).

4

5

10

15

20

25

30

35

40

45

50

55

R

Claims (3)

640,494 2 (or1> 2 1. Ethylene hydroxyacetal, characterized in that it corresponds to the general formula:. E ^ vk / vv '° " oh in which R represents a trimethyl-2,6,6-cyclohexen-l-yl or dimethyl-2,6-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 ethylene hydroxyacetal according to claim 1, characterized in that a gold-ganometallic derivative of general formula CH3Z is reacted, in which Z is lithium, a halogenomagnesium residue MgX or a halogen residue zinc ZnX, X being a halogen atom, on an ethylenic ketone of general formula: .ch (° R1> 2 r / nn characterized in that a product according to claim 1 is dehydrated and hydrolyzed, wherein R is defined as in claim 1. 6. Use according to claim 5, characterized in that the dehydration and hydrolysis are carried out in acetone with aqueous hydrochloric or hydrobromic acid.