BE513954A - - Google Patents

Description

       

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  PROCESS FOR PREPARATION OF POLYENE ALDEHYDES AND ITS APPLICATIONS
IN PARTICULAR TO THE PREPARATION OF VITAMIN A.



   The present invention relates to a process for preparing polyene 1-cyclo-hexene-1-yl aldehydes with an alpha-beta double bond and, more particularly but not exclusively, to the preparation of the aldehyde of vitamin A and to the applications. of said process, in particular for the preparation of vitamin A.



   Substances that exhibit high biological activity of vitamin A type, are characterized by a specific basic structure and differ from each other only in the nature of the terminal group. Thus the substance can be an ester, an acid, an alcohol, an aldehyde, an ether etc ..., but it must always have the fundamental structure represented by the formula (I).
 EMI1.1
 where Z is a group -CH2OH, -COOH, -CHO, -COOR, -CH2OR, etc. .., R being a hydrocarbon radical.

   All! change in the position of a double bond itself, or the saturation of one of the double bonds, or the change in position of a substituted methyl group, or the addition of another substitution group has the effect of considerably reduce or de-

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 completely destroy the characteristic biological activity of vitamin A of the substance under consideration.



   For these reasons, the synthesis of vitamin A presents difficulties, in particular as a result of the fact that substances of the vitamin A series are unstable and decompose or isomerize easily. Thus, most of the syntheses of vitamin A which have been proposed involve a Reformatsky reaction or a Grignard reaction leading to a hydroxyl compound, generally an ester, the type of which is the ester of 1 '. [alpha], ss -dihydro- ss -hydroxy-vitamin A of formula (II)
 EMI2.1
 or the diol of formula (III)
 EMI2.2
 or the ester of hydroxy- -ionylidene-acetic acid of formula (IV)
 EMI2.3
 
By dehydration of these hydroxyl compounds,

   only a small fraction dehydrates to give the desired alpha-beta double bonded compound and the balance dehydrates by affecting the ring and giving a 2-cyclo-hexene-1-ylidene compound which is the isomer of the desired compound.



  The conversion of the unwanted isomer to the desired compound is expensive and time consuming due to the formation of an equilibrium during isomerization, which necessitates separation and recycling. Therefore, dehydration of the ester of [alpha], ss -dihydro- -hydroxy-vitamin A, a substantial fraction of the product has the formula (V)
 EMI2.4
 and the dehydration product of the diol comprises two possible isomers next to the desired vitamin A ester,

   which are

 <Desc / Clms Page number 3>

 
 EMI3.1
 while the ester of hydroxy- -ionylidene-acetic acid dehydrates to give the isomer
 EMI3.2
 
The displacement of the double bonds and the interposition of a -CH2- group in the chain give compounds largely devoid of the characteristic biological activity of vitamin A and from which it is difficult to obtain the compounds. research.



   Consequently, the subject of the invention is a process which makes it possible in particular: to prepare, in an improved manner, completely conjugated polyene 1-cy-clohexene-1-yl compounds with an alpha-beta double bond; - converting the unwanted isomers of the compounds of the vitamin A series to the desired compounds; - to facilitate the syntheses of vitamin A which involve a Grigard reaction, a Reformatsky reaction or a similar reaction giving a hydroxylated compound which ordinarily dehydrates in an undesirable manner;

   - converting unwanted isomers of the vitamin A series with a high yield into compounds with conjugated double bonds, one of which is alpha-beta; - Preparing polyene 1-cyclo-hexene-1-yl aldehydes with an alpha-beta double bond from the -cyclohexene-1-ylidene isomers of these aldehydes; - to prepare the aldehyde of vitamin A, a compound having the structure of vitamin A from a product of the same chemical composition as the aldehyde of vitamin A, but of different structure; - converting a product without vitamin A activity into vitamin A aldehyde;

   - to increase the yield of vitamin A in the syntheses which implement the dehydration of a hydroxylated compound, thanks to the possibility offered by said process of modifying the structure of the compound which results

 <Desc / Clms Page number 4>

 of this dehydration; - converting relatively inactive polyene ethers, whether monoethers or diethers (or acetals) into vitamin A alcohol;

   - a new synthesis of vitamin A alcohol via the aldehyde of vitamin A. -
The process according to the invention is remarkable in particular in that a 2-cyclohexene-1-ylidenic aldehyde of formula (VIII) is treated with a basic catalyst.
 EMI4.1
 where R is an unsaturated aliphatic hydrocarbon radical of at least five carbon atoms whose chain contains only one -CH2- group, said group being in an even position from the ring, which converts the 2- aldehyde cyclohexene-1-ylidene to a fully conjugated polyene 1-cyclohexene-1-yl aldehyde, with an alpha-beta double bond and not containing a -CH2- group in the aliphatic hydrocarbon radical.
The Applicant has discovered that, against acids, esters and ethers of the vitamin A series,

   aldehydes readily transpose to the desired fully conjugated, alpha-beta double bonded structure when treated with a catalytic amount of a basic character product and the yield of such transposition is almost quantitative, without formation of a mixture in equilibrium.



   Thus, by applying the process according to the invention, it is possible to carry out syntheses of vitamin A by passing through stages in which dehydration of hydroxyl compounds takes place during which the isomerization of the unsaturated bonds takes place. normally produced, provided that the terminal group is an aldehyde group or is readily convertible to an aldehyde group, which allows easy rearrangement of the compounds to result in the desired structure.



   The invention applies in particular to the preparation of ss -ionylidene-acetaldehyde and it is particularly useful for the preparation of vitamin A aldehyde which can easily be reduced to vitamin A alcohol.



   The 2-cyclohexene-1-ylidene compounds treated in accordance with the invention, of the aforementioned formula VIII, contain from five to ten carbon atoms in the aliphatic hydrocarbon radical R. The aliphatic chain contains only one -CH2- group and this group is in the even position from the ring. In the case of a radical with ten carbon atoms, the radical contains a substituted methyl group on the carbon atoms at the 3 and 7 position from the ring. In the other shorter chain compounds, a substituted methyl group is attached to the third carbon atom from the ring.



   Preferably, for carrying out the process according to the invention, the 2-cyclohexene-1-ylidene aldehyde is dissolved in an organic solvent, such as benzene, toluene, petroleum ether, ethyl ether, etc. The conversion to the desired 1-cyclohexene-1-yl aldehyde is advantageously promoted by basic catalysis. Any of the known products of a basic character can be used, whether organic or

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 inorganic. Among the suitable products, there may be mentioned inorganic hydroxides, salts of strong bases and weak acids, organic bases such as amines, etc. The amount of basic product is not critical, traces being sufficient to catalyze the transposition according to the invention.



   Among the typical basic products which are suitable as catalysts, there may be mentioned sodium hydroxide, potassium hydroxide, potassium acetate, sodium acetate, pyridine, lutidine, picolines, lutidine aniline, morpholine, double sodium aluminum silicate, sodium ethoxide, aluminum alkoxides, ammonium hydroxide, piperidine, alkaline soaps, etc ...



   According to the invention, the 2-cyclohexene-1-yli- denic aldehydes which are, to a large extent, devoid of vitamin A activity are transposed, by means of a basic catalysis, into the aldehyde of vitamin A which is easily reduced to vitamin A alcohol by conventional methods of reducing aldehydes to alcohols.



   The invention is illustrated by the following examples of preferred embodiments of the invention.



  EXAMPLE 1.-
 EMI5.1
 0.58 g of 9- (2,6,--trimethyl-2lyclohexpne-1-ylidin) 3,7-dimethyl-2,1,6-nonatrïene-1-al, absorption EIcm (328 m, .tV) = 900, in 100 cm3 of petroleum ether and the solution is passed through a colone of double silicate of sodium and synthetic aluminum. After washing the column with new quantities of petroleum ether, 0.50 g of vitamin A aldehyde with absorption E1% (377 m #) = 1115 is collected; the yield of the transposition by passage through the alkaline adsorbent is 67%.



  EXAMPLE 2. -
 EMI5.2
 1.0 g of 9- (2,6,6-trimethyl? 2-cyolohexene-l-ylidene) - 3,7-dimethyl (2,4,6-nonatriene-1-al, absorption E1%) is dissolved (328 m #) = 794, in 5 cm3 of benzene. To an aliquot of 1 cm3, two drops of pyridine are added and the mixture is left to stand overnight at room temperature. The pyridine catalyzes the conversion into aldehyde of vitamin A of max. = 370 m # An analogous sample treated with pyridine hydrochloride, a non-basic compound, remains unchanged with a / \ max. = 328 m # A sample treated with an iodine solution, an iso- catalyst usual merization, also remains unchanged.



  EXAMPLE 3.-
Another aliquot, as in Example 2, is treated with a pinch of double sodium synthetic aluminum silicate and left to stand overnight at room temperature. It is found that the aldehyde of max. = 328 m # is converted to vitamin A aldehyde of}. max. = 370 m #.



  EXAMPLE 4.-
A sample of 0.8 g of 2-cyclohexene-1-ylidene aldehyde, absorption E1% (330 m #) = 705, is dissolved in 6 cm3 of ethanol. Nine drops of 0.5N potassium hydroxide were added to the solution and the mixture was allowed to stand at room temperature for three hours. The product is washed with water and dried over anhydrous sodium sulfate.



    This gives the aldehyde of vitamin A, absorption E1% (370 m #) = 527. 1cm

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 EXAMPLE 5. -
A sample of 0.9 g of 2-cyclohexene-1-ylidene aldehyde, absorption E1% (328 m #) = 630 ,, is dissolved in 10 cm3 of ether, - and it is treated with a mixture of acetic acid and potassium acetate, basic character system. After standing overnight at room temperature, the product is vitamin A aldehyde, absorption E1% (370 m #) = 567.



   The transposition of other 2-cyclohexene-1-ylidene aldehydes is likewise catalyzed using other customary products of a basic character.



   The invention thus achieves a very efficient process for overcoming the troublesome isomerization of vitamin A series compounds during dehydration following a Grignard or Reformatsky reaction. 2-Cyclohexene-1-ylidene aldehydes, unlike other 2-cyclohexene-1-ylidene compounds, such as esters, etc., are easily transposed, with good yield, to 1-cyclohexene aldehydes Fully conjugated, alpha-beta double bonded -1-yls are desired, when treated with a basic product according to the invention.



   The 2-cyclohexene-1-ylidene aldehydes which are processed according to the invention can be prepared in any suitable manner.



   For example, the 2-cyclohexene-1-ylidene aldehyde 9- (2,6,6-trimethyl-2-cyclohexene-1-ylidene) -3,7-dimethyl-3,5 can be prepared. , 7, -nonatriene-1-al by condensing ss -ionone and a propynyl halide, to form a propynyl-carbinol, by dehydrating the carbinol to the corresponding 2-cyclohexene-1-ylidene compound, by condensing this compound and a dialkylacetal of ss -ketobutyraldehyde to form a 3-hydroxy-2-cyclohexene-1-ylidene acetal, by hydrogenating the acetylene bond to an olefinic bond and subjecting the resulting compound to controlled dehydration followed by hydrolysis to give the compound. 2-cyclohexene-1-ylidene aldehyde of formula (IX)

   
 EMI6.1
 
The aldehyde whose -CH2- group is in position 4 counted from the ring can be prepared by following practically the same process as for the aldehyde in which the -CH2- group is in position 8 from the ring, with this exception that the 7-hydroxy compound is dehydrated before partially hydrogenating the acetylenic bond.

   The aldehyde in which the CH2- group is in the 6-position from the ring can be prepared first by condensation of the propargyl halide and an ss-ketobutyraldehyde dialkylacetal and dehydration of the resulting carbinol, condensing. sation of the alpha-beta unsaturated dehydration product and -ionone, hydrogenation of the acetylene bond to an olefin bond, dehydration of the resulting 7-hydroxy acetal to the corresponding enol ether, and hydrolysis of the enol ether to 2-cyclohexene-1-ylidene aldehyde. The aldehydes can be prepared by analogous methods

 <Desc / Clms Page number 7>

   Shorter chain 2-cyclohexene-1-ylidene.



   The process for the transposition of 2-cyclohexene-1-yli- denic aldehydes is however particularly advantageous in its applications to the preparation of vitamin A from certain polyene ethers.



   A subject of the invention is therefore also a process for the preparation of vitamin A, which is remarkable in particular in that a polyether which can be a monoether of formula (X) is hydrolyzed.
 EMI7.1
 or an acetal of formula (XI)
 EMI7.2
 formulas where R is a hydrocarbon radical and, preferably an alkyl radical, to form the corresponding aldehyde, said aldehyde is transposed into vitamin A aldehyde and the vitamin A aldehyde is reduced to vitamin A alcohol.



   In the synthesis of vitamin A, prior to this invention, it was customary to submit the (9 -ionone or a ketone of formula (XII)
 EMI7.3
 Reformatsky reaction with an alkyl haloacetate, such as ethyl bromoacetate, to form a hydroxyl ester such as an) -ionolacetic acid ester or an [alpha] -hydro- acid ester -hydroxy-vitamin A. As already indicated, the dehydration of such hydroxy esters usually gives only a small fraction of the desired product, consisting of the fully conjugated ester with the alpha-beta double bond mixed with the isomer. double bond beta-gamma.



   The Applicant has now discovered according to the invention that it is possible to hydrolyze the relatively inactive product obtained by dehydration of a hydroxylated ether of vitamin A, whether it is a monoether or an aoetal, to obtain the cyclohex-2 aldehyde. The corresponding relatively inactive -ene-1-ylidene, which can be easily transposed with an excellent yield of vitamin A aldehyde, according to the process of the invention described above. The vitamin A aldehyde can then be easily reduced to vitamin A alcohol with high biological activity. The alcohol function of vitamin A can be esterified to obtain acetate, pal- mitate etc., by known methods and vitamin A is normally supplied.

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 commercially due in ester state.



   A typical embodiment of this characteristic of the invention is illustrated graphically by the following equations in which the ether group of compound XIII can be the monoether group -CH = CH (OR) or the diether or acetal group -CH2- CH (OR) 2 'R being each time an alkyl radical such as methyl, ethyl, propyl, butyl or a similar alkyl group.
 EMI8.1
 



   Usually, by hydrolysis, compound XIV is formed with the -CH2- group in position 2 from the ring. However, it does not matter which of the even positions is occupied by this group, since this does not interfere with the subsequent transposition into vitamin A aldehyde.



   Compound XIII is readily hydrolyzed to the corresponding aldehyde by means of an acid; it is advantageous to carry out the hydrolysis by means of a mineral acid, in an organic solvent. So we can

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 use any of the known ionizable acids, for example hydrochloric, acetic, phosphoric, sulfuric, etc. acids. In order to minimize unwanted decomposition, it is advantageous to carry out the hydrolysis in solvents, ketones such as acetone, diethylketone, methyl ethyl ketone, etc. being particularly suitable, although other known and acid-proof solvents such as benzene, toluene, hexane, etc. can be used.



   The compound XIV thus formed is easily transposed into vitamin A aldehyde, the transposition being advantageously catalyzed by a basic product according to the process of the invention described above.



   The vitamin A aldehyde (compound XV) is then reduced to vitamin A alcohol. This reduction is easily accomplished by any of the known methods of reducing olefin aldehydes to alcohols.



  Typical reduction methods suitable for the reduction of vitamin A aldehyde to vitamin A alcohol are treatment with an ether soluble metal hydride, such as lithium aluminum hydride, lithium borohydride, hydride. aluminum, sodium hydride, etc. or Meerwein-Ponndorff reduction using aluminum alkoxide, such as aluminum isopropoxide, etc. and the corresponding alcohol, or other known reduction methods. When a basic metal-containing reducing agent is used, the metal reducing agent converts cyclohex-2-en-1-ylidene aldehyde to vitamin A aldehyde and then reduces l vitamin A aldehyde to vitamin A alcohol.



   Examples 6 to 9, which are not limiting, describe embodiments of the process according to the invention for the preparation of vitamin A.



  EXAMPLE 6.-
0.60 g of 9- (2,6,6-trimethyl-cyclohex-2-en-1-yli-
 EMI9.1
 dene) -3, 7-dimethyl-1-methoxy-1,3, 5, 7-nonatetraènea (Compound XIII) and 5 em3 of acetone containing a drop of concentrated hydrochloric acid in a colored 50 cm3 Erlenmeyer flask equipped with a reflux condenser . It is boiled under reflux for fifteen minutes. The acetone is removed by evaporation, the residue is taken up in ether and washed with a saturated solution of sodium bicarbonate and water.

   The ether phase is then dried over anhydrous sodium sulfate and the ether is removed by evaporation to give 0.58 g of 9- (2,6,6-trimethylcyclohex-2-en-1-ylidene) - 3 , 7-dimethyl-2,4,6-nonatrienal (Compound XIV) in the form of a red oil of absorption E1% (328 m #) = 900. Similarly, using other iomizable acids, Such as sulfuric acid, phosphoric acid, acetic acid, etc., the hydrolysis of monomethyl ether and analogous monoalkyl ethers is carried out, as are dialkyl ethers or acetals.



   The compound XIV thus obtained is subjected to a retort transposition Indicated in Example 1 to give 0.50 g of vitamin A aldehyde (Compound XV). Similar results are obtained by dissolving compound XIV in petroleum ether and adding to the solution double sodium aluminum silicate in a catalytic amount. Other basic products, such as alkalis, alkaline soaps, etc. also catalyze the transposition of compound XIV into compound XV.



  EXAMPLE 7.-
0.84 g of vitamin A aldehyde (compound XV) dissolved in 20 cm3 of absolute isopropyl alcohol and 1.85 g of aluminum isopropylate suspended in 10 cm3 of absolute ispropyl alcohol are charged in a 40 cm3 three-nozzle flask fitted with a stirrer and a descending cooler. The mixture is boiled under reflux on a diet

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 sufficient to flow about ten drops of distillate per minute, and isopropyl alcohol is added periodically to maintain a constant volume. After boiling the mixture at reflux for thirty minutes, the distillate no longer gave a positive acetone test with 2,4-dinitrophenylhydrazine as a reagent.

   The mixture is boiled under reflux for a further thirty minutes and most of the excess isopropyl alcohol is removed by evaporation under slightly reduced pressure. The residue is cooled, hydrolyzed with cold 5% hydrochloric acid, and extracted with ether four times. The ethereal extracts are mixed, stabilized with a few crystals of hydroquinone, washed twice with sodium bicarbonate solution and twice with water. The washed extract is then dried over anhydrous sodium sulfate and the solvent is removed by evaporation to obtain 0.85 g of crude vitamin A alcohol (Compound XVI) in the form of a viscous reddish oil. of absorption E1% 1cm (325 m #) = 1175 and blue coloring power of 2,120,000 units per gram.



  EXAMPLE 8.-
The conversion of compound XITT to compound XV and the reduction of compound XV to compound XVI can be carried out in the same reaction mixture, using an alkaline reducing agent such as lithium aluminum double hydride. . In a typical example, 0.63 g of compound XIV dissolved in 6.3 cm3 of absolute ether is charged into a 40 cm3 three-necked flask equipped with a stirrer, a dropping funnel and a condenser. at reflux. A mixture of 3.8 cc of a 1M ethereal solution of lithium aluminum double hydride diluted with 3.8 cc of absolute ether is added to the solution of Compound XIV as "rapidly" as possible, within the thirty second period during which the initial reflux vigorous uri occurs.

   The mixture is stirred for a further minute and the excess lithium aluminum hydride is decomposed by successively adding to the mixture wet ether, acetone and hydrochloric acid. 5%. The mixture is then extracted with ether and the ethereal extract is washed with a solution of sodium bicarbonate and with water. The extract is dried over anhydrous sodium sulfate and the solvent is removed by evaporation to obtain a dark brown concentrate of vitamin A alcohol (Compound XVI) of absorption E1% 1cm (328 m #) = 566.



    EXAMPLE 9.-
The direct reduction of vitamin A aldehyde (compound XV) to vitamin A alcohol (compound XVI) by double lithium aluminum hydride is carried out in an analogous manner, adding 0.6 cm3 of l. hydride (1M) in 0.6 cc of absolute ether to a solution of 0.32 g of vitamin A aldehyde in 3.2 cc of absolute ether. The mixture is stirred for two minutes after the addition of reagent and the product is treated as described in Example 8. The vitamin A alcohol concentrate thus obtained weighs 0.35 g, its absorption E1% 1cm (326 m # ) is 1,100 and its blue coloring power is 2,010,000 units per gram with antimony trichloride.



   The invention thus provides an efficient process for preparing vitamin alcohol from a cyclohex-2-en-1-ylidene ether by a simple and efficient combination of reaction steps.



   Compound XIII can be prepared by condensing propargyl bromide with an ss -ketobutyraldehyde dialkylacetal to obtain a propynyl-hydroxyacetal, condensing this propynyl-hydroxyacetal with ionone, partially hydrogenating the reaction product to give the dihydroxyacetal and by dehydrating the latter to form compound XIII.

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  Another method of preparing compound XIII comprises
 EMI11.1
 condensation of acetylene and a dialkyl acetal of fi -ketobutyraldehy- de9 and reacting the product with 2-m "th1-4- (2.-96,6-frimthyl-1-cyclohexene-1 -yl) -2-butenal, the hydrogenation of the acetylene bond of the product to form the corresponding hydroxyacetal, and the dehydration of said hydroxyacetal to form compound XIII.



   According to an important characteristic of the invention, the de-
 EMI11.2
 However, manderesse has discovered that the compounds XIII in which the "ether" group represents -CH = CH (OR), that is to say the compounds of formula X, can be advantageously prepared as follows.



   The 0 -ionone is reacted with a propynyl halide in the presence of a metal such as zinc or magnesium, thereby forming -carbinol, 4-methyl-4-hydroxy-6- (2,6,6-trimethylcyclohex -1-enyl) -hex-5-ene-1-yne, this carbinol and an -oetobutyraldehyde acetal are condensed to form an acetylenic 3,7-diol acetal, the acetylenic bond of this acetal is partially hydrogenated and dehydrated. the resulting olefinic acetal.



   In this last aspect, the process according to the invention for the preparation of vitamin A therefore comprises the reaction of -ioncne with a propynyl halide to give a carbinol, the condensation of the carbinol with an acetal of an ss -cétobutyraldehyde, preferably 4,4-dialkoxy-2-butanone, to form an acetal of 3,7-diol acetylenic, hydrogenation of the acetal of the 3,7-diol acetylenic to the corresponding olefinic 3,7-diol acetal and the conversion of the acetal of the 3,7-olefinic diol into vitamin A alcohol by dehydration and hydrolysis resulting in a cyclohex-2-en-1-ylidene aldehyde,

     the transposition of cyclohex-2-en-1-ylidene aldehyde into vitamin A aldehyde and the reduction of vitamin A aldehyde into vitamin A alcohol. Dehydration, hydrolysis, transposition and reduction which ensure the Conversion of the 3,7-olefinic diol acetal to vitamin A alcohol can be carried out either in a succession of stages or by combinations of stages, as will be described in more detail below.



   This mode of implementation is illustrated by the reactions and the equations which follow. These equations are set forth as separate steps for illustrative purposes, but it will be apparent that one or more individual reactions can be carried out in the same reaction mixture, as described below without having to isolate the intermediates. although it is possible to do so and conduct the various stages one after the other, if desired.



   As an initial step, the) -ionone is reacted with a propynyl halide such as propargyl bromide, propargyl chloride or propargyl iodide to give the following carbinol:
 EMI11.3
 ! -methyl 4-hydroxy-b- (2, b, b-trimethyl-cyclohex-1-enyl) hex-5 -ene-1-yne.



  The reaction is carried out using zinc or magnesium, the use of magnesium being preferable especially when the magnesium is catalyzed by a product containing mercury, which results in the formation of a magnesium amalgam. Mercury can be introduced as an element, as an amalgam prepared beforehand with magnesium or as a mercury compound, such as mercuric chloride or a mercury salt of this guy. The reaction product is advantageously hydrolyzed to decompose the organometallic complex into carbinol.



  The reaction is illustrated by Equation A where X is a halogen atom.
 EMI11.4
 

 <Desc / Clms Page number 12>

 
 EMI12.1
 



   The carbinol (compound XVIII) and an acetal of ss -cétobutyraldehyde, such as a dialkyl, cyclic aryl, aryl-alkyl or mixed acetal of 0-ketobutyraldehyde, are then condensed by a Grignard reaction leading to the acetal of a 3,7-acetylenic diol, in this case a l, l-dial-
 EMI12.2
 koxy 3,7-dimethyl 3,1-dihydroxy-9- (2,6,6-trimethyl-cyclohex-1-enyl) -nona-8-en-4-yne in a characteristic condensation using a dialkyl-acetal . The reaction is easily carried out using one of the Grignard reagents, including amides, alkyl or aryl derivatives of metals such as sodium, potassium, lithium, magnesium, cadmium, etc., in accordance with usual condensation practices.

   Preferred are alkyl-magnesium halides such as ethyl magnesium bromide, but
 EMI12.3
 any of the other strongly basic Grigna reagents can be used. The nature of the acetal group in -ketobutyraldehydes acetal does not affect the course of the reaction. Among the acetals, we pre-
 EMI12.4
 dialkyl acetals and any 4,4-dia> oxy-2-butanone can be used, with lower alkoxy compounds such as dimethoxy, diethoxy, dipropoxy and dibutoxy being preferred for convenience. The reaction is illustrated by Equation B where R is an alkyl radical and X is a halogen atom.



   EQUATION B.
 EMI12.5
 



  Compound XVIII + CH 3COCH 2-CH (OR) 2
 EMI12.6
 The acetal of the acetylenic 3,7-diol is then hydrogenated (compound
 EMI12.7
 se XIX) in the corresponding 3,7-olefinic diol acetal, 1,1-dialkoxy-3, 7-dimethyl 3,7-di-hydroxy-9- (2,, 6-trimethyl-cyclohex-1-enyl) - nona 1,., $ - diene, by partial hydrogenation of the acetylenic bond. This partial hydrogenation is easily accomplished by reacting approximately one molecular equivalent of hydrogen with compound XIX, in the presence of a hydrogenation catalyst such as palladium, Raney nickel or other conventional hydrogenation catalyst. in accordance with usual hydrogenation practices, the reaction is represented by Equation C.



   EQUATION C.
 EMI12.8
 

 <Desc / Clms Page number 13>

 



   The olefinic 3,7-diol acetal (Compound XX) is then converted to vitamin A alcohol by dehydration, hydrolysis, rearrangement and reduction. According to one embodiment of the invention, the compound XX is treated with a dehydrating agent which is a phosphorus halide or a phosphorus oxyhalide to dehydrate and convert the compound XX.
 EMI13.1
 enol ether, l-a1koxY-3,7-dimethyl-9 (2,6,6-trimethyl-cyclohex-2-èrie- - 1-ylidene) -nona-1,3,5,7-tetraene (compound X ).

   The reaction is carried out by treating the compound XX in solution in a suitable solvent such as benzene, toluene, ether, etc., with a halogenated or oxyhalogenated dehydrating agent, and advantageously by presence of an amine, preferably a tertiary amine such as pyridine, lutidine, etc. Any of the conventional halogenated or oxyhalogenated dehydrating agents may be used, typical dehydrating agents which can be advantageously used including phosphorus oxychloride, benzene-phosphorus oxy-dichloride, boron trifluoride, aluminum chloride, pentachloride of phosphorus, stannic chloride, & c. Treatment with such dehydrating agents further converts the acetal group to the ether group.

   Equation D illustrates the reaction.



   EQUATION D.



   Compound XX Dehydrating agent @
Tertiary amine
 EMI13.2
 
The compound X is then subjected to the transposition and reduction hydrolysis operations under the conditions of the invention described above.



   A small fraction of the hydroxyether of formula XX sometimes dehydrates to the ether of vitamin A, without changing the cycle, so that the product obtained by dehydrating a hydroxyether of vitamin A is a mixture of polyene ethers comprising the ether. dice vitamin A and a
 EMI13.3
 cyclohex-2-en-1-ylidene ether. This polyene product can then be hydrolyzed in accordance with the invention to obtain a mixed polyene aldehyde comprising a small proportion of vitamin A aldehyde and a large proportion of [alpha] -cyclohexenyl aldehyde (Compound XIV).

   This mixed polyene aldehyde is then treated with a basic catalyst, which
 EMI13.4
 transposes the fraction formed from cyclohex-2-en-1-ylidene aldehyde to vitamin A aldehyde; all present amount of vitamin A aldehyde is reduced to vitamin A alcohol, either simultaneously when the basic catalyst is also a reducing agent, or subsequently by separate reduction.



   According to a preferred embodiment, the conversion of the acetal of the 3,7-olefinic diol (compound XX) into vitamin alcohol A is advantageously carried out by dehydration, hydrolysis, transposition and reduction, by treating compound XX with a mixture of a mineral acid and an organic base such as pyridine, litidine, quinoline, morpholine, piperidine, etc., or by an adduct of an organic base and an acid mineral such as pyridine hydrochloride, etc. which determines the dehydration of compound XX, hydrolysis and conversion to vitamin A aldehyde in the same reaction mixture, the vitamin A aldehyde then being reduced in alcohol -Vitamin A, such as

 <Desc / Clms Page number 14>

 it is described above.



   It should be noted that the compounds of formula XIX, XX and the compound XIV resulting from the hydrolysis of the compounds XX are new bodies. The invention therefore also targets these compounds as new industrial products.



   The following examples of preferred embodiments illustrate this characteristic of the invention.



    EXAMPLE 10.-
Carbinol (compound XVIII) is prepared as follows. A mixture of 37.4 g of iodine activated zinc and 0.1 g of ethyl copper acetyl acetate is introduced into a three-necked flask fitted with a stirrer. a reflux condenser and a bromine funnel. 40 cm3 of a solution of 64 g of ss -ionone, 37.4 g of propargyl bromide and 0.2 g of hydroquinone in 100 cm3 of absolute ether are added to this mixture and the mixture is heated to start the reaction. The remaining 60 cm3 of solution is diluted with 200 cm3 of absolute ether and 22 cm3 of absolute benzene, and the diluted solution is added to the reaction mixture over a period of thirty minutes, heating the mixture to reflux and stirring for 1 hour. 'addition.

   When the addition is complete, the mixture is heated again at reflux for thirty minutes. Then added to the mixture 250 cm3 of 3N sulfuric acid to decompose the zinc complex, the mixture being cooled during the addition by an ice water bath. The reaction mixture is then filtered and the filtrate is extracted with ether. The aqueous phase is saturated with sodium chloride and extracted three times with ether. The ethereal extracts are combined, washed with sodium bicarbonate solution and with water, and then dried over anhydrous sodium sulfate. The solvent is removed and 77.7 g of crude compound XVIII are obtained, with absorption Elfm (232 m #) = 251 and Elfm (284 m #) = 198.

   The product is purified by chromatography on double synthetic sodium aluminum silicate and 61.4 g of absorption compound XVIII are obtained.
 EMI14.1
 Eim (23 2 Ù '= 242.



  EXAMPLE 11.-
The compound XVIII is prepared in the same way, replacing the zinc with magnesium according to the following process. A mixture of 1.2 g of magnesium foil, 10 cm3 of anhydrous ether and 75 mg of mercuric chloride is introduced into a 200 cm3 three-necked flask equipped with a stirrer, a reflux condenser and of a bromine bulb. A mixture of 9.1 g of -ionone and 5.9 g of propargyl bromide is dissolved in 35 cm 3 of anhydrous ether and the solution is poured into the flask. The mixture is then heated at gentle reflux for five to ten minutes to start the reaction.

   Thereafter, the reaction is continued vigorously without heating and the spontaneous reflux continues for thirty minutes during which the reaction is controlled by cooling with an ice-water bath. After this spontaneous reflux, the mixture is heated at reflux for a further thirty minutes, stirring during this time. The product is in the form of a clear, light yellow solution. The magnesium complex is decomposed into compound XVIII by cautiously adding a 5% sulfuric acid solution, cooling the mixture with ice water. The ethereal phase is then separated from the aqueous phase and the aqueous phase is saturated with sodium chloride and extracted three times with ether.

   The ethereal extracts are combined, washed twice with saturated sodium bicarbonate solution and the sodium bicarbonate solution extracted with ether. The ethereal extracts were combined, dried over anhydrous sodium sulfate and the ether removed to give 11.25 g of a slightly viscous yellow product, absorption E1% 1 cm (232 m # ) = 234. This crude product is chromatographed on activated alumina to obtain 10.57 g of compound XVIII, absorption

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E1% 1cm (232m #) = 240.



   EXAMPLE 12.-
Likewise, compound XVIII is prepared from propegyl iodide. 0.6 g of magnesium turnip, 4.55 g of -ionone are mixed,
4.1 g of propargile iodide, 0.035 g of mercuric chloride and 25 cm3 of anhydrous ether. The mixture is heated to 60 ° C. until the reaction starts. The mixture is cooled in an ice-water bath and allowed to spontaneously reflux for thirty minutes, after which it is refluxed in an oil bath for a further forty-five minutes. The mixture is then cooled, poured onto crushed ice and diluted with
25 cm3 of cold 3N sulfuric acid.

   The product is extracted with ether and the ethereal extract washed successively with water, saturated sodium bicarbonate and water. The ethereal extract was dried over sodium sulfate and the ether removed under nitrogen to give 5.18 g of compound XVIII as a clear yellow, low viscous liquid.



   EXAMPLE 13.-
The carbinol (compound XVIII) and a 4,4-dialkoxy-
2-Butanone, as follows to prepare acetylenic 3,7-diol acetal (Compound XIX). 50 cm3 of absolute ether containing 25.42 g of compound XVIII are slowly added over a period of 30 minutes to
92.7 cm3 of an ethereal solution containing 0.2306 gram-molecules of ethylmagnesium bromine. The solution is heated to reflux and stirred for five hours. The solution is then cooled to 0 C and 18.2 g of 4,4-dimethoxy-2-butanone (boiling point 49 -50 C, under a pressure of 6 mm) dissolved in 50 cm3 of absolute ether are added thereto. , this addition taking one hour and leading to the formation of a white gummy product.

   The mixture is left to stand overnight at 4 ° C. and the mixture is diluted with 150 cm3 of a saturated solution of ammonium chloride to decompose the magnesian complex into acetal of the acetylenic 3,7-diol. The ethereal and aqueous phases are separated and the latter is extracted three times with ether. The ethereal phases are combined and dried over anhydrous sodium sulfate and the solvent is removed by evaporation. The excess 4,4-dimethoxy-2-butanone is removed from the residue at 60 ° C. under vacuum, and 40.1 g of crude compound XIX is obtained which is purified by chromatography, which yields 36.3 g. of yellow and viscous compound XIX, absorption E1% 1cm (232 m #) = 146 and index n25 = 1.4995.



  EXAMPLE 14.-
The acetylenic 3,7-diol acetal (compound XIX) is hydrogenated to the olefinic 3,7-diol acetal (compound XX) by dissolving 3.5 g of compound XIX in 35 cm3 of methanol containing three drops of quinoline and 0.2 g of 5% palladium carbon and passing hydrogen through the solution. The absorption of hydrogen essentially ceases after six minutes when 1.0 molecular equivalent has been absorbed, and the addition of hydrogen is discontinued after eighteen minutes, during which time the absorption has been carried out. 1.05 molecular equivalent (244 cm3) of hydrogen. The mixture is then diluted with 100 cm3 of petroleum ether and filtered to remove the catalyst. The ethereal phases are washed with 5% sulfuric acid, with dilute sodium bicarbonate solution and with water.

   After drying over anhydrous sodium sulfate, the solvent is evaporated which leaves 3.41 g of compound XX in the form of a viscous yellow oil, absorption E1% 1 cm (232 m #) 157.



  EXAMPLE 15.-
6.6 g of anhydrous pyridine are introduced into a 40 cm3 flask equipped with a reflux condenser, a bromine funnel and a

 <Desc / Clms Page number 16>

 stirrer. 1.19 cc of phosphorus oxychloride in 10 cc of toluene are added, the mixture being cooled during this addition. A solution of 1.83 g of compound XX in 5.0 cm 3 of toluene is then added and the resulting mixture is heated at 90-95 ° C. for 75 minutes with rapid stirring.



  The red product is cooled and stirred in crushed ice and ether. The aqueous phase is separated from the ethereal phase and the aqueous phase is extracted six times with ether. The ethereal phases are combined, which are washed successively with saturated potassium carbonate solution, 5% sulfuric acid and saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. After evaporation of the solvent under vacuum, 1.5 g of enolic ether (compound X) are obtained in the form of a viscous red residue, absorption E1% 1 cm (372 m #) = 1080. The mixture is purified. fie the product by chromatography on double silicate of sodium and synthetic aluminum and one obtains 0.78 g of viscous yellow product, absorption E1% 1cm (372 m #) = 1800.



    EXAMPLE 16.-
A mixture of 7 cm3 of pyridine and 10 cm3 of anhydrous toluene containing 2.7 g of benzene-phosphorus oxidichluride is introduced into a 50 cm3 flask equipped with a stirrer and a condenser. To this mixture is added 5 cm 3 of toluene containing 1.83 g of the acetal of the olefinic 3,7-diol (compound XX). The mixture was heated at 90 -95 ° C. for 75 minutes and poured onto 20 g of crushed ice. The aqueous phase is made basic with potassium carbonate and then extracted three times with ether. The ethereal extracts are combined and washed successively with a solution of potassium carbonate, with 10% sulfuric acid, with a saturated solution of sodium bicarbonate and finally with water.

   The extract is dried, the solvent is removed by evaporation and 1.27 g of enol ether (compound X) with absorption E1% 1 cm (372 m #) = 790 are obtained.



   Compound X is hydrolyzed as indicated in Example 6 to obtain 9- (2,6,6-trimethyl-cyclohex-2-en-1-ylidene) -3,7-dimethyl-2,4,6-nonatrienal (compound XIV) which is then transposed as indicated in Example 1, in Example 2 or in Example 4. The aldehyde is then reduced to vitamin alcohol A as described in Example 7.



   It is also possible to carry out the rearrangement and the reduction in the same reaction mixture as indicated in Example 8 or in Example 17.



  EXAMPLE 17.-
The transposition and reduction of compound XIV is also carried out in a single operation using an aluminum alkoxide. 0.61 g of compound XIV dissolved in 25 cm3 of isopropyl alcohol is added to a suspension of 1.35 g of aluminum isopropylate in 10 cm3 of isopropyl alcohol. The mixture was boiled at reflux until the distillate gave an acetone test negative for 2,4-dinitrophenylhydrazine. The excess alcohol is removed by vacuum distillation, the residue is cooled and the excess aluminum isopropoxide is decomposed by the addition of 20 cm 3 of 10% sulfuric acid. The mixture is extracted with ether and the ethereal extract is washed with water until neutral. The ether is removed by evaporation and a concentrate of vitamin A alcohol is collected, absorption E1% 1 cm (328 m #) = 690.



  EXAMPLE 18.-
According to a preferred embodiment of the invention, the conversion of the acetal of the 3,7 olefinic diol (compound XX) into vitamin alcohol A is advantageously carried out by treating the compound XX with a mixture of a mineral acid. and an organic base, which leads to effect

 <Desc / Clms Page number 17>

   killing the dehydration, hydrolysis and transposition in a single reaction mixture, resulting in the aldehyde of vitamin A which can then be reduced as described above. Thus in a typical example, 40 cm3 of methyl ethyl ketone containing 1.45 g of quinoline and 20 cm3 of methyl ethyl ketone containing 1.17 g of concentrated hydrochloric acid are added to a solution of 11.0 g of compound XX in 80 cm3 of methyl ethyl ketone .



  The mixture is boiled under reflux for an hour and a half, cooled, poured into 500 cm3 of water and extracted with ether. The ethereal extract is washed successively with 5% hydrochloric acid, 0.5N potassium hydroxide and water. The washed extract is dried and evaporated to obtain 8.7 g of vitamin A aldehyde in the form of a reddish oil, absorption E1% 1 cm cm (372 m #) = 870.



  EXAMPLE 19. - Analogously, the compound XX is converted into vitamin A aldehyde, by refluxing for two hours a mixture of 1.0 g of compound XX, 0.092 g of pyridine and 0.117 g of concentrated hydrochloric acid in 12 cm3 of methyl ethyl ketone . The treatment of the product is completed as in the previous example and an aldehyde concentrate of vitamin A is thus obtained, absorption E1% 1 cm (369 m #) = 716.



  EXAMPLE 20 1.0 g of compound XX is boiled under reflux in 12 cm3 of methyl ethyl ketone containing 0.1 g of piperidine and 0.117 g of concentrated hydrochloric acid. After two hours of reflux, the crude vitamin A aldehyde is obtained, absorption E1% 1cm (368 m #) = 610.



  Vitamin A aldehyde can also be easily reduced to vitamin A alcohol, as shown in Example 9.



  The invention thus provides a new and improved synthesis of a product active in vitamin A, without the undesirable yield losses due to isomerization during dehydration.



  Of course, the invention is not limited to the embodiments described which have been chosen only by way of example.


    

Claims (1)

ABSTRACT. The main objects of the invention are: 1 - a process for preparing fully conjugated 1-cyclohexene -1-yl [alpha] ss -unaturated polyene aldehydes, said process being remarkable in particular by the following characteristics considered separately or in combinations: a) it comprises the treatment of a 2-cylohexene-1-ylidene aldehyde of formula: EMI17.1 wherein R is an unsaturated aliphatic hydrocarbon radical containing at least five and preferably at most 10 carbon atoms and comprising <Desc / Clms Page number 18> having a single -CH2- group on the chain, said -CH2- group being in an even position starting from the ring, by means of a basic catalyst, which has the effect of converting said 2-cyclohexene-1- aldehyde ylidene to a fully conjugated unsaturated 1-cyclohexene-1-yl aldehyde, [alpha] ss, containing no -CH2- group in the aliphatic hydrocarbon radical; b) 2-cyclohexene-1-ylidene aldehyde is treated in solution in an organic solvent; c) the unsaturated hydrocarbon radical comprises 5 carbon atoms with a substituted methyl group on the third carbon from the ring: d) the unsaturated hydrocarbon radical comprises 10 carbon atoms with a substituted methyl group on the third and seventh carbon from the cycle; e) the starting aldehyde is an isomer of the aldehyde of vitamin A having the formula: EMI18.1 that is converted into aldehyde of vitamin A of formula <Desc / Clms Page number 19> EMI19.1 @ f) the alkaline catalyst is an organic or inorganic base; g) the rearrangement treatment is carried out by passing said 2-cyclohexene-1-ylidene aldehyde in solution through a certain quantity of alkaline adsorbent, in particular sodium aluminum silicate; 2 - The applications of the aforementioned process and, in particular a process for the preparation of vitamin A, remarkable in particular by the following characteristics considered separately or in combinations: a) it comprises the hydrolysis of a polyene ether of formula R - CH = CH (OR) or R ss - CH2 - CH (OR). in which R ss is the following radical: EMI19.2 and R is a hydrocarbon radical, in particular an alkyl radical, which converts said ether to the corresponding aldehyde, rearrangement of said aldehyde to vitamin A aldehyde and reduction of said vitamin A aldehyde to vitamin A alcohol; b) the hydrolysis of the polyene ether to the corresponding aldehyde is carried out with an ionizable acid and, preferably, in an organic solvent, in particular with a mineral acid in a ketone such as the ketone; . c) said ether of formula R '-CH = CH (OR) is obtained by reacting the -ionone with a propynyl halide in the presence of a metal such as zinc or magnesium, thereby forming the carbon- EMI19.3 nol, 4-methyl! ,, - hydroxy-6- (2,6,6-trim.ethyl clohex-1-enyl) hex-5-en-1-yne, by condensing this carbinol and an acetal of / 9 - ketobutyraldehyde thereby forming an acetal of 3,7-acetylenic diol, partially hydrogenating the acetylenic bond of this acetylenic 3,7-diol acetal thereby forming the acetal of 3, Corresponding olefinic 7-diol and dehydrating this 3,7-olefinic diol acetal; d) said -ketobutyraldehyde acetal is a 4,4-dialkoxy-butanone, the acetylenic 3,7-diol acetal then being 1,1-dialkoxy- EMI19.4 3,7-dimethyl-3,7-dihydroxy-9- (2,6,6-trimethyl cyclohex-1-enyl) -nona-g'-en- <Desc / Clms Page number 20> EMI20.1 4-yne, and the corresponding olefinic acetal 1,1-dialkoxy-3,7-dimethyl-3,7-dihydroxy-9- (2,6,6-trimethyl-cyclohex-1-enyl-nona4,8- diene; e) 1% propynyl halide is propargyl bromide; f) the condensation of said propynyl halide and -ionone takes place in the presence of magnesium with a catalytic amount of product containing mercury, in particular in the presence of magnesium amalgam; g) the condensation of said carbinol into acetylenic 3,7-diol acetal is carried out by a Grignard reaction: h) the partial hydrogenation of said acetal of the acetylenic 3,7-diol is carried out by reacting said acetylenic 3,7-diol. 3,7 diolacetylenic acetal with one molecular equivalent of hydrogen in the presence of a hydrogenation catalyst; i) dehydration of the olefinic 3,7-diol acetal-diol takes place by means of a dehydrating agent, such as a halide or an oxyhalide, in particular with phosphorus oxychloride and . results in EMI20.2 1-alkoxy-3,7-dimethyl-9- (2,6,6-trimethylcyclohex-2-en-1-ylidene) -nona-1,3,5,7-tetraene enol ether; j) hydrolysis of said enol ether to aldehyde 3,7-dimethyl-9- (2,6,6-trimethyl cyclohex-2-en-1-ylidene) -nona-2,4,6-triene-1-al is done by means of a mineral acid; k) converting the olefinic 3,7-diol acetal to the vitamin aldehyde. A is done in one step, using a mixture of an organic base and an ionizable acid; 1) the transposition of the cyclohex-2-en-1-ylidene aldehyde and the reduction to vitamin A alcohol are carried out in a single step *, by treating said aldehyde with a basic reducing agent such as a hydride or a basic metal alkoxide; 3 - as new intermediate products: EMI20.3 a) 1,1-dialkoxy 3,7-dimetlpl 3,7-d.ihydroxy-9- (z, 6,6-trimethyl-cyciohex-i-enyi) -nona-8-en-4-yne ; b) 1,1-diakoxy-3, 7-dimethyl-3, 7-dihydroxy-9- (2,6,6-trimethyl cyclohex-1-enyl) -nona-4,8-diene; c) 3,7-dimethyl-9 (2,6,6-trimethyl-qyclohex-2-en-1-ylidene) - nona-2,1,6-triene-1-a1.