Title of Invention	A PROCESS FOR THE MANUFACTURE OF A POLYENE ALDEHYDE
Abstract	A process for the manufacture of polyene aldehydes comprises reacting a polyene 0,0ethylene acetal with a 1-alkoxy-1,3-diene in the presence of a Lewis acid or Bronsted acid, hydrolyzing the resulting condensation product and cleaving off alcohol under basic or acidic conditions from the polyene derivative produced at this stage. The novel polyene 0,0-ethylene acetals as well as the likewise novel condensation products in this process form further aspects of the invention. The final products are primarily carotenoids which find corresponding use, e.g. as colorants and pigments for foodstuffs, animal products etc.

Title of Invention

A PROCESS FOR THE MANUFACTURE OF A POLYENE ALDEHYDE

Abstract

A process for the manufacture of polyene aldehydes comprises reacting a polyene 0,0ethylene acetal with a 1-alkoxy-1,3-diene in the presence of a Lewis acid or Bronsted acid, hydrolyzing the resulting condensation product and cleaving off alcohol under basic or acidic conditions from the polyene derivative produced at this stage. The novel polyene 0,0-ethylene acetals as well as the likewise novel condensation products in this process form further aspects of the invention. The final products are primarily carotenoids which find corresponding use, e.g. as colorants and pigments for foodstuffs, animal products etc.

Full Text	The present invention is conceded with a novel process for the manufacture of polygene baldheads from actualized polygene baldheads of shorter chain length by an acid-catalyzed condensation reaction with alkoxydienes. Lewis acid-catalyzed additions of a,3-unsaturated ethers (enol ethers) to acetyls have been known for a long time and date back to the work of Miiller-Cunradi and Pierson (see US Patent 2,165,962). Hoaglin and Hirsch [J.A.C.S. 71, 3468 et seq. (1949)] investigated this reaction further and broadened the possible applications, which Islet et al. likewise did in the nineteen fifties with respect to the synthesis of 3-carotene, crocetin dialdehyde, lycopene as well as P-apocarotenoids [see Helv. Chim. Acta 39, 249 et seq. and 463 el seq. (1956), ibid. 42, 854 et seq. (1959) as well as US Patents 2,827,481 and 2,827,482]. Later, Mukaiyama [Angew. Chem. 89, 858 et seq. (1977) and Org. Reactions 28, 203 et seq. (1982)] extended the reaction by using the readily accessible trimethylsilyl enol ethers. Reactions of ethenol alkyl ethers with cyclic acetals, e.g. ethylene acetals, are also known; they afford by addition cyclic compounds having two ring oxygen atoms, e.g. 1,4-dioxacycloheptane [see Mikhailov et al., Izv. Akad. Nauk. SSSR, Otd. Khim. Nauk. 1960, 1903 et seq./Chem. Abs. 55,13409 f (1961) and German Patent 1,031,301/Chem. Abs. 54. 22712 d (I960)]. The first Lewis acid-catalyzed condensations of l-alkoxy-l,3-dienes (dienol ethers) with a,3-unsaturated acetals were reported by Nazarov and Krasnaya [J. Gen. Chem. USSR 28, 2477 et seq. (1958)] and by Makin [Pure & Appl. Chem. 47,173 et seq. (1976), J. Gen. Chem. USSR 31, 3096 et seq. (1961) and 32, 3112 et seq. (1962)]. Here, the coupling of the acetal to the dienol ether takes place as far as can be seen exclusively at its y-position with the formation of a chain-lengthened a,\|3-unsaturated acetal, which, however, in competition with the first acetal reacts with further dienol ether with the formation of a further, chain-lengthened a,3-unsaturated acetal etc. [telomer formation; see also Chemla et al.. Bull. Soc. Chim. Fr. 130, 200 et seq. (1993)]. For this reason such a condensation has been found not to be workable for synthetic purposes, especially for the synthesis of apocarotenoids [Isleretal., Adv. Org. Chem. 4,115 et seq. (1963)]. Not only l-alkoxy-l,3-dienes, but also trimethylsilyloxydienes [of the type CH2=CH-CH=CH-OSi(CH3)3] can be condensed with a,P-unsaturated acetals in the presence of Lewis acid catalysts, as disclosed by Mukaiyama et al. in Chem. Lett. 1975, 319 et seq. In this coupling too the attack seems to take place exclusively at the terminal (y-) carbon atom of the diene system in order to form "v-products" [see Mukaiyama et al., Bull. Chem. Soc. Jap 50,1161 et seq. (1977) and Japanese Patent Publication (Kokai) 36,645/1977/Chem. Abs. 87, 201825 t (1977)]. In contrast to the reaction with 1-alkoxy-1,3-dienes, in which an a,3-unsaturated acetal results, the reaction of trimethyl¬silyloxydienes with acetals affords an aldehyde which does not react further with the diene (no lelomer formation). Thereby, zinc bromide and many other Lewis acids are required as catalysts only in small amounts [Fleming (et al.), Tetr. Lett. 1979, 3209 et seq. and Chimia 34, 265 et seq. (1980) as well as Brownbridge, Synth. 1983, 85 et seq]. By using this method Mukaiyama et al. were able to synthesize vitamin A [see Kokai 36,645/1977, Chem. Lett. 1975,1201 et seq. and Bull. Chem. Soc. Japan 5j., 2077 et seq. (1978)] and workers from Rhone-Potilenc developed new routes to carotenoids and vitanun A (see DOS 2,701,489 and A.E.C. Social de Chimie Organique et Biologique No. 7824350). The aforementioned Lewis acid-catalyzed condensation of a dienol ether with an a,P-unsaturated acetal based on the works of Nazarov and Krasnaya, Makin as well as Chemla et al. would be a very valuable access to apocarotenals and bis-apocarotenals if the yield of the desired primary product of the type ...CH=CH-CH(0alkyli)-CH2-CH=CH-CH(0alkyli)(0alkyl2) could be increased and the telomer formation could be suppressed. Thus, the desired polyene aldehyde of the type CH=CH-CH=CH-CH=CH-CHO could be obtained from this primary product by hydrolysis of the acetal group ClOalkyUXOalkyl^) and elimination of alkyl^OH. In addition to the fact that in this reaction the formation of the double bond lakes place under catalytic conditions, no phosphorus-, silicon- or sulphur-containing reagents are required. Less known from the scientific literature is the coupling of an a,3-unsaturated ethylene acetal with a trimethylsilyloxydiene. Analogously to the "usual" dienol ether condensations with dialkyl acetals, the product results in moderate yields [see again Chem. Lett. 1975, 319 et seq. and Bull. Chem. Soc. Japan 50,1161 et seq. (1977)] according to the equation: The object of the present invention is to manufacture chain-lengthened polyene aldehydes starting from polyene acetals while avoiding as far as possible the aforementioned disadvantages of the state of the art and replacing the Wittig, Homer or Juha reaction hitherto used for this purpose. This object is achieved in accordance with the invention by reacting a polyene 0,0-ethylene acetal with a l-alkoxy-l,3-diene in the presence of a suitable catalyst, namely a Lewis acid or Bronsted acid, to give the corresponding chain-lengthened 6-alkoxy-a,P-unsaturated polyene aldehyde in the form of its ethylene acetal, hydro!yzing this ethylene acetal to the corresponding aldehyde and finally eliminating the y-positioned alkanol from this aldehyde under basic or acidic conditions in order to obtain the desired conjugated polyene aldehyde. Not only is the reaction of the l-alkoxy-l,3-diene with the polyene 0,0-ethylene acetal novel, but it takes place (so far as can be seen) with exclusive attack at the y-position of the alkoxydiene. The formation of the 5-alkoxy-a,P-unsaturated polyene 0,0-ethyIene acetal must be seen to be a complete surprise. Through the base- or acid-induced elimination of the alkano! subsequent to the hydrolysis a (conjugated) C-C double bond is formed without requiring a phosphorus-, silicon- or sulphur-containing reagent, which is in contrast to the methodology hitherto usually employed in this field. Accordingly, the present invention is concerned with a process for the manufacture of a polyene aldehyde of the general formula wherein A signifies a monovalent, optionally methyl-substituted, conjugated polyene group and Rl and R2 each signify hydrogen or methyl, with the -CH=CH-C(R^)=C(R2).CHO group being situated at the terminal position of the conjugated chain of group A, which process comprises reacting a polyene 0,0-ethylene acetal of the general formula wherein A has the significance given above, with in this case the ethylene acetal group being situated at the terminal position of the conjugated chain of group A, and R3 and R"* each signify hydrogen or Ci-4-alkyl, with a l-alkoxy-l,3-diene of the general formula wherein R1 and R2 have the significances given above and R5 signifies C1-6-alky], in the present of a Lewis acid or Br5nsted acid to give the compound of the general formula wherein A, R1, R2, R3, R4 and R5 have the significances given above, hydrolyzing the compound of formula IV and cleaving off the alkanol R5OH under basic or acidic conditions from the thus-obtained compound of the general formula wherein A, R1 R2 and R5 have the significances given above, with in this case the -CH(OR5)-CH2-C(R1)=C(R2)_CHO group being situated at the terminal position of the conjugated chain of group A. The process in accordance with the invention can in principle be used in the case of all of the aforementioned polyene 0,0-ethylene acetats of formula H which feature the ethylene acelal group at the end of the polyene chain. Among such educts there are to be found, inter alia, the following sub-classes [with the abbreviated form of presentation which is usual in carotenoid chemistry (using simple lines) being used for the structural formulae]: Alicyclic-aliphatic polyene 0,0-ethylene aceials, which mainly belong to the carotenoid field [as ethylene acetals of asymmetric carotenoid aldehydes having a six-membered (cyclohexene) ring], of the general formula wherein R3 and R4 have the significances given above and R6 and R7" each independently signify hydrogen, an opdonally protected hydroxy group or an optionally protected oxo group, m signifies 0, 1, 2, 3 or 4 and n signifies 0 or 1, which, after carrying out the multistage process in accordance with the invention, are converted into the corresponding alicyclic-aliphatic polyene aldehydes of the general formula as well as aliphatic polyene 0,0-ethylene acetals, which likewise mainly belong to the carotenoid field (as ethylene acetals of open-chain asymmetric carotenoid aldehydes), of the general formula wherein R3 and R4 have the significances given above and p signifies 0, 1 or 2, q signifies 0, 1, 2 or 3 and n signifies 0 or 1, which, after carrying out the multistage process in accordance with the invention, are converted into the corresponding aliphatic polyene aldehydes of the general formula The educts of general formulae Ha and lib can be embraced by general formula 11": wherein R signifies a group (a) or (b) and R3, R4, R6, R"7, m, n, p and q have the significances given above. After carrying out the multiage process in accordance with the invention the educt of formula 11" is converted into the corresponding product of formula I": I Formula I" then embraces formulae la and lb. Where the product of formula I, especially of formula la, has one or two protected groups (R6, R"^) on the cyclohexene ring, the protecting group(s) present can, if desired, be cleaved off, which represents a further aspect of the present invention. In the scope of the present invention the term "Ci.4-alk;y]", "Ci-5-aIkyl" or "C1.6-alkyl" embraces straight-chain and branched groups such as, for example, methyl, ethyl and isobutyl. This applies analogously to the alkoxy groups. The term "protected hydroxy group" embraces usual protected hydroxy groups (especially those vifhich are famihar from the carotenoid field), particularly etherified hydroxy groups and acyloxy groups. The "etherified hydroxy groups" are, for example, C]-5-alkoxy groups, preferably methoxy and ethoxy; C2.4-alkoxy alkoxy groups, preferably 1-methoxy-l-methylethoxy; arylalkoxy groups, preferably benzyloxy; tetrahydro-pyranyloxy; and tri(Ci.5-alkyl)silyloxy groups, preferably trimethylsilyloxy. The acyloxy groups embrace especially alkanoyloxy and aroyloxy groups with up to 8 carbon atoms such as, for example, formyloxy, acetoxy, propionyioxy and benzoyloxy. The term "protected oxo group" also embraces usual protected oxo groups (especially those which are familiar from the carotenoid field). Acetahzed oxo groups, especially those in which the term protected oxo stands for two Ci.5-aIkoxy groups (e.g. two methoxy groups) or for a C2-6-alkylenedioxy group (e.g. ethylenedioxy or 2,3-butylenedioxy) are preferred. Further, an oxo group can also be protected as an enol ether, primarily in the case of a-hydroxyketones (e.g. R6 and R7 signify hydroxy or oxo or vice versa), whereby the esterification of the enediol can preferably also be effected by the formation of a cyclic acetal or ketal (e.g. with acetone to the acetonide). The oxo group can also be protected, for example, as an imine. The formulae of polyenes disclosed in the scope of the present invention embrace in each case isomeric forms, e.g. optically active and cis/trans or E/Z isomers, as well as mixtures thereof, unless expressly indicated to the contrary. The carbon atom carrying the residue R6 or R7 where R6 or R7 signifies an optionally protected hydroxy group (see formulae la and Ha) can be mentioned as an example of a chiral (optically active) centre. With respect to E/Z isomerism, there are generally preferred the (ail-E) isomers of the educts and of the products of the process in accordance with the invention. The first step of the process in accordance with the invention is conveniently carried out by reacting the polyene 0,0-ethylene acetal of formula II with the 1-alkoxy-1,3-diene of formula IH in an organic solvent at temperatures in the range of about -6(PC to about +60°C, preferably in the temperature range of about -20°C to room temperature, and in the presence of a Lewis acid or Brionsted acid. Suitable organic solvents are, in general, all aprotic polar or non-polar solvents. Preferred among such solvents are lower aliphatic and cyclic hydrocarbons, e.g. pentane, hexane and cyclohexane; lower, halogenated aliphatic hydrocarbons, e.g. methylene chloride and chloroform; lower aliphatic and cyclic ethers, e.g. diethyl ether, tert.butyl methyl ether and tetrahydrofuran; lower aliphatic nitriles, e.g. acetonitrile; as well as aromatic hydrocarbons, e.g. toluene. Toluene is the especially preferred solvent. Examples of Lewis acids which can be used are zinc chloride, zinc bromide, titanium tetrachloride, lithium perchlorate, boron trifluoride etherate as well as iron(III) chloride; and of Bronsted acids which can be used are p-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid. sulphuric acid as well as trifluoroacedc acid. These are generally used in catalytic amounts, conveniently in an amount of between about 0.5 and 5 mol percent based on the amount of polyene 0,0-ethylene acetal employed and preferably in a mol percent range of 1% to 2%. Moreover, about 1.05 to about 2 equivalents, preferably about 1.2 to about 1.4 equivalents, of l-alkoxy-l,3-diene are conveniently used per equivalent of polyene 0,0-ethylene acetal. Furthermore, the reaction is conveniently effected at normal pressure, although generally the pressure is not critical. If desired, the intermediate of formula IV can be isolated from the reaction mixture and subsequently hydrolyzed lo the corresponding compound of formula V. However, it has been found to be more convenient not to undertake such an isolation and subsequent hydrolysis, but to hydrolyze the intermediate in the reaction mixture itself immediately after completion of the reaction II + III in order in these cases to proceed to the compound of formula V. The hydrolysis can be suitably effected by adding an acid, preferably p-toluenesulphonic acid or slightly diluted aqueous acetic acid, lo the reaction mixture and subsequently stirring the mixture for a time, for example about 30 minutes to about 2 hours, conveniently in the temperature range of about 0°C to room temperature. The product of formula V can be isolated from the reaction mixture and, if desired, purified in a manner known per se. Typically, the mixture is combined with water and the whole is extracted with a water-immiscible organic solvent such as, for example, with a lower alkane, dialkyl ether or aliphatic ester, e.g. hexane, tert.butyl methyl ether or ethyl acetate, and the organic phase is washed with water and/or sodium bicarbonate solution and/or saturated aqueous sodium chloride, dried and concentrated. The thus-isolated and at least to some extent washed crude product, can then, if desired, be purified further, for example by column chromatography, e.g. using eluents such as hexane, ethyl acetate, toluene or mixtures thereof, or (re)crysiallizaticfn, for example from an alcohol, e.g. methanol or ethanol. Alternatively, and often preferably, the crude product taken up, for example, in a lower alkanol can be reacted directly in the last process step of the present invention, i.e. in the manner of a "through process" II + IE -4 IV ^ V —> I. With respect to the last process step, i.e. the cleavage of the alkano! R^OH from the compound of formula V, eliminations of the alkanol from P-alkoxyaldehydes or 5-a!koxy- a,P-unsaturated aldehydes with the formation of the corresponding a,p-unsaturated aldehydes are known from the scientific literature and can be carried out under a variety of conditions. For example, in the manner of known base-induced eliminations 1,8-diaza-bicyclo[5.4.01undec-7-ene is very often used as the base in an amount of about 2 to 4 equivalents based on the amount of aldehyde used. Such conditions are used in the known production of carotenoids [see, inter alia. Bull. Chem. Soc. Japan 50,1161 et seq. (1977), ibid. 51, 2077 et seq. (1978), Chem. Lett. 1975,1201 et seq. and German Offenlegungsschrift 2,701,489] and of vitamin A (see, inter alia, Chem. Lett. 1975,1201 et seq.). Aluminium oxide has also been in the production of vitamin A by alkanol cleavage [J. Gen. Chem. USSR 32, 63 et seq. (1962)]. As examples of acid-induced alkanol cleavages reference is again made to Bull. Chem. Soc. Japan 50, 1161 et seq. (1977) and to J. Gen. Chem. USSR ^0, 3875 el seq. (1960) in which p-toluenesulphonic acid or 85% phosphoric acid is used as the acid catalyst. The buffer system sodium acetate/acetic acid [Helv. Chem. Acta. 32, 249 et seq. and 463 et seq. (1956) and US Patents 2,827,481 and 2,827,482] or sodium formate/formic acid [Synthesis 1981,137 et seq.] has been used for such a cleavage especially in the production of carotenoids. Taking into consideration this and other pertinent literature a person skilled in the art will have no difficulties in finding suitable reaction conditions for the successful performance of the last step of the process in accordance with the invention. Furthermore, the cleavage of the alkanol R^OH can also be carried out using only catalytic amounts of a base, i.e. with less that one equivalent based on one equivalent of the compound of formula V. Thus, the last process step in this case is conveniently carried out by converting the compound of formula V dissolved in a suitable organic solvent into the corresponding polyene aldehyde of formula 1 in the presence of a catalytic amount of base with cleavage of the alkanol R^OH. Suitable organic solvents are in general protic, aprotic or mixtures thereof such as, for example, alcohols and alcohol mixtures; or aromatic hydrocarbons, e.g. toluene; and lower aliphatic esters, e.g. ethyl acetate. The base can be inorganic or organic, and there are suitable in general strong bases such as, for example, alkali metal alcoholates, e.g. sodium methylate, sodium eihylate, potassium methyiate, potassium eihylate and potassium teri.butylale; amines, e.g. triethylamine, 1,5 diazabicyclo[4.3.0]non-5-ene and l,8-diazabicyclo[5.4.0]undec-7-ene; as well as alkali metal hydroxides and carbonates, especially sodium and potassium hydroxide or carbonate. As mentioned above, a maximum of one equivalent of base per equivalent of the compound of formula V is conveniently used, preferably about 0.05 to about 0.3 equivalent. The reaction is suitably effected in the temperature range of about -2(PC to about 100°C, preferably at temperatures of about 0°C to about 50°C. Moreover, the reaction is conveniently effected at normal pressure, although in general the pressure is not critical. It has been found to be especially advantageous to carry out the last process step using a sodium alkoxide as the base and the corresponding alkanol as the solvent at temperatures between about -20°C and the reflux temperature of the respective reaction mixture, preferably in a temperature range of about CPC to about 40^0. Conveniently, either a solution of the sodium alkoxide in the alcohol is prepared in advance or this solution is prepared freshly from metallic sodium and the alkanol. The bringing together of the alkanolic solution of the sodium alkoxide with the solution of the compound of formula V in the (same) alkanol, preferably likewise previously prepared, can be effected in any sequence and preferably at room temperature. The reaction mixture is subsequently stirred and the reaction has normally finished at the the latest after one to three hours. Irrespective of the chosen procedure for the last process step, the product can be isolated from the reaction mixture and purified in a manner known per se. When a basic catalyst is used, the respective working up normally comprises neutralization of the residual base by addition of an organic or inorganic acid such as, for example, a carboxylic acid, e.g. acetic acid, or an aqueous mineral acid, e.g. dilute sulphuric acid. In the particular embodiment of the procedure described above using a sodium alkoxide as the base, after completion of the reaction the mixture is conveniently cooled to room temperature or even to about 0°C and thereafter neutralized, preferably with aqueous acetic acid. The crystallization of the product of formula I can also be promoted by further cooling. After its isolation, suitably by filu-ation, the product can be washed, for example with water and/or aqueous alcohol, and finally dried, optionally under reduced pressure. If desired, further methods such as column chromatography andrecrystallization can be employed in order to provide an even purer product. If desired, protecting groups (R6 and/or R7 as a protected hydroxy or oxo group) which may be present in the obtained product of formula I can be cleaved off according to methods known per se, e.g. by hydrolysis with acid or base. In the above-defmed process in accordance with the invention A or R preferably signifies a group (a) in which R6 and R7 both signify hydrogen and n signifies 0, R^ and R2 preferably signify hydrogen and methyl, respectively, and R^ and R"* both preferably signify hydrogen. As mentioned above, in carrying out the process in accordance with the invention there is the advantage over the state of the art (especially the aforementioned works of Nazarov and Krasnaya, Makin as well as Chemla et al.) in that, inter alia, the telomer formation is largely suppressed. Although in the process in accordance with the invention the telomer formation resulting from the further reaction of the compound of formula IV with the l-alkoxy-l,3-diene of formula IH cannot always be suppressed completely, this is finally much less serious than expected. The cleavage of the alcohol R^OH from the compound of V, occurring after the intermediate stage hydrolysis, can be effected readily in the presence of a telomer co-produced in a relatively small amount as a byproduct, e.g. of the formula A-CH(0R5)-CH2-C(R1)=C(R2)-CH(0R5)-CH2-C(R1)=C(R2).CH0 (a single additional reaction), with an analogous alcohol cleavage from the telomer also taking place under the special reaction conditions which are used. However, the latter cleavage does not take place completely in that practically only the alkoxy group OR5 (5-alkoxy) situated next to the terminal aldehyde group is cleaved off. The result of this incomplete alcohol cleavage from the telomer is that the desired product of formula I can be removed much more readily from the byproduct present at this stage than if all alkoxy groups OR5 had been cleaved off from the telomer. Thus, the byproduct, which still has one or more substituents OR5, remains in the mother liquor of the reaction mixture, while the desired product crystallizes out and is accordingly simple to remove, e.g. by filtration. It is wholly surprising that the telomer loses only the (respective) Y-posiiioned alcohol R5OH in the cleavage step of the process in accordance with the invention. While some of the educts of the process in accordance with the invention are known, other precursors, which are in part known, can be produced according to methods known per se. Thus, for example, the novel polyene 0,0-ethyIene acetals of formula II can be produced very simply in a known general manner by reacting the polyene aldehyde of the formula A-CHO with an optionally alkyl- or dialkyl-substiiuted 2-lower alkoxy-1,3-dioxolane of the general formula wherein R^ and R"* have the significances given above and R^ signifies lower alkyl, preferably Ci-4-alkyl, especially methyl, in the presence of a catalytic amount of a Lewis acid, e.g. p-toluenesulphonic acid or zinc chloride. The reaction conveniently takes place in an organic solvent, which is suitably an aprotic polar or non-polar solvent. Preferred among such solvents are lower ahphatic hydrocarbons, e.g. hexane; lower halogenated aliphatic hydrocarbons, e.g. methylene chloride and chloroform; lower aliphatic ethers, e.g. diethyl ether; lower aliphatic esters, e.g. ethyl acetate; as well as aromatic hydrocarbons, e.g. benzene and toluene. The reaction is conveniently carried out in the temperature range of about -2(PC to about +50OC, and as a rule takes about 1 to 4 hours. Many examples of the general methodology are known from the literature; see, inter alia, J.A.C.S. 109, 1597 et seq. (1987), ibid, 101, 2171 et seq. (1979) and Synlett 1992, 766 et seq. The optionally alkyl- or di alkyl-substituted 2-lower alkoxy-l,3-dioxolanes themselves can be produced previously in situ from the corresponding lower alkyl orthoformate and the corresponding optionally alkyl- or dialkyl-substituted ethylene glycol in the presence of an aforementioned Lewis acid. The alkanol R^OH which thereby results must be removed very carefully, preferably continuously, from the equilibrium, conveniently by continuous evaporation under reduced pressure. The polyene aldehydes A-CHO in turn are either known, especially from the scientific literature concerning carotenoids, or - where novel - can be produced according to methods known per se. Thus, for example, the reaction of various Cjs-Witlig salts with 2,7-dimethyl-2,4,6-octatiiene-l,8-dial (the so-called "Cso-dial") to give the corresponding monoaldehydes, the reaction of various Cs-Wittig aldehydes with long-chain polyene aldehydes likewise to give such monoaldehydes as well as the two-fold reaction of the Cjo-dialdehyde with Cy or Cio-Wittig aldehydes to give various dialdehydes are known from this literature. The textbooks "Carotenoids" (O. Isler, pubUshed by Birkhauser, Base] and Stuttgart, 1971), especially chapters VI and XII thereof and the further literature mentioned therein, and "Carotenoids, Volume 2 : Synthesis" (G- Britton, S. Liaaen-Jensen and H. Pfander, published by Birkhauser, Basel Boston Berlin, 1996), especially chapters in and Vn therein, provide much useful information relating to the production and the occurrence of the known mono- and dialdehydes. Where educts which feature protected hydroxy, oxo or formyl groups are used, such "protected" educts can be produced, for example, directly from the corresponding unprotected educts according to methods known per se. The l-alkoxy-l,3-dienes of formula IQ are in part known compounds; the remaining (novel) compounds can be produced from known starting materials according to methods known per se. Thus, for example, l-ethoxy-2-methyl-l,3-butadiene (formula EI in which R" signifies hydrogen, R2 signifies methyl and R^ signifies ethyl) has been known from the literature for a long time [see, inter alia, J.A.C.S. 91, 3281 et seq. (1969), Bull. Soc. Chim. Fr. 1963,1646 et seq. as well as J. Gen. Chem. USSR 29, 3649 et seq. (1959)] and has in each case been produced by the two-fold cleavage of ethanol from 1,1,3-triethoxy-2-methyi-butane. The butane, in turn, can be produced by an enol ether condensation which has been known for a long time (see US Patent 2,165,962) from the two readily accessible starting materials acetaldehyde diethyl acetal and ethyl (1-propenyl) ether [see in addition J.A.C.S. 71. 3468 et seq. (1949) as well as J. Gen. Chem. USSR 29, 3641 et seq. (1959)]. In this method about 2 to 3 equivalents of the acetal per equivalent of ethyl propenyl ether are heated slightly at about 35°C for up to about 2 hours with about 0.2 mol percent of boron trifluoride etherate as the catalyst in the absence of a solvent, the desired butane being obtained in an about 66% yield. The subsequent two-fold cleavage of eihanol from the l,l,3-tfiethoxy-2-methyl-butane has been realized in accordance with the relevant state of the art in two different ways, namely by cleavage in the liquid phase (Bull. Soc. Chim. Fr. 1963,1646 et seq.) or by cleavage in the gas phase [J. Gen. Chem. USSR 29, 3649 et seq. (1959) and US Patent 2,573,678], preferably according to the latter method. The l-methoxy-2-methyl"l,3-butadiene (formula HI in which Rl^ signifies hydrogen and R2 and R^ both signify methyl) is also known from the literature [Japanese Patent Publication (Kokai) 50891/1989]. It can be produced, for example, analogously to the production of l-ethoxy-2-methyl-l,3-butadiene described above starting from acetaldehyde dimethyl acetal and methyl (1-propenyl) ether via l,l,3-trimethoxy-2-methy]-butane. Review aiticles for the production of l-alkoxy-l,3-dienes will be found in Russian Chem. Rev. 38. 237 et seq. (1969) and in Pure and Appl. Chem. 47, 173 et seq. (1976); for additional literature concerning their production by gas phase catalysis reference is made to Lieb. Ann. Chem. 568,1 et seq. (1950), Can. J. Res. B 28, 689 et seq. (1950), ibid. B 25, 118 et seq. (1947) as well as Chem. Her. 77,108 et seq. (1944). The novel starting materials and intermediates of the process in accordance with the invention, i-e. the compounds of general formulae 11 and IV, especially 11" and IV" (TV in which the symbol A is replaced by R) represent a further aspect of the present invention. Among these novel compounds there are to be found: 12"-Apo-3-carotenal ethylene acetal and S"-Apo-p-carotenal ethylene acetal and, respectively, 12"-methoxy-ir,12"-dihydro-8-apo-p-carotenal ethylene acetal. The final products of the process in accordance with the invention, i.e. the polyene aldehydes of general formula I, belong for the most part to the carotenoid field and can be used appropriately, for example as colorants or pigments for foodstuffs, egg yolk, the integuments (especially skin, legs and beak) and/or the subcutaneous fat of poultry, the flesh and/or the integuments (especially skin, scales and shell) of fish and crustaceans etc. This use can be effected according to methods known per se, as described, for example, in European Patent Publication No. 630,578. The use of the novel final products represents a further aspect of the present invention. The invention is illustrated on the basis of the following Examples. A. Production of the polvene 0.0-ethvlene acetals (compounds of the formula 11) Example 1 12-Apo-β-carotenal ethylene acetal 18.6 g (16.7 ml, 0.3 mol) of ethylene glycol, 21.2 g (22 ml, 0.2 mol) of trimethyl orthoformate and 0.1 g of p-toluenesulphonic acid monohydrate were placed in a round flask. The methanol resulting from trans-acetalization was removed on a rotary evaporator at 30OC/100 mbar (10 kPa) for 1 1/2-2 hours to a constant weight of 25 g. The resulting water-clear solution was then added to a suspension of 35.1 g (O.I moi) of 12-apo-P-carotenal in 350 ml of hexane. The reaction mixture was stirred at room temperature, with the educt slowly passing into solution. The product began to crystallize out after about one hour. After a total of 3 1/2. hours 0.5 ml of triethylamine was added thereto, the mixture was poured into 100 ml of water and extracted with 600 ml of diethyl ether, and the solution was washed with 100 ml of saturated sodium chloride solution. After drying with anhydrous magnesium sulphate it was filtered and concentrated. This gave 39.5 g of crude product as yellow needles which were dissolved in 600 ml of diethyl ether, treated with 350 ml of methanol and again freed from ether on a rotary evaporator at 200 mbar (20 kPa). The ice-cold suspension which thereby resulted was suction filtered and the crystals were washed with 300 ml of ice-cold methanol. Drying for eighteen hours at room temperature/0.1 mbar (10 Pa) gave 32.7 g (83%) of 12"- apo-3-carotenal ethylene acetal as pale yellow needles with m.p. l28°C; conieni according to HPLC: 99.3%; UV (hexane): 392 nm (log E = 4.93), 376 nm (log E = 4,94); IR {no CHO). MS: 394 (M+, 100); ^H-NMR (400 MHz. CDCI3): 3.9-4.1 (2m, in each case 2H, OCH2CH2O), 5.19 (s, IH, OCHO), no CHO. Microanalyis: Calc: C 82.18% H 9.71% Found.: C 82.38% H 9.78% Example 2 8"-Apo-B-carotenal ethylene acetal 3.7 g (60 mmol) of ethylene glycol, 4.25 g (40 mmol) of triinethyl onhofonnate and 20 mg of p-toluenesulphonic acid monohydiate were placed in a round flask. The methanol resulting by trans-acetalization was removed on a rotary evaporator at 30°C/100 mbar (10 kPa) for 2 V2 hours to a constant weight of 4.4 g. The resulting solution was then added to 4.17 g (10 mmol) of 8"-apo-p-carotenal in 50 ml of toluene. The reaction mixture was stirred at room temperature for 6 hours. Then it was neutralized with 0.5 ml of triethylamine, diluted with 100 ml of diethyl ether, washed with 50 ml of water and with 50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. This gave 5.0 g of dark red, oily crystals, which were recrystallized from 20 nil of ethyl acetate (4(PC) and 50 ml of methanol (about 16 hours at 0°C). In this manner there were obtained 2.81 g (61%) of 8"-apo-P-carotenal ethylene acetal as reddish crystals with m.p. 135°C. An analytical sample had m.p. 136°C; content according to HPLC: 99%; UV (cycIohexane/3% CHCI3): 454 nm (log e ~ 5.04), 443 nm (log e = 5.08); MS: 460 (M+, 100); IR (no CHO); ^H-NMR (400 MHz, CDCI3): 3.9-4.1 (2m, in each case 2H, OCH2CH2O), 5.19 (s, IH, OCHO); Microanalysis: Calc: C83.43% H9.63% Found.: C83.14% H 9.45% B. Production of the compounds of formulae IV and V Example 3 12-Methoxv-ir.l2"-dihvdro-8"-apo-B-carotenal ethylene acetal 1.97 g (5 mmol) of 12"-apo-P-carotenal ethylene acetal were suspended in 30 ml of hexane and reacted at 0°C with 1.1 g(ll mmol) of l-methoxy-2-methyl-i,3-butadienein the presence of 10 mg of p-toluenesulphonic acid monohydrate. After 2 1/2 hours the mixture was neutralized with 0.1 ml of tri ethyl amine, diluted with 30 ml of hexane, washed with 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulphate, and the solution was concentrated on a rotary evaporator. This gave 2.8 g of a viscous, dark red oil, which was chromatographed on 140 g of sihca gel (0.04-0.063 mm) with toluene/hexane (95/5). In this manner there was obtained 0.49 g (20%) of 12"-methoxy-l r,12"-dihydro-8"-apo-p-carotenal ethylene acetal as a (9" E/Z) isomer mixture; ^H-NMR (400 MHz, CDCI3): 3.9-4.0 (2 m, in each case 2H, OCH2CH2O), 5.1 (s, IH, OCHO), no CHO; MS 492 (M+, 100). Example 4 12"-Methoxv-ir.l2"-dihvdjo-8"-apo-B-carotenal (through process from 12"-apo-\|3-carotenai ethylene acetal and l-methoxv-2-methvl-l.3-butadiene via 12-methoxv-ir.l2"-dihvdro-8"-apo-\|3-carotenal ethylene acetal) 1.97 g (5 mmol) of I2"-apo-P-carotenal ethylene acetal were reacted with 0.79 g (8 mmol) of I-methoxy-2-methyl-l,3-butadiene in 30 ml of toluene in the presence of 19 mg (2 mol%) of p-loluenesulphonic acid monohydrate at -20oC. After 6 V2 hours at -20°C 10 ml of 90% aqueous acetic acid were added thereto for the hydrolysis and the mixture was stirred at room temperature for about 30 minutes. Then the mixture was washed twice with 20 ml of water, twice with 20 ml of saturated sodium bicarbonate solution and twice with 20 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator. This gave 2.7 g of crude 12" methoxy-ir,12"-dihydro-8"-apo-f3-carotenal as an orange oil. Chromatography on 135 g of silica gel (0.04-0.063 mm) with toluene/ethyl acetate (19:1) gave 1.2 g (54%) of 12"-methoxy-ir,12"-dihydro-8"-apo-p-carotenal as an orange, viscous oil. Purity according to HPLC: 95%; IR (film): 1690 cm-i(CHO); MS: 448 (M+, 100); iR-NMR (400 MHz, CDCI3): 3.2 (s, 3H, OCH3), 3.67 (t, IH, CH-0), 9.40 (s, IH, CHO). Example 5 8"-Methoxy-7".8"-dihvdro-4"-apo-\|3-carotenal (through process from S"-aoo-B-carotenal ethylene acetal and l-methoxy-2-methyl-1.3-butadiene via 8"-methoxv-7".8"-dihvdro-4"-apo-p-carotenal ethylene acetal) 3.35 g (7.5 mmol) of 8"-apo-p-carotena] ethylene acetal were reacted in a 100 ml round flask provided with a magnetic stirrer and argon gasification with 1.3 g (13.5 mmol) of l-methoxy-2-methyl-l,3-butadiene in 50 ml of toluene in the presence of 30 mg of p-toluenesulphonic acid monohydrate at -1(PC. After 3 hours at -lO^C 15 ml of 90% aqueous acetic acid were added in order to hydrolyze the 8-methoxy-7",8"-dihydro-4"-apo-j3-carotenal ethylene acetal formed as the intermediate. The mixture was stirred at room temperature for 2 hours and worked up and chromatographed as described in Example 4, This gave 2.4 g of crude 8"-methoxy-7",8"-dihydro-4"-apo-\|3-carotenal, which was digested in 30 ml of methanol at 45oC, cooled to OoC, filtered off and dried. In this manner there were obtained 1.45 g (36%) of 8"-methoxy-7",8-dihydro-4"-apo-^-carotenal as an orange solid with m.p. 152-30C; purity according to HPLC: 97%; UV (cyclohexane/2% CHCI3): 457 nm (log £ = 5.03), 430 nm (log e = 5.08); ^H-NMR (400 MHz, CDCI3): 3.15 (s, 3H, OCH3); 9.35 (s, IH, CHO); MS: 514 (M+, 100). C. Manufacture of the polyene aldehydes of formula I from the compounds of formula V or II and III (through process) Example 6 8 -Apo- p-carotenal 1.16 g (2.6 mmol) of 12"-methoxy-ir,12"-dihydro-8"-apo-3-carotenal were dissolved in 15 ml of ethano! in a 50 ml round flask and the solution was treated at room temperature with 0.1 ml (0.5 mmol) of 5.4M sodium melhylate solution in methanol, the solution immediately becoming dark and the product crystallizing out slowly. After 30 minutes the mixture was neutralized with 0.2 ml of acetic acid and 1.5 ml of water were added. Then the mixture was cooled, suction filtered and washed once with 2 ml of ethanol/water (19:1) atQoC, once with 2 ml of water and once with 2 ml of ethanol/water (19:1) at QOC. The filter material was dried for 3 hours at SQoC/l.O mbar (10 Pa). In this manner there was obtained 0.80 g (74%) of 8"-apo-3-carotenal as blue-violet crystals with m.p. 135.5-136.5oC; content according to HPLC: 97.7%. Example 7 8-Apo-P-carotenal ("through process from 12-apo-\|3-carotena] ethylene aceta! and l-methoxy-2-methvl-1.3-butadiene via 12"-methoxv-ir.l2"-dihvdro-8-apo-B-carotena! ethylene acetal and 12"-methoxv-ir.l2"-dihydro-8"-apo-[3-carotenal) 57 mg (2 mol%) of p-to!uenesulphonic acid monohydrate were added at -20OC to a solution of 5.91 g (15 mmol) of 12-apo-!3-carotenal ethylene acetyl and 2.36 g (24 mmol) of l-methoxy-2-methyl-l,3-butadiene in 90 ml of toluene. After 4 V2 hours 30 mi of 90% aqueous acetic acid were added for the hydrolysis, the cooling was removed and the mixture was stirred at room temperature for 2 hours. The solution was then washed twice with 60 ml of water each time and twice with 30 ml of saturated sodium bicarbonate solution each time and once with 30 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated. This gave 6,8 g of crude 12"-methoxy-11,12"-dihydro-8"-apo-P-carotenal as an orange viscous oil. This oil was then dissolved in 100 ml of ethanol at room temperature and treated under argon with about 0.3 ml {16 mmol, 11 mo!%) of a 5.4M sodium mevhylate solution, the solution immediately becoming dark and the product crystallizing out. After 40 minutes the mixture was cooled to 0°C, neutralized with 0.6 ml of acetic acid and 4 mi of water were added dropwise. Then the mixture was filtered, washed with 10 ml of elhanol/water (19:1) at 0°C, twice with 10 mi of water each time and twice with lOmlof ethanol/water (19:1) each time at 0°C. After drying for 2 hours at 50°C and 0.1 mbar (10 Pa) there were obtained 4.02 g (63%) of S"-apo-^-caiotenal as blue-violet crystals with m.p. 129-131°C, Content according to HPLC 97.6%. For further purification, the above product (4.02 g) was dissolved in 70 ml of acetone under reflux for about 10 minutes. Then 25 ml of water were added dropwise to the solution through the condenser under reflux and while stirring vigorously, which gave rise to a crystallization, and then the mixture was cooled slowly to 0°C. After stirring in an ice bath for about 2 hours the precipitate was filtered off and washed twice with in each case 10 ml, atotalof 20 ml, of ethanol/water (9:1) at 0°C, twice within each case 25 ml, a total of 50 ml, of water and finally three times with in each case 5 ml, a total of 15 ml, of ethanol/water (9:1) at 0°C. After drying under a high vacuum at room temperature there were obtained 3.40 g (54% yield) of pure 8"-apo-P-carotenal as blue-violet metallic glistening crystals with m.p. 138-138.5°C and a content according to HPLC of 99.5%. A further 0.3 g (about 5%) of 8"-apo-(3-carotenal with m.p. 132°C could be obtained from the mother liquor hy chromatography on silica gel [toluene/ethyl acetate (19:1)], In total there were obtained 3.7 g (about 59%) of S"-apo-p-carotenal. Example 8 4-Apo-P-carotenal 1.30 g (2.37 mmol) of 8"-methoxy-7",8"-dihydro-4-apo-P-carotenal in 30 ml of methanol/ethyl acetate (1:1) were placed in a 100 ml round flask, treated with 0.1 ml (0.5 mmol) of a 5.4M sodium methylate solution in methanol and stirred at 50°C for 2 hours. The dark suspension which formed was then cooled (0°C), filtered off, washed with methanol/water (9:1) and methanol (0°C) and dried under a high vacuum. This gave 1.0 g (81%) of 4-apo-p-carotenal as violet crystals with m.p. 155°C. Content according to HPLC: 96%; UV (cyclohexane/2% CHCI3): 491 nm (log e = 5.11); iR-NMR (400 MHz, CDCI3): 9.45 ppm (CHO). MS: 482 (M+, 100%); IR (Nujol): 1680 cm-i. 1. A process for the manufacture of a polyene aldehyde of the general formula wherein A signifies a monovalent, optionally methyl-substituted, conjugated polyene group and R1 and R2 each signify hydrogen or methyl, with the -CH=CH-C(R1)=C(R2)-CH0 group being situated at the terminal position of the conjugated chain of group A, which process comprises reacting a polyene 0,0-ethylene acetal of the general formula wherein A has the significance given above, with in this case the ethylene acetal group being situated at the terminal position of the conjugated chain of group A, and R3 and R"" each signify hydrogen or Ci-4-alkyl, with a l-alkoxy-l,3-diene of the general formula wherein R1 and R2 have the significances given above and R5 signifies C1-6-alkyl, in the present of a Lewis acid or Bronsted acid to give the compound of the general formula wherein A, R1, R2, R3, R4 and R5 have the significances given above, hydrolyzing the compound of formula IV and cleaving off the alkanol R5OH under basic or acidic conditions from the thus-obtained compound of the general formula wherein A, R1, R2 and R5 have the significances given above, with in this case the -CH(OR5).CH2-C{R1)=C(R2)-CHO group being situated at the terminal position of the conjugated chain of group A. 2. A process according to claim 1, wherein the polyene 0,0-ethylene acetal used is a compound of the general formula wherein R signifies a group (a) or (b) R3 and R4 have the significances given in claim 1, R6 and R7 each independently signify hydrogen, an optionally protected hydroxy group or an optionally protected oxo group, m signifies 0,1, 2, 3 or 4, n signifies 0 or 1, p signifies 0,1 or 2 and q signifies 0,1, 2 or 3, which after carrying out the multistage process in accordance with the invention is converted into the corresponding alicyclic-aiiphatic polyene aldehyde of the general formula or into the corresponding aliphatic polyene aldehyde of the general formula and, where a group (a) is present in the product of formula I, a protecting group which may be present is cleaved off, if desired. 3. A process according to claim 2, wherein R signifies a group (a) in which R^ and R7 both signify hydrogen and n signifies 0. 4. A process according to any one of claims 1 to 3, wherein zinc chloride, zinc bromide, titanium tetrachloride, lithium perchlorate, boron trifluoride etherate or iron(III) chloride is used as the Lewis acid or p-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid, sulphuric acid or trifluoroacetic acid is used as the Bronsted acid. 5. A process according to any one of claims 1 to 4, wherein the Lewis acid or Bronsted acid is used in a catalytic amount which is between about 0.5 and 5 mol percent based on the amount of the polyene 0,0-ethylene acetal of formula H or 13" which is used. 6. A process according to any one of claims 1 to 5, wherein about 1.05 to about 2 equivalents of l-alkoxy-l,3-diene are reacted per equivalent of polyene O,0-ethylene acetal. 7. A process according to any one of claims 1 to 6, wherein the polyene 0,0- ethylene acetal of formula II or II is reacted with the l-alkoxy-l,3-diene of formula III in an organic solvent at temperatures in the range of about -60°C to about +60°C, with a lower aliphatic or cyclic hydrocarbon, a lower halogenated aliphatic hydrocarbon, a lower aliphatic or cyclic ether, a lower aliphatic nitrile or an aromatic hydrocarbon being used as the organic solvent. 8. A process according to claim 7, wherein pentane, hexane, cyclohexane, methylene chloride, chloroform, diethyl ether, tert.butyl methyl ether, telrahydrofuran, acetonitrile or toluene is used as the organic solvent and the reaction is effected in the temperature range of about -20°C to room temperature. 9. A process according to any one of claims 1 to 8, wherein immediately after completion of the reaction of the polyene 0,0-ethylene acelal of formula II or E" with the l-alkoxy-l,3-diene of formula in the intermediate resulting therefrom is itself hydrolyzed in the reaction mixture by adding to the reaction mixture an aqueous solution-of a weak acid, preferably slightly diluted aqueous acetic acid, and subsequently stirring the mixture in the temperature range of about 0°C to room temperature. 10. A process according to any one of claims 1 to 9, wherein the cleavage of the alkanol R5OH from the compound of formula V is carried out by reacting the compound of formula V, dissolved in an organic solvent, in the presence of a catalytic amount of a base such as, for example, an alkali alcoholate, preferably sodium methylate, sodium ethylate, potassium methylate, potassium ethyiate or potassium tert.butyl ate; an amine, preferably triethylamine, l,5-dia2abicyclo[4.3.0]non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene; an alkali metal hydroxide, preferably sodium or potassium hydroxide, or an alkali metal carbonate, preferably sodium or potassium carbonate. J1. Compounds of the general formula wherein R signifies a group (a) or (b) and R3 and R4 each signify hydrogen or C1-4-alkyl, R6 and R7 each independently signify hydrogen, an optionally protected hydroxy group or an optionally protected oxo group, m signifies 0, 1, 2, 3 or 4, n signifies 0 or 1, p signifies 0, 1 or 2 and q signifies 0,1, 2 or 3. 12. Compounds of the general formula wherein R signifies a group (a) or (b) and R1 and R2 each signify hydrogen or methyl, R3 and R4 each signify hydrogen or C1-4-alkyl, R5 signifies C1-6 alkyl, R6 and R7 each independently signify hydrogen, an optionally protected hydroxy group or an optionally protected oxo group, m signifies 0,1, 2, 3 or 4, n signifies 0 or 1, p signifies 0,1 or 2 and q signifies 0, 1, 2 or 3. 13. A compound according to claim 11, selected from 12"-apo-P-carotenal ethylene acetal and 8"-apo-p-carotenaI ethylene acetal. 14. A compound according to claim 12, 12"-methoxy-l r,12"-dihydro-8-apo-p-carotenal ethylene acetal. 15. A process for the manufacture of a polyene aldehyde substantially as herein described and exemplified.

Full Text

The present invention is conceded with a novel process for the manufacture of polygene baldheads from actualized polygene baldheads of shorter chain length by an acid-catalyzed condensation reaction with alkoxydienes.
Lewis acid-catalyzed additions of a,3-unsaturated ethers (enol ethers) to acetyls have been known for a long time and date back to the work of Miiller-Cunradi and Pierson (see US Patent 2,165,962). Hoaglin and Hirsch [J.A.C.S. 71, 3468 et seq. (1949)] investigated this reaction further and broadened the possible applications, which Islet et al. likewise did in the nineteen fifties with respect to the synthesis of 3-carotene, crocetin dialdehyde, lycopene as well as P-apocarotenoids [see Helv. Chim. Acta 39, 249 et seq. and 463 el seq. (1956), ibid. 42, 854 et seq. (1959) as well as US Patents 2,827,481 and 2,827,482]. Later, Mukaiyama [Angew. Chem. 89, 858 et seq. (1977) and Org. Reactions 28, 203 et seq. (1982)] extended the reaction by using the readily accessible trimethylsilyl enol ethers.
Reactions of ethenol alkyl ethers with cyclic acetals, e.g. ethylene acetals, are also known; they afford by addition cyclic compounds having two ring oxygen atoms, e.g. 1,4-dioxacycloheptane [see Mikhailov et al., Izv. Akad. Nauk. SSSR, Otd. Khim. Nauk. 1960, 1903 et seq./Chem. Abs. 55,13409 f (1961) and German Patent 1,031,301/Chem. Abs. 54. 22712 d (I960)].
The first Lewis acid-catalyzed condensations of l-alkoxy-l,3-dienes (dienol ethers) with a,3-unsaturated acetals were reported by Nazarov and Krasnaya [J. Gen. Chem. USSR 28, 2477 et seq. (1958)] and by Makin [Pure & Appl. Chem. 47,173 et seq. (1976), J. Gen. Chem. USSR 31, 3096 et seq. (1961) and 32, 3112 et seq. (1962)]. Here, the coupling of the acetal to the dienol ether takes place as far as can be seen exclusively at its y-position with the formation of a chain-lengthened a,|3-unsaturated acetal, which, however, in competition with the first acetal reacts with further dienol ether with the formation of a further, chain-lengthened a,3-unsaturated acetal etc. [telomer formation; see

also Chemla et al.. Bull. Soc. Chim. Fr. 130, 200 et seq. (1993)]. For this reason such a condensation has been found not to be workable for synthetic purposes, especially for the synthesis of apocarotenoids [Isleretal., Adv. Org. Chem. 4,115 et seq. (1963)].
Not only l-alkoxy-l,3-dienes, but also trimethylsilyloxydienes [of the type CH2=CH-CH=CH-OSi(CH3)3] can be condensed with a,P-unsaturated acetals in the
presence of Lewis acid catalysts, as disclosed by Mukaiyama et al. in Chem. Lett. 1975, 319 et seq. In this coupling too the attack seems to take place exclusively at the terminal (y-) carbon atom of the diene system in order to form "v-products" [see Mukaiyama et al., Bull. Chem. Soc. Jap 50,1161 et seq. (1977) and Japanese Patent Publication (Kokai) 36,645/1977/Chem. Abs. 87, 201825 t (1977)]. In contrast to the reaction with 1-alkoxy-1,3-dienes, in which an a,3-unsaturated acetal results, the reaction of trimethyl¬silyloxydienes with acetals affords an aldehyde which does not react further with the diene (no lelomer formation). Thereby, zinc bromide and many other Lewis acids are required as catalysts only in small amounts [Fleming (et al.), Tetr. Lett. 1979, 3209 et seq. and Chimia 34, 265 et seq. (1980) as well as Brownbridge, Synth. 1983, 85 et seq]. By using this method Mukaiyama et al. were able to synthesize vitamin A [see Kokai 36,645/1977, Chem. Lett. 1975,1201 et seq. and Bull. Chem. Soc. Japan 5j., 2077 et seq. (1978)] and workers from Rhone-Potilenc developed new routes to carotenoids and vitanun A (see DOS 2,701,489 and A.E.C. Social de Chimie Organique et Biologique No. 7824350).
The aforementioned Lewis acid-catalyzed condensation of a dienol ether with an a,P-unsaturated acetal based on the works of Nazarov and Krasnaya, Makin as well as Chemla et al. would be a very valuable access to apocarotenals and bis-apocarotenals if the yield of the desired primary product of the type ...CH=CH-CH(0alkyli)-CH2-CH=CH-CH(0alkyli)(0alkyl2) could be increased and the telomer formation could be suppressed. Thus, the desired polyene aldehyde of the type CH=CH-CH=CH-CH=CH-CHO could be obtained from this primary product by hydrolysis of the acetal group ClOalkyUXOalkyl^) and elimination of alkyl^OH. In addition to the fact that in this reaction the formation of the double bond lakes place under catalytic conditions, no phosphorus-, silicon- or sulphur-containing reagents are required.

Less known from the scientific literature is the coupling of an a,3-unsaturated ethylene acetal with a trimethylsilyloxydiene. Analogously to the "usual" dienol ether condensations with dialkyl acetals, the product results in moderate yields [see again Chem. Lett. 1975, 319 et seq. and Bull. Chem. Soc. Japan 50,1161 et seq. (1977)] according to the equation:

The object of the present invention is to manufacture chain-lengthened polyene aldehydes starting from polyene acetals while avoiding as far as possible the aforementioned disadvantages of the state of the art and replacing the Wittig, Homer or Juha reaction hitherto used for this purpose. This object is achieved in accordance with the invention by reacting a polyene 0,0-ethylene acetal with a l-alkoxy-l,3-diene in the presence of a suitable catalyst, namely a Lewis acid or Bronsted acid, to give the corresponding chain-lengthened 6-alkoxy-a,P-unsaturated polyene aldehyde in the form of its ethylene acetal, hydro!yzing this ethylene acetal to the corresponding aldehyde and finally eliminating the y-positioned alkanol from this aldehyde under basic or acidic conditions in order to obtain the desired conjugated polyene aldehyde. Not only is the reaction of the l-alkoxy-l,3-diene with the polyene 0,0-ethylene acetal novel, but it takes place (so far as can be seen) with exclusive attack at the y-position of the alkoxydiene. The formation of the 5-alkoxy-a,P-unsaturated polyene 0,0-ethyIene acetal must be seen to be a complete surprise. Through the base- or acid-induced elimination of the alkano! subsequent to the hydrolysis a (conjugated) C-C double bond is formed without requiring a phosphorus-, silicon- or sulphur-containing reagent, which is in contrast to the methodology hitherto usually employed in this field.

Accordingly, the present invention is concerned with a process for the manufacture of a polyene aldehyde of the general formula

wherein
A signifies a monovalent, optionally methyl-substituted, conjugated polyene
group and Rl and R2 each signify hydrogen or methyl,
with the -CH=CH-C(R^)=C(R2).CHO group being situated at the terminal
position of the conjugated chain of group A, which process comprises reacting a polyene 0,0-ethylene acetal of the general formula

wherein
A has the significance given above, with in this case the ethylene
acetal group

being situated at the terminal position of the conjugated chain of group A, and R3 and R"* each signify hydrogen or Ci-4-alkyl,

with a l-alkoxy-l,3-diene of the general formula

wherein
R1 and R2 have the significances given above and
R5 signifies C1-6-alky],
in the present of a Lewis acid or Br5nsted acid to give the compound of the general formula

wherein A, R1, R2, R3, R4 and R5 have the significances given above, hydrolyzing the compound of formula IV and cleaving off the alkanol R5OH under basic or acidic conditions from the thus-obtained compound of the general formula

wherein A, R1 R2 and R5 have the significances given above,
with in this case the -CH(OR5)-CH2-C(R1)=C(R2)_CHO group being situated at the
terminal position of the conjugated chain of group A.
The process in accordance with the invention can in principle be used in the case of all of the aforementioned polyene 0,0-ethylene acetats of formula H which feature the ethylene acelal group at the end of the polyene chain. Among such educts there are to be found, inter alia, the following sub-classes [with the abbreviated form of presentation

which is usual in carotenoid chemistry (using simple lines) being used for the structural formulae]:
Alicyclic-aliphatic polyene 0,0-ethylene aceials, which mainly belong to the carotenoid field [as ethylene acetals of asymmetric carotenoid aldehydes having a six-membered (cyclohexene) ring], of the general formula

wherein
R3 and R4 have the significances given above and
R6 and R7" each independently signify hydrogen, an opdonally
protected hydroxy group or an optionally protected oxo group,
m signifies 0, 1, 2, 3 or 4 and
n signifies 0 or 1,
which, after carrying out the multistage process in accordance with the invention, are converted into the corresponding alicyclic-aliphatic polyene aldehydes of the general formula

as well as
aliphatic polyene 0,0-ethylene acetals, which likewise mainly belong to the carotenoid field (as ethylene acetals of open-chain asymmetric carotenoid aldehydes), of the general formula

wherein
R3 and R4 have the significances given above and
p signifies 0, 1 or 2,
q signifies 0, 1, 2 or 3 and
n signifies 0 or 1,
which, after carrying out the multistage process in accordance with the invention, are
converted into the corresponding aliphatic polyene aldehydes of the general formula

The educts of general formulae Ha and lib can be embraced by general formula 11":

wherein
R signifies a group (a) or (b)

and
R3, R4, R6, R"7, m, n, p and q have the significances given above.
After carrying out the multiage process in accordance with the invention the educt of formula 11" is converted into the corresponding product of formula I":

I
Formula I" then embraces formulae la and lb.
Where the product of formula I, especially of formula la, has one or two protected groups (R6, R"^) on the cyclohexene ring, the protecting group(s) present can, if desired, be cleaved off, which represents a further aspect of the present invention.
In the scope of the present invention the term "Ci.4-alk;y]", "Ci-5-aIkyl" or "C1.6-alkyl" embraces straight-chain and branched groups such as, for example, methyl, ethyl and isobutyl. This applies analogously to the alkoxy groups.
The term "protected hydroxy group" embraces usual protected hydroxy groups (especially those vifhich are famihar from the carotenoid field), particularly etherified hydroxy groups and acyloxy groups. The "etherified hydroxy groups" are, for example, C]-5-alkoxy groups, preferably methoxy and ethoxy; C2.4-alkoxy alkoxy groups, preferably 1-methoxy-l-methylethoxy; arylalkoxy groups, preferably benzyloxy; tetrahydro-pyranyloxy; and tri(Ci.5-alkyl)silyloxy groups, preferably trimethylsilyloxy. The acyloxy groups embrace especially alkanoyloxy and aroyloxy groups with up to 8 carbon atoms such as, for example, formyloxy, acetoxy, propionyioxy and benzoyloxy.

The term "protected oxo group" also embraces usual protected oxo groups (especially those which are familiar from the carotenoid field). Acetahzed oxo groups, especially those in which the term protected oxo stands for two Ci.5-aIkoxy groups (e.g. two methoxy groups) or for a C2-6-alkylenedioxy group (e.g. ethylenedioxy or 2,3-butylenedioxy) are preferred. Further, an oxo group can also be protected as an enol ether, primarily in the case of a-hydroxyketones (e.g. R6 and R7 signify hydroxy or oxo or vice versa), whereby the esterification of the enediol can preferably also be effected by the formation of a cyclic acetal or ketal (e.g. with acetone to the acetonide). The oxo group can also be protected, for example, as an imine.
The formulae of polyenes disclosed in the scope of the present invention embrace in each case isomeric forms, e.g. optically active and cis/trans or E/Z isomers, as well as mixtures thereof, unless expressly indicated to the contrary. The carbon atom carrying the residue R6 or R7 where R6 or R7 signifies an optionally protected hydroxy group (see formulae la and Ha) can be mentioned as an example of a chiral (optically active) centre. With respect to E/Z isomerism, there are generally preferred the (ail-E) isomers of the educts and of the products of the process in accordance with the invention.
The first step of the process in accordance with the invention is conveniently carried out by reacting the polyene 0,0-ethylene acetal of formula II with the 1-alkoxy-1,3-diene of formula IH in an organic solvent at temperatures in the range of about -6(PC to about +60°C, preferably in the temperature range of about -20°C to room temperature, and in the presence of a Lewis acid or Brionsted acid. Suitable organic solvents are, in general, all aprotic polar or non-polar solvents. Preferred among such solvents are lower aliphatic and cyclic hydrocarbons, e.g. pentane, hexane and cyclohexane; lower, halogenated aliphatic hydrocarbons, e.g. methylene chloride and chloroform; lower aliphatic and cyclic ethers, e.g. diethyl ether, tert.butyl methyl ether and tetrahydrofuran; lower aliphatic nitriles, e.g. acetonitrile; as well as aromatic hydrocarbons, e.g. toluene. Toluene is the especially preferred solvent. Examples of Lewis acids which can be used are zinc chloride, zinc bromide, titanium tetrachloride, lithium perchlorate, boron trifluoride etherate as well as iron(III) chloride; and of Bronsted acids which can be used are p-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid.

sulphuric acid as well as trifluoroacedc acid. These are generally used in catalytic amounts, conveniently in an amount of between about 0.5 and 5 mol percent based on the amount of polyene 0,0-ethylene acetal employed and preferably in a mol percent range of 1% to 2%. Moreover, about 1.05 to about 2 equivalents, preferably about 1.2 to about 1.4 equivalents, of l-alkoxy-l,3-diene are conveniently used per equivalent of polyene 0,0-ethylene acetal. Furthermore, the reaction is conveniently effected at normal pressure, although generally the pressure is not critical.
If desired, the intermediate of formula IV can be isolated from the reaction mixture and subsequently hydrolyzed lo the corresponding compound of formula V. However, it has been found to be more convenient not to undertake such an isolation and subsequent hydrolysis, but to hydrolyze the intermediate in the reaction mixture itself immediately after completion of the reaction II + III in order in these cases to proceed to the compound of formula V. The hydrolysis can be suitably effected by adding an acid, preferably p-toluenesulphonic acid or slightly diluted aqueous acetic acid, lo the reaction mixture and subsequently stirring the mixture for a time, for example about 30 minutes to about 2 hours, conveniently in the temperature range of about 0°C to room temperature.
The product of formula V can be isolated from the reaction mixture and, if desired, purified in a manner known per se. Typically, the mixture is combined with water and the whole is extracted with a water-immiscible organic solvent such as, for example, with a lower alkane, dialkyl ether or aliphatic ester, e.g. hexane, tert.butyl methyl ether or ethyl acetate, and the organic phase is washed with water and/or sodium bicarbonate solution and/or saturated aqueous sodium chloride, dried and concentrated. The thus-isolated and at least to some extent washed crude product, can then, if desired, be purified further, for example by column chromatography, e.g. using eluents such as hexane, ethyl acetate, toluene or mixtures thereof, or (re)crysiallizaticfn, for example from an alcohol, e.g. methanol or ethanol. Alternatively, and often preferably, the crude product taken up, for example, in a lower alkanol can be reacted directly in the last process step of the present invention, i.e. in the manner of a "through process" II + IE -4 IV ^ V —> I.
With respect to the last process step, i.e. the cleavage of the alkano! R^OH from the compound of formula V, eliminations of the alkanol from P-alkoxyaldehydes or 5-a!koxy-

a,P-unsaturated aldehydes with the formation of the corresponding a,p-unsaturated aldehydes are known from the scientific literature and can be carried out under a variety of conditions. For example, in the manner of known base-induced eliminations 1,8-diaza-bicyclo[5.4.01undec-7-ene is very often used as the base in an amount of about 2 to 4 equivalents based on the amount of aldehyde used. Such conditions are used in the known production of carotenoids [see, inter alia. Bull. Chem. Soc. Japan 50,1161 et seq. (1977), ibid. 51, 2077 et seq. (1978), Chem. Lett. 1975,1201 et seq. and German Offenlegungsschrift 2,701,489] and of vitamin A (see, inter alia, Chem. Lett. 1975,1201 et seq.). Aluminium oxide has also been in the production of vitamin A by alkanol cleavage [J. Gen. Chem. USSR 32, 63 et seq. (1962)]. As examples of acid-induced alkanol cleavages reference is again made to Bull. Chem. Soc. Japan 50, 1161 et seq. (1977) and to J. Gen. Chem. USSR ^0, 3875 el seq. (1960) in which p-toluenesulphonic acid or 85% phosphoric acid is used as the acid catalyst. The buffer system sodium acetate/acetic acid [Helv. Chem. Acta. 32, 249 et seq. and 463 et seq. (1956) and US Patents 2,827,481 and 2,827,482] or sodium formate/formic acid [Synthesis 1981,137 et seq.] has been used for such a cleavage especially in the production of carotenoids. Taking into consideration this and other pertinent literature a person skilled in the art will have no difficulties in finding suitable reaction conditions for the successful performance of the last step of the process in accordance with the invention.
Furthermore, the cleavage of the alkanol R^OH can also be carried out using only catalytic amounts of a base, i.e. with less that one equivalent based on one equivalent of the compound of formula V. Thus, the last process step in this case is conveniently carried out by converting the compound of formula V dissolved in a suitable organic solvent into the corresponding polyene aldehyde of formula 1 in the presence of a catalytic amount of base with cleavage of the alkanol R^OH. Suitable organic solvents are in general protic, aprotic or mixtures thereof such as, for example, alcohols and alcohol mixtures; or aromatic hydrocarbons, e.g. toluene; and lower aliphatic esters, e.g. ethyl acetate. The base can be inorganic or organic, and there are suitable in general strong bases such as, for example, alkali metal alcoholates, e.g. sodium methylate, sodium eihylate, potassium methyiate, potassium eihylate and potassium teri.butylale; amines, e.g. triethylamine, 1,5 diazabicyclo[4.3.0]non-5-ene and l,8-diazabicyclo[5.4.0]undec-7-ene; as well as alkali metal hydroxides and carbonates, especially sodium and potassium hydroxide or carbonate.

As mentioned above, a maximum of one equivalent of base per equivalent of the compound of formula V is conveniently used, preferably about 0.05 to about 0.3 equivalent. The reaction is suitably effected in the temperature range of about -2(PC to about 100°C, preferably at temperatures of about 0°C to about 50°C. Moreover, the reaction is conveniently effected at normal pressure, although in general the pressure is not critical.
It has been found to be especially advantageous to carry out the last process step using a sodium alkoxide as the base and the corresponding alkanol as the solvent at temperatures between about -20°C and the reflux temperature of the respective reaction mixture, preferably in a temperature range of about CPC to about 40^0. Conveniently, either a solution of the sodium alkoxide in the alcohol is prepared in advance or this solution is prepared freshly from metallic sodium and the alkanol. The bringing together of the alkanolic solution of the sodium alkoxide with the solution of the compound of formula V in the (same) alkanol, preferably likewise previously prepared, can be effected in any sequence and preferably at room temperature. The reaction mixture is subsequently stirred and the reaction has normally finished at the the latest after one to three hours.
Irrespective of the chosen procedure for the last process step, the product can be isolated from the reaction mixture and purified in a manner known per se. When a basic catalyst is used, the respective working up normally comprises neutralization of the residual base by addition of an organic or inorganic acid such as, for example, a carboxylic acid, e.g. acetic acid, or an aqueous mineral acid, e.g. dilute sulphuric acid.
In the particular embodiment of the procedure described above using a sodium alkoxide as the base, after completion of the reaction the mixture is conveniently cooled to room temperature or even to about 0°C and thereafter neutralized, preferably with aqueous acetic acid. The crystallization of the product of formula I can also be promoted by further cooling. After its isolation, suitably by filu-ation, the product can be washed, for example with water and/or aqueous alcohol, and finally dried, optionally under reduced pressure. If desired, further methods such as column chromatography andrecrystallization can be employed in order to provide an even purer product.

If desired, protecting groups (R6 and/or R7 as a protected hydroxy or oxo group) which may be present in the obtained product of formula I can be cleaved off according to methods known per se, e.g. by hydrolysis with acid or base.
In the above-defmed process in accordance with the invention A or R preferably signifies a group (a) in which R6 and R7 both signify hydrogen and n signifies 0, R^ and R2 preferably signify hydrogen and methyl, respectively, and R^ and R"* both preferably signify hydrogen.
As mentioned above, in carrying out the process in accordance with the invention there is the advantage over the state of the art (especially the aforementioned works of Nazarov and Krasnaya, Makin as well as Chemla et al.) in that, inter alia, the telomer formation is largely suppressed. Although in the process in accordance with the invention the telomer formation resulting from the further reaction of the compound of formula IV with the l-alkoxy-l,3-diene of formula IH cannot always be suppressed completely, this is finally much less serious than expected. The cleavage of the alcohol R^OH from the compound of V, occurring after the intermediate stage hydrolysis, can be effected readily in the presence of a telomer co-produced in a relatively small amount as a byproduct, e.g. of the formula A-CH(0R5)-CH2-C(R1)=C(R2)-CH(0R5)-CH2-C(R1)=C(R2).CH0 (a single additional reaction), with an analogous alcohol cleavage from the telomer also taking place under the special reaction conditions which are used. However, the latter cleavage does not take place completely in that practically only the alkoxy group OR5 (5-alkoxy) situated next to the terminal aldehyde group is cleaved off. The result of this incomplete alcohol cleavage from the telomer is that the desired product of formula I can be removed much more readily from the byproduct present at this stage than if all alkoxy groups OR5 had been cleaved off from the telomer. Thus, the byproduct, which still has one or more substituents OR5, remains in the mother liquor of the reaction mixture, while the desired product crystallizes out and is accordingly simple to remove, e.g. by filtration. It is wholly surprising that the telomer loses only the (respective) Y-posiiioned alcohol R5OH in the cleavage step of the process in accordance with the invention.

While some of the educts of the process in accordance with the invention are known, other precursors, which are in part known, can be produced according to methods known per se.
Thus, for example, the novel polyene 0,0-ethyIene acetals of formula II can be produced very simply in a known general manner by reacting the polyene aldehyde of the formula A-CHO with an optionally alkyl- or dialkyl-substiiuted 2-lower alkoxy-1,3-dioxolane of the general formula

wherein R^ and R"* have the significances given above and R^ signifies lower alkyl, preferably Ci-4-alkyl, especially methyl,
in the presence of a catalytic amount of a Lewis acid, e.g. p-toluenesulphonic acid or zinc chloride. The reaction conveniently takes place in an organic solvent, which is suitably an aprotic polar or non-polar solvent. Preferred among such solvents are lower ahphatic hydrocarbons, e.g. hexane; lower halogenated aliphatic hydrocarbons, e.g. methylene chloride and chloroform; lower aliphatic ethers, e.g. diethyl ether; lower aliphatic esters, e.g. ethyl acetate; as well as aromatic hydrocarbons, e.g. benzene and toluene. The reaction is conveniently carried out in the temperature range of about -2(PC to about +50OC, and as a rule takes about 1 to 4 hours. Many examples of the general methodology are known from the literature; see, inter alia, J.A.C.S. 109, 1597 et seq. (1987), ibid, 101, 2171 et seq. (1979) and Synlett 1992, 766 et seq.
The optionally alkyl- or di alkyl-substituted 2-lower alkoxy-l,3-dioxolanes themselves can be produced previously in situ from the corresponding lower alkyl orthoformate and the corresponding optionally alkyl- or dialkyl-substituted ethylene glycol in the presence of an aforementioned Lewis acid. The alkanol R^OH which thereby results

must be removed very carefully, preferably continuously, from the equilibrium, conveniently by continuous evaporation under reduced pressure.
The polyene aldehydes A-CHO in turn are either known, especially from the scientific literature concerning carotenoids, or - where novel - can be produced according to methods known per se. Thus, for example, the reaction of various Cjs-Witlig salts with 2,7-dimethyl-2,4,6-octatiiene-l,8-dial (the so-called "Cso-dial") to give the corresponding monoaldehydes, the reaction of various Cs-Wittig aldehydes with long-chain polyene aldehydes likewise to give such monoaldehydes as well as the two-fold reaction of the Cjo-dialdehyde with Cy or Cio-Wittig aldehydes to give various dialdehydes are known from this literature. The textbooks "Carotenoids" (O. Isler, pubUshed by Birkhauser, Base] and Stuttgart, 1971), especially chapters VI and XII thereof and the further literature mentioned therein, and "Carotenoids, Volume 2 : Synthesis" (G- Britton, S. Liaaen-Jensen and H. Pfander, published by Birkhauser, Basel Boston Berlin, 1996), especially chapters in and Vn therein, provide much useful information relating to the production and the occurrence of the known mono- and dialdehydes. Where educts which feature protected hydroxy, oxo or formyl groups are used, such "protected" educts can be produced, for example, directly from the corresponding unprotected educts according to methods known per se.
The l-alkoxy-l,3-dienes of formula IQ are in part known compounds; the remaining (novel) compounds can be produced from known starting materials according to methods known per se.
Thus, for example, l-ethoxy-2-methyl-l,3-butadiene (formula EI in which R" signifies hydrogen, R2 signifies methyl and R^ signifies ethyl) has been known from the literature for a long time [see, inter alia, J.A.C.S. 91, 3281 et seq. (1969), Bull. Soc. Chim. Fr. 1963,1646 et seq. as well as J. Gen. Chem. USSR 29, 3649 et seq. (1959)] and has in each case been produced by the two-fold cleavage of ethanol from 1,1,3-triethoxy-2-methyi-butane. The butane, in turn, can be produced by an enol ether condensation which has been known for a long time (see US Patent 2,165,962) from the two readily accessible starting materials acetaldehyde diethyl acetal and ethyl (1-propenyl) ether [see in addition J.A.C.S. 71. 3468 et seq. (1949) as well as J. Gen. Chem. USSR 29, 3641 et seq. (1959)]. In this method about 2 to 3 equivalents of the acetal per equivalent of ethyl propenyl ether

are heated slightly at about 35°C for up to about 2 hours with about 0.2 mol percent of boron trifluoride etherate as the catalyst in the absence of a solvent, the desired butane being obtained in an about 66% yield. The subsequent two-fold cleavage of eihanol from the l,l,3-tfiethoxy-2-methyl-butane has been realized in accordance with the relevant state of the art in two different ways, namely by cleavage in the liquid phase (Bull. Soc. Chim. Fr. 1963,1646 et seq.) or by cleavage in the gas phase [J. Gen. Chem. USSR 29, 3649 et seq. (1959) and US Patent 2,573,678], preferably according to the latter method.
The l-methoxy-2-methyl"l,3-butadiene (formula HI in which Rl^ signifies hydrogen and R2 and R^ both signify methyl) is also known from the literature [Japanese Patent Publication (Kokai) 50891/1989]. It can be produced, for example, analogously to the production of l-ethoxy-2-methyl-l,3-butadiene described above starting from acetaldehyde dimethyl acetal and methyl (1-propenyl) ether via l,l,3-trimethoxy-2-methy]-butane.
Review aiticles for the production of l-alkoxy-l,3-dienes will be found in Russian Chem. Rev. 38. 237 et seq. (1969) and in Pure and Appl. Chem. 47, 173 et seq. (1976); for additional literature concerning their production by gas phase catalysis reference is made to Lieb. Ann. Chem. 568,1 et seq. (1950), Can. J. Res. B 28, 689 et seq. (1950), ibid. B 25, 118 et seq. (1947) as well as Chem. Her. 77,108 et seq. (1944).
The novel starting materials and intermediates of the process in accordance with the invention, i-e. the compounds of general formulae 11 and IV, especially 11" and IV" (TV in which the symbol A is replaced by R) represent a further aspect of the present invention.
Among these novel compounds there are to be found:
12"-Apo-3-carotenal ethylene acetal and S"-Apo-p-carotenal ethylene acetal and, respectively, 12"-methoxy-ir,12"-dihydro-8-apo-p-carotenal ethylene acetal.
The final products of the process in accordance with the invention, i.e. the polyene aldehydes of general formula I, belong for the most part to the carotenoid field and can be used appropriately, for example as colorants or pigments for foodstuffs, egg yolk, the

integuments (especially skin, legs and beak) and/or the subcutaneous fat of poultry, the flesh and/or the integuments (especially skin, scales and shell) of fish and crustaceans etc. This use can be effected according to methods known per se, as described, for example, in European Patent Publication No. 630,578.
The use of the novel final products represents a further aspect of the present invention.
The invention is illustrated on the basis of the following Examples.
A. Production of the polvene 0.0-ethvlene acetals (compounds of the formula 11)
Example 1
12-Apo-β-carotenal ethylene acetal
18.6 g (16.7 ml, 0.3 mol) of ethylene glycol, 21.2 g (22 ml, 0.2 mol) of trimethyl orthoformate and 0.1 g of p-toluenesulphonic acid monohydrate were placed in a round flask. The methanol resulting from trans-acetalization was removed on a rotary evaporator at 30OC/100 mbar (10 kPa) for 1 1/2-2 hours to a constant weight of 25 g.
The resulting water-clear solution was then added to a suspension of 35.1 g (O.I moi) of 12-apo-P-carotenal in 350 ml of hexane. The reaction mixture was stirred at room temperature, with the educt slowly passing into solution. The product began to crystallize out after about one hour. After a total of 3 1/2. hours 0.5 ml of triethylamine was added thereto, the mixture was poured into 100 ml of water and extracted with 600 ml of diethyl ether, and the solution was washed with 100 ml of saturated sodium chloride solution. After drying with anhydrous magnesium sulphate it was filtered and concentrated. This gave 39.5 g of crude product as yellow needles which were dissolved in 600 ml of diethyl ether, treated with 350 ml of methanol and again freed from ether on a rotary evaporator at 200 mbar (20 kPa). The ice-cold suspension which thereby resulted was suction filtered and the crystals were washed with 300 ml of ice-cold methanol. Drying for eighteen hours at room temperature/0.1 mbar (10 Pa) gave 32.7 g (83%) of 12"-

apo-3-carotenal ethylene acetal as pale yellow needles with m.p. l28°C; conieni according to HPLC: 99.3%; UV (hexane): 392 nm (log E = 4.93), 376 nm (log E = 4,94); IR {no CHO). MS: 394 (M+, 100); ^H-NMR (400 MHz. CDCI3): 3.9-4.1 (2m, in each case 2H, OCH2CH2O), 5.19 (s, IH, OCHO), no CHO.
Microanalyis: Calc: C 82.18% H 9.71%
Found.: C 82.38% H 9.78%
Example 2
8"-Apo-B-carotenal ethylene acetal
3.7 g (60 mmol) of ethylene glycol, 4.25 g (40 mmol) of triinethyl onhofonnate and 20 mg of p-toluenesulphonic acid monohydiate were placed in a round flask. The methanol resulting by trans-acetalization was removed on a rotary evaporator at 30°C/100 mbar (10 kPa) for 2 V2 hours to a constant weight of 4.4 g.
The resulting solution was then added to 4.17 g (10 mmol) of 8"-apo-p-carotenal in 50 ml of toluene. The reaction mixture was stirred at room temperature for 6 hours. Then it was neutralized with 0.5 ml of triethylamine, diluted with 100 ml of diethyl ether, washed with 50 ml of water and with 50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. This gave 5.0 g of dark red, oily crystals, which were recrystallized from 20 nil of ethyl acetate (4(PC) and 50 ml of methanol (about 16 hours at 0°C).
In this manner there were obtained 2.81 g (61%) of 8"-apo-P-carotenal ethylene
acetal as reddish crystals with m.p. 135°C. An analytical sample had m.p. 136°C; content according to HPLC: 99%; UV (cycIohexane/3% CHCI3):
454 nm (log e ~ 5.04), 443 nm (log e = 5.08); MS: 460 (M+, 100); IR (no CHO); ^H-NMR (400 MHz, CDCI3): 3.9-4.1 (2m, in each case 2H, OCH2CH2O), 5.19 (s, IH, OCHO);

Microanalysis: Calc: C83.43% H9.63%
Found.: C83.14% H 9.45%
B. Production of the compounds of formulae IV and V
Example 3
12-Methoxv-ir.l2"-dihvdro-8"-apo-B-carotenal ethylene acetal
1.97 g (5 mmol) of 12"-apo-P-carotenal ethylene acetal were suspended in 30 ml of
hexane and reacted at 0°C with 1.1 g(ll mmol) of l-methoxy-2-methyl-i,3-butadienein the presence of 10 mg of p-toluenesulphonic acid monohydrate. After 2 1/2 hours the mixture was neutralized with 0.1 ml of tri ethyl amine, diluted with 30 ml of hexane, washed with 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulphate, and the solution was concentrated on a rotary evaporator. This gave 2.8 g of a viscous, dark red oil, which was chromatographed on 140 g of sihca gel (0.04-0.063 mm) with toluene/hexane (95/5).
In this manner there was obtained 0.49 g (20%) of 12"-methoxy-l r,12"-dihydro-8"-apo-p-carotenal ethylene acetal as a (9" E/Z) isomer mixture; ^H-NMR (400 MHz, CDCI3): 3.9-4.0 (2 m, in each case 2H, OCH2CH2O), 5.1 (s, IH, OCHO), no CHO; MS 492 (M+, 100).
Example 4
12"-Methoxv-ir.l2"-dihvdjo-8"-apo-B-carotenal (through process from 12"-apo-|3-carotenai ethylene acetal and l-methoxv-2-methvl-l.3-butadiene via 12-methoxv-ir.l2"-dihvdro-8"-apo-|3-carotenal ethylene acetal)
1.97 g (5 mmol) of I2"-apo-P-carotenal ethylene acetal were reacted with 0.79 g (8 mmol) of I-methoxy-2-methyl-l,3-butadiene in 30 ml of toluene in the presence of

19 mg (2 mol%) of p-loluenesulphonic acid monohydrate at -20oC. After 6 V2 hours at -20°C 10 ml of 90% aqueous acetic acid were added thereto for the hydrolysis and the mixture was stirred at room temperature for about 30 minutes. Then the mixture was washed twice with 20 ml of water, twice with 20 ml of saturated sodium bicarbonate solution and twice with 20 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator. This gave 2.7 g of crude 12" methoxy-ir,12"-dihydro-8"-apo-f3-carotenal as an orange oil. Chromatography on 135 g of silica gel (0.04-0.063 mm) with toluene/ethyl acetate (19:1) gave 1.2 g (54%) of 12"-methoxy-ir,12"-dihydro-8"-apo-p-carotenal as an orange, viscous oil. Purity according to
HPLC: 95%; IR (film): 1690 cm-i(CHO); MS: 448 (M+, 100); iR-NMR (400 MHz, CDCI3): 3.2 (s, 3H, OCH3), 3.67 (t, IH, CH-0), 9.40 (s, IH, CHO).
Example 5
8"-Methoxy-7".8"-dihvdro-4"-apo-|3-carotenal (through process from S"-aoo-B-carotenal ethylene acetal and l-methoxy-2-methyl-1.3-butadiene via 8"-methoxv-7".8"-dihvdro-4"-apo-p-carotenal ethylene acetal)
3.35 g (7.5 mmol) of 8"-apo-p-carotena] ethylene acetal were reacted in a 100 ml round flask provided with a magnetic stirrer and argon gasification with 1.3 g (13.5 mmol) of l-methoxy-2-methyl-l,3-butadiene in 50 ml of toluene in the presence of 30 mg of p-toluenesulphonic acid monohydrate at -1(PC. After 3 hours at -lO^C 15 ml of 90% aqueous acetic acid were added in order to hydrolyze the 8-methoxy-7",8"-dihydro-4"-apo-j3-carotenal ethylene acetal formed as the intermediate. The mixture was stirred at room temperature for 2 hours and worked up and chromatographed as described in Example 4, This gave 2.4 g of crude 8"-methoxy-7",8"-dihydro-4"-apo-|3-carotenal, which was digested in 30 ml of methanol at 45oC, cooled to OoC, filtered off and dried.
In this manner there were obtained 1.45 g (36%) of 8"-methoxy-7",8-dihydro-4"-apo-^-carotenal as an orange solid with m.p. 152-30C; purity according to HPLC: 97%; UV (cyclohexane/2% CHCI3): 457 nm (log £ = 5.03), 430 nm (log e = 5.08); ^H-NMR (400 MHz, CDCI3): 3.15 (s, 3H, OCH3); 9.35 (s, IH, CHO); MS: 514 (M+, 100).

C. Manufacture of the polyene aldehydes of formula I from the compounds of formula V or II and III (through process)
Example 6
8 -Apo- p-carotenal
1.16 g (2.6 mmol) of 12"-methoxy-ir,12"-dihydro-8"-apo-3-carotenal were dissolved in 15 ml of ethano! in a 50 ml round flask and the solution was treated at room temperature with 0.1 ml (0.5 mmol) of 5.4M sodium melhylate solution in methanol, the solution immediately becoming dark and the product crystallizing out slowly. After 30 minutes the mixture was neutralized with 0.2 ml of acetic acid and 1.5 ml of water were added. Then the mixture was cooled, suction filtered and washed once with 2 ml of ethanol/water (19:1) atQoC, once with 2 ml of water and once with 2 ml of ethanol/water (19:1) at QOC. The filter material was dried for 3 hours at SQoC/l.O mbar (10 Pa).
In this manner there was obtained 0.80 g (74%) of 8"-apo-3-carotenal as blue-violet crystals with m.p. 135.5-136.5oC; content according to HPLC: 97.7%.
Example 7
8-Apo-P-carotenal ("through process from 12-apo-|3-carotena] ethylene aceta! and l-methoxy-2-methvl-1.3-butadiene via 12"-methoxv-ir.l2"-dihvdro-8-apo-B-carotena! ethylene acetal and 12"-methoxv-ir.l2"-dihydro-8"-apo-[3-carotenal)
57 mg (2 mol%) of p-to!uenesulphonic acid monohydrate were added at -20OC to a solution of 5.91 g (15 mmol) of 12-apo-!3-carotenal ethylene acetyl and 2.36 g (24 mmol) of l-methoxy-2-methyl-l,3-butadiene in 90 ml of toluene. After 4 V2 hours 30 mi of 90% aqueous acetic acid were added for the hydrolysis, the cooling was removed and the mixture was stirred at room temperature for 2 hours. The solution was then washed twice with 60 ml of water each time and twice with 30 ml of saturated sodium

bicarbonate solution each time and once with 30 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated. This gave 6,8 g of crude 12"-methoxy-11,12"-dihydro-8"-apo-P-carotenal as an orange viscous oil. This oil was then dissolved in 100 ml of ethanol at room temperature and treated under argon with about 0.3 ml {16 mmol, 11 mo!%) of a 5.4M sodium mevhylate solution, the solution immediately becoming dark and the product crystallizing out. After 40 minutes the mixture was cooled to 0°C, neutralized with 0.6 ml of acetic acid and 4 mi of water were added dropwise. Then the mixture was filtered, washed with 10 ml of elhanol/water (19:1) at 0°C, twice with 10 mi of water each time and twice with lOmlof ethanol/water (19:1) each time at 0°C. After drying for 2 hours at 50°C and 0.1 mbar (10 Pa) there were obtained 4.02 g (63%) of S"-apo-^-caiotenal as blue-violet crystals with m.p. 129-131°C, Content according to HPLC 97.6%.
For further purification, the above product (4.02 g) was dissolved in 70 ml of acetone under reflux for about 10 minutes. Then 25 ml of water were added dropwise to the solution through the condenser under reflux and while stirring vigorously, which gave rise to a crystallization, and then the mixture was cooled slowly to 0°C. After stirring in an ice bath for about 2 hours the precipitate was filtered off and washed twice with in each case 10 ml, atotalof 20 ml, of ethanol/water (9:1) at 0°C, twice within each case 25 ml, a total of 50 ml, of water and finally three times with in each case 5 ml, a total of 15 ml, of ethanol/water (9:1) at 0°C. After drying under a high vacuum at room temperature there were obtained 3.40 g (54% yield) of pure 8"-apo-P-carotenal as blue-violet metallic glistening crystals with m.p. 138-138.5°C and a content according to HPLC of 99.5%.
A further 0.3 g (about 5%) of 8"-apo-(3-carotenal with m.p. 132°C could be obtained from the mother liquor hy chromatography on silica gel [toluene/ethyl acetate (19:1)], In total there were obtained 3.7 g (about 59%) of S"-apo-p-carotenal.

Example 8
4-Apo-P-carotenal
1.30 g (2.37 mmol) of 8"-methoxy-7",8"-dihydro-4-apo-P-carotenal in 30 ml of methanol/ethyl acetate (1:1) were placed in a 100 ml round flask, treated with 0.1 ml (0.5 mmol) of a 5.4M sodium methylate solution in methanol and stirred at 50°C for 2 hours. The dark suspension which formed was then cooled (0°C), filtered off, washed with methanol/water (9:1) and methanol (0°C) and dried under a high vacuum. This gave 1.0 g (81%) of 4-apo-p-carotenal as violet crystals with m.p. 155°C. Content according to HPLC: 96%; UV (cyclohexane/2% CHCI3): 491 nm (log e = 5.11); iR-NMR (400 MHz, CDCI3): 9.45 ppm (CHO). MS: 482 (M+, 100%); IR (Nujol): 1680 cm-i.

1. A process for the manufacture of a polyene aldehyde of the general formula

wherein
A signifies a monovalent, optionally methyl-substituted,
conjugated polyene group and R1 and R2 each signify hydrogen or methyl,
with the -CH=CH-C(R1)=C(R2)-CH0 group being situated at the terminal
position of the conjugated chain of group A, which process comprises reacting a polyene 0,0-ethylene acetal of the general formula
wherein
A has the significance given above, with in this case the ethylene acetal group

being situated at the terminal position of the conjugated chain of group A, and R3 and R"" each signify hydrogen or Ci-4-alkyl,

with a l-alkoxy-l,3-diene of the general formula
wherein
R1 and R2 have the significances given above and
R5 signifies C1-6-alkyl,
in the present of a Lewis acid or Bronsted acid to give the compound of the general
formula

wherein A, R1, R2, R3, R4 and R5 have the significances given above, hydrolyzing the compound of formula IV and cleaving off the alkanol R5OH under basic or acidic conditions from the thus-obtained compound of the general formula

wherein A, R1, R2 and R5 have the significances given above, with in this case the -CH(OR5).CH2-C{R1)=C(R2)-CHO group being situated at the terminal position of the conjugated chain of group A.
2. A process according to claim 1, wherein the polyene 0,0-ethylene acetal used is a compound of the general formula

wherein
R signifies a group (a) or (b)

R3 and R4 have the significances given in claim 1,
R6 and R7 each independently signify hydrogen, an optionally protected
hydroxy group or an optionally protected oxo group,
m signifies 0,1, 2, 3 or 4,
n signifies 0 or 1,
p signifies 0,1 or 2 and
q signifies 0,1, 2 or 3,
which after carrying out the multistage process in accordance with the invention is converted into the corresponding alicyclic-aiiphatic polyene aldehyde of the general formula

or into the corresponding aliphatic polyene aldehyde of the general formula

and, where a group (a) is present in the product of formula I, a protecting group which may be present is cleaved off, if desired.
3. A process according to claim 2, wherein R signifies a group (a) in which R^ and
R7 both signify hydrogen and n signifies 0.
4. A process according to any one of claims 1 to 3, wherein zinc chloride, zinc
bromide, titanium tetrachloride, lithium perchlorate, boron trifluoride etherate or iron(III)
chloride is used as the Lewis acid or p-toluenesulphonic acid, methanesulphonic acid,
trifluoromethanesulphonic acid, sulphuric acid or trifluoroacetic acid is used as the
Bronsted acid.
5. A process according to any one of claims 1 to 4, wherein the Lewis acid or
Bronsted acid is used in a catalytic amount which is between about 0.5 and 5 mol percent
based on the amount of the polyene 0,0-ethylene acetal of formula H or 13" which is used.
6. A process according to any one of claims 1 to 5, wherein about 1.05 to about 2
equivalents of l-alkoxy-l,3-diene are reacted per equivalent of polyene O,0-ethylene
acetal.
7. A process according to any one of claims 1 to 6, wherein the polyene 0,0-
ethylene acetal of formula II or II is reacted with the l-alkoxy-l,3-diene of formula III in
an organic solvent at temperatures in the range of about -60°C to about +60°C, with a
lower aliphatic or cyclic hydrocarbon, a lower halogenated aliphatic hydrocarbon, a lower
aliphatic or cyclic ether, a lower aliphatic nitrile or an aromatic hydrocarbon being used as
the organic solvent.

8. A process according to claim 7, wherein pentane, hexane, cyclohexane, methylene chloride, chloroform, diethyl ether, tert.butyl methyl ether, telrahydrofuran, acetonitrile or toluene is used as the organic solvent and the reaction is effected in the temperature range of about -20°C to room temperature.
9. A process according to any one of claims 1 to 8, wherein immediately after completion of the reaction of the polyene 0,0-ethylene acelal of formula II or E" with the l-alkoxy-l,3-diene of formula in the intermediate resulting therefrom is itself hydrolyzed in the reaction mixture by adding to the reaction mixture an aqueous solution-of a weak acid, preferably slightly diluted aqueous acetic acid, and subsequently stirring the mixture in the temperature range of about 0°C to room temperature.
10. A process according to any one of claims 1 to 9, wherein the cleavage of the
alkanol R5OH from the compound of formula V is carried out by reacting the compound of
formula V, dissolved in an organic solvent, in the presence of a catalytic amount of a base
such as, for example, an alkali alcoholate, preferably sodium methylate, sodium ethylate,
potassium methylate, potassium ethyiate or potassium tert.butyl ate; an amine, preferably
triethylamine, l,5-dia2abicyclo[4.3.0]non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene; an
alkali metal hydroxide, preferably sodium or potassium hydroxide, or an alkali metal
carbonate, preferably sodium or potassium carbonate.
J1. Compounds of the general formula

wherein
R signifies a group (a) or (b)

and
R3 and R4 each signify hydrogen or C1-4-alkyl,
R6 and R7 each independently signify hydrogen, an optionally protected
hydroxy group or an optionally protected oxo group,
m signifies 0, 1, 2, 3 or 4,
n signifies 0 or 1,
p signifies 0, 1 or 2 and
q signifies 0,1, 2 or 3.
12. Compounds of the general formula

wherein
R signifies a group (a) or (b)

and
R1 and R2 each signify hydrogen or methyl,
R3 and R4 each signify hydrogen or C1-4-alkyl,
R5 signifies C1-6 alkyl,
R6 and R7 each independently signify hydrogen, an optionally protected
hydroxy group or an optionally protected oxo group,
m signifies 0,1, 2, 3 or 4,
n signifies 0 or 1,
p signifies 0,1 or 2 and
q signifies 0, 1, 2 or 3.
13. A compound according to claim 11, selected from
12"-apo-P-carotenal ethylene acetal and 8"-apo-p-carotenaI ethylene acetal.
14. A compound according to claim 12,
12"-methoxy-l r,12"-dihydro-8-apo-p-carotenal ethylene acetal. 15. A process for the manufacture of a polyene aldehyde substantially as herein described and exemplified.

Documents:

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Patent Number

216617

Indian Patent Application Number

2673/MAS/1998

PG Journal Number

17/2008

Publication Date

25-Apr-2008

Grant Date

17-Mar-2008

Date of Filing

26-Nov-1998

Name of Patentee

DSM IP ASSETS B.V.

Applicant Address

HET OVERLOON 1, 6411 TE HEERLEN,

Inventors:

#	Inventor's Name	Inventor's Address
1	AUGUST RUTTIMANN, CHEMIST	41 GENERAL GUISAN-STRASSE, CH-4144 ARLESHEIM,

PCT International Classification Number

C07C 47/21

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	97120814.5	1997-11-27	EUROPEAN UNION