FI63213C - FOERFARANDE FOER FRAMSTAELLNING AV NYA POLYENFOERENINGAR - Google Patents

Description

RSSr ^ l M (11) KUU * UTUSJULKA, SU A7oi7 fUA L J UTLÄGGNINGSSKIIIPT ΟΟ ^ Ί 3 3¾¾ C. Pc. exam your work It? 10 05 1903

Fa tent cetficlat ^ ^ ^ (51) Kv.ik.3 / i «.a3 0 07 c 57 / ^ 2, 57/60, '; 69/618, 69/615, 105/76 SUOH I —FINLAND (21) Pmnttttukmut - PKiwoWtotot 2837 / T ^ (22) HaInmiapUvi —AmttnlAgri * 27.OQ.7l * (23) Aikup4tvi — GiKi | h «ud« (27.09.7 ^ (41) Tullut | uIMmI (* 1 - Mvlt affwidlg 28.03 76 ** "** · i * registry board f kud» ll <* «n pmt. - ./ m 'och regittantjrralMn An * öfc * n uttajd adi utUkrlftwi publkwrtd JJ-.uj_.0j (32) (33) (31) Fry *** tCMoHww l «| W priorlm (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Grenzacherstrasse I2I + -I8U, CH- 1 + 002 Basel, Switzerland-Switzerland (CH) (72) Werner Bollag, Basel, Rudolf Ruegg, Bottmingen, Gottlieb Ryser,

Basel, Switzerland-Switzerland (CH) (7 ^) Oy Kolster Ab (5 * 0 Process for the preparation of new polyene compounds -Förfarande för framställning av nya polyenföreningar (6l) Addition to patent 62280 - Tillägg till patent 62280

The invention relates to a process for the preparation of novel polyene compounds of the formula I2 according to claim 1 of patent application 90/71 »

R 11 and R 1 R 5 wherein R 1 is halogen or lower alkyl, R 8 is halogen or lower alkoxy,

R 9 is hydrogen, lower alkyl or halogen, R 8 is lower alkoxy, R 6 is hydrogen or lower alkyl and R 9 is carboxyl, alkoxycarbonyl, mono-lower alkylcarbamoyl and salts thereof.

Said lower alkyl groups preferably contain up to 6 carbon atoms, and denote, for example, a methyl, ethyl, propyl, isopropyl, 6321 3 or 2-methylpropyl group. Lower alkoxy groups likewise preferably contain up to 6 carbon atoms and denote, for example, a methoxy, ethoxy or isopropoxy group.

Preferred halogen atoms are fluorine and chlorine.

Said alkoxymethyl and alkoxycarbonyl groups preferably contain alkoxy radicals having up to 6 carbon atoms. These can be branched or straight-chain, e.g. methoxy, ethoxy or isopropoxy residues. But in addition, higher alkoxy radicals having 7 to 20 carbon atoms, in particular a cetyloxy radical, are also possible. Substituents for said alkoxy radicals can be reactive groups such as nitrogen-containing groups, e.g. an optionally alkyl-substituted amino or morpholino group or a piperidyl or pyridyl group.

The monosubstitutes of the carbamoyl group are branched or straight-chain lower alkyl, e.g. methyl, ethyl or isopropyl, e.g. methylcarbamoyl.

With the method according to the invention it is possible to prepare e.g. the following compounds: N- (5-chloro-4-methoxy-5,5,6-trimethylphenyl) -3,7-dimethyl-nona-2,6,6-tetraene-1-acid ethyl ester, 9- (2,6-Dichloro-H-methoxyphenyl) -3,7-dimethyl-nona-2H, 6,8-tetraene-1-acid ethyl ester, 9- (5-chloro-2, U-d imetoxi-6-methylphenyl) -3,7-dimethyl-non-α, 2,2,6-tetraene-1-acid ethyl ester, 9- (2,3,5,6- pentachlorophenyl) -3,7 'dimethyl-nona-2,4,6,8-tetraene-1-acid ethyl ester, 9- (6-methyl-2,2-dimethoxyphenyl) -3,7-dimethyl-nona-2 , 6,8-Tetraene-1-acid ethyl ester, 9 "(2-chloro-U-methoxy-5,6-dimethylphenyl) -3,7" dimethyl-nona-2,1 +, 6,8-tetraene- 1-acid ethyl ester and 9- (6-chloro-1'-methoxy-2,5-dimethylphenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid ethyl ester.

The former ester is most preferred.

The invention is characterized in that a compound of the formula "2 R 5 \", 3 6321 3 is reacted with a compound of the formula

L J n III

in which formulas ms 0 and n = 1 or m = 1 and n = 0, one of the symbols A and B is a formyl group and the other is a triphenylphosphonium methyl group of the formula -CHg-PfXj, wherein X is a phenyl radical and Y is an organic or the anion of the inorganic acid, R 1, R 2, R 2, R 2 and R 2 are as defined above and R 2 is alkoxycarbonyl, and that the carboxylic acid of formula I is optionally saponified and the resulting acid is optionally converted to a salt or amide of formula 1.

Of the inorganic acid anions, Y is chlorine, bromine, iodine or hydrogen sulfate tion, and of the orgasmic acid anions, tosyloxy ion is preferred.

The starting materials of the formulas II and III are in part new compounds. They are obtained, for example, as described in DE-A-25 to 2612.

According to Wittig's instructions, the components of formula II and III are reacted in the presence of an acid scavenger, e.g. an alkali metal alcoholate such as sodium methylate or an optionally alkyl substituted alkylene oxide, especially ethylene oxide or 1,2-butylene oxide, optionally in a solvent, e.g. at a temperature between the temperature and the boiling point of the reaction mixture.

The carboxylic acid ester of the formula I can be hydrolysed in a known manner, e.g. by treatment with bases, in particular aqueous alcoholic solutions of sodium or potassium hydroxide at a temperature between room temperature and the boiling point of the reaction mixture, and the resulting carboxylic acid of the formula I e.g.

The carboxylic acid of the formula I forms salts with bases, in particular alkali metal hydroxides and preferably sodium or potassium hydroxide.

The compounds of the formula I can be obtained as cis-trans mixtures, which, if desired, can be separated into the cis and trans components in a known manner or isomerized entirely into trans compounds.

The compounds of formula I are valuable drugs. They can be used in the local and systemic treatment of benign and malignant neoplasms and pre-malignant lesions, as well as in the systemic and local prevention of said disease states.

In addition, they are suitable for the local or systemic treatment of pimples, dandruff and other skin diseases associated with intensified or morbid cornea, as well as inflammatory and allergic skin diseases. In addition, the process products of formula 6321 3 I can be used to control mucosal diseases involving inflammatory, degenerative or transformative changes.

The toxicity of the new group of compounds is low. For example, when administered intraperitoneally to pregnant mice weighing 30 g, for example, 200 mg / kg of 9- (2-chloro-h-methoxy-3,5,6-trimethylphenyl) -3,7-dimethylnona-2, k , 6,8-t etraene-1-acid ethyl ester was not detectable after fourteen days (ten days of administration in total).

It is only at a daily dose of 1 * 00 mg / kg that the animals show the first symptoms of mild hypervitaminosis A fourteen days (ten days in total), manifested as a 20% weight loss, low hair loss and slight flaking of the skin.

The tumor suppressive effect of the method products is clear. In a papilloma experiment, tumors born with dimethyl tentanthracene and croton oil shrink. Papilloma diameter decreases by 6.1% in two weeks with administration of UOO mg / kg / Week 9- (2-chloro-U-methoxy-3,5,6-trimethylphenyl) -3,7-dimethylnona-2, 6.8 -t etrene-1-acid ethyl esters and U5% at the same compound at 200 mg / kg / week.

The compounds of the formula I can then be used as medicaments, e.g. in the form of pharmaceutical preparations.

Preparations suitable for systemic use can be prepared, for example, by adding to the compound of the formula I as active ingredient non-toxic, unreacted, solid or liquid carriers which are customary in such preparations.

The substances can be administered in or outside the intestine. For intestinal administration, the agents may be in the form of tablets, capsules, granules, syrups, suspensions, solutions, and suppositories. For parenteral administration, injectable solutions are suitable forms of administration.

The dosage of the products according to the invention may vary depending on the mode of use and administration and the needs of the patients.

The daily dose of the products according to the invention may be from 5 to 200 mg in one or more doses. The preferred form of administration is capsules containing from about 10 to about 100 mg of active ingredient.

The preparations may contain inert or also pharmaceutical additives. For example, tablets and granules may contain binders, excipients, carriers, or diluents. For example, liquid preparations may be in the form of a sterile, water-miscible solution. In addition to the active ingredient, the capsules may contain an excipient or a thickening agent. In addition, flavoring agents, conventional preservatives, stabilizers, humectants and emulsifiers, salts for varying the osmotic pressure, buffers and other additives may be used.

The above-mentioned carriers and diluents may be organic or inorganic substances, e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, acacia or polyalkylene glycols. It is a condition that all excipients used in the preparation of the preparations are non-toxic.

For topical treatment, the products according to the invention are preferably used, for example, as ointments, tinctures, beauty creams, solutions, washing liquids, sprays or suspensions. Ointments, lotions and solutions are recommended. Formulations for topical use may be prepared by mixing the active ingredients as active ingredients with non-toxic, inert, topical solid or liquid carriers suitable for such preparations.

Suitable for topical treatment are solutions of about 0.01 to 0.3, preferably 0.02 to 0.1% and about 0.05 to 5, preferably about 0.1 to 2%. , 0% ointments and Beauty Creams.

If desired, antioxidants, e.g. tocopherol, N-methyl-γ-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene, can be incorporated into the preparations.

Effect of the compounds of the invention on the development of skin papilloma compared to retinoic anhydride derivatives.

Experimental Procedure

Groups of four mice were treated with test compounds and the diameter of the papilloma of each mouse was determined and the sum of the diameters was calculated and the diameters of each group were averaged. The measurement was performed before starting medication (day zero) and 2 weeks after the first medication (day lU).

The increase or decrease in mean papilloma diameter was calculated as a percentage of the 0-day value.

The results are shown in Table I, which shows the parameters hypervitaminosis A and the therapeutic ratio T.R. = ^ pUlSg !! a_reE.e | sio :, ED ^ O E / viifcto hypervitaminosis A: min.dose / day is given in Bollag. Europ. J. Cancer, vol. 10 (1971 *) »P · T32-733.

The lower the T.R. that is, the better the relationship between the antitumor activity and toxicity of the test compound.

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Example 1

Dissolve 9.9 g of 2-chloro-L-methoxy-3,5,6-trimethylbenzyltriphenylphosphonium chloride in 50 ml of dimethylformamide. After the addition of 11.6 g of 7-formyl-3-methylocta-2,6,6-triene-1-acid ethyl ester, 10 ml of a freshly prepared sodium ethylate solution prepared from 0.160 g of sodium and 10 ml of absolute ethanol. The reaction mixture is stirred for 12 hours at room temperature, poured into 100% water and extracted with hexane. The hexane extract is shaken three times with methanol-water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by absorption on silica gel (eluent: methylene chloride-hexane 8: 2). The melting point of 9- (2-chloro-U-methoxy-3,5,6-trimethylphenyl) -3,7-dimethylnona-2,2,6-tetraene-1-acid ethyl ester obtained from the eluate after recrystallization from hexane is 90 ° C.

The starting compound 2-chloro-1 + -methoxy-3,5,6-trimethylbenzyl-triphenylphosphonium chloride can be prepared, e.g., as follows:

189 g of 3'-chloro-1,6-dimethylbenzyl chloride are added to 1500 ml of 5N sodium hydroxide solution. 195 g of pink dust are added to the mixture with stirring over a period of two hours. The temperature of the exothermic reaction is maintained by cooling to 70 ° C. The reaction mixture is stirred for 12 hours at 50 ° C and filtered. The filtrate is extracted three times with 800 ml of methylene chloride. The methylene chloride extract is washed with water until neutral, dried over sodium sulfate and evaporated to dryness. The remaining 2-chloro-3,5,6-trimethylbenzene is purified by absorption on silica gel (eluting with hexane-methylene chloride 9-1). The compound has a boiling point of 81 ° C / 9 torr.

70 g of 2-chloro-3,5,6-trimethylbenzene are added dropwise over 30 minutes with stirring to 1 * 00 ml of nitric acid precooled to 0 [deg.] C. (70% v / v). The mixture is stirred for four hours as the temperature slowly rises to + 20 ° C, poured into ice-water and extracted thoroughly with ether. The ether extract is washed six times with 1000 ml of water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining 2-chloro-U-nitro-3,5,6-trimethylbenzene is purified by absorption on silica gel (eluent: hexane-benzene 3: 7). · The melting point of the compound recrystallized from low-boiling petroleum ether is 79 ° C.

Dissolve 11.5 g of 2-chloro-1 + -nitro-3,5,6-trimethylbenzene in 500 ml of ethyl acetate. The solution is diluted with 300 ml of ethanol and hydrogenated under normal conditions by adding 20 ml of Raney nickel. Hydrogenation is stopped when U3 1 hydrogen has been consumed. The catalyst is removed by filtration under a carbon dioxide atmosphere and washed with ethanol. The combined extracts are evaporated to dryness in vacuo.

The residual 1 * -amino-2-chloro-3,5,6-trimethylbenzene has a melting point of 93 ° C after recrystallization from hexane.

11 6321 3

65 g of U-amino-2-chloro-3,5,6-trimethylbenzene are slowly added to 250 ml of concentrated sulfuric acid with stirring and cooling. In this case, the temperature rises to + 60 ° C. By gradually adding 750 g of ice, the mixture is cooled to 0 [deg.] C. and 26 g of sodium nitrite in 80 ml of water are added dropwise over three hours. The reaction mixture is stirred for 90 minutes at 0 ° to + 10 ° C and filtered. The filtrate is distilled with water while adding dropwise 600 ml of sulfuric acid (50% by weight). The distillate is extracted three times with 1000 ml of methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated to dryness. The melting point of the remaining 2-chloro-U-hydroxy-3,5,6-trimethylhentene after recrystallization from hexane is 97 ° C.

Add dropwise, with stirring, 256.5 ml of potassium hydroxide solution (25 w / v) to a solution of 76 g of 2-chloro-k-hydroxy-3,5,6-trimethylbenzene in 1 * 00 ml of metemol and 85.5 ml of in dimethyl sulfate. In this case, the boiling reaction mixture is stirred for four hours under vertical cooling! and then evaporated to dryness. The residue is dissolved in 600 ml of water. The aqueous solution is extracted three times with 600 ml of ether. The ether extract is washed with water until neutral, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oily 2-chloro-h-methoxy-3,5,6-trimethylbenzene has a boiling point of 77 ° ~ 79 ° C / 1 Torr.

65.35 g of 2-chloro-1 + -methoxy-3,5,6-trimethylbenzene, 235 ml of acetic acid, 6 ml of hydrochloric acid (37 w / v) and 107 ml of formaldehyde are mixed. The mixture is stirred for three hours at 70 [deg.] C. and, after cooling, poured into 2000 ml of water. The aqueous solution is extracted three times with 1000 ml of methylene chloride. The methylene chloride extract is washed three times with 1000 ml of water, dried over sodium sulfate and evaporated to dryness. The remaining 2-chloro-h-methoxy-3,5,6-trimethylbenzyl chloride is purified by adsorption on silica gel (low boiling petroleum ether as eluent). After recrystallization from low boiling petroleum ether, the compound has a melting point of 59 ° -63 ° C.

Dissolve 70.8 g of 2-chloro-U-methoxy-3,5,6-trimethylbenzyl chloride in 500 ml of toluene. 77 g of triphenylphosphine are added to the solution and stirred for 18 hours at 100 ° C. The 2-chloro-1 * -methoxy-3,5,6-trimethylbenzyltriphenylphosphonium chloride which precipitates as white crystals is washed with ether and dried in vacuo. The phosphonium salt has a melting point of 215 ° C.

The 7-formyl-3-methylocta-2,2,6-triene-1-acid ethyl ester used as the condensing component can be prepared, e.g., as follows:

Add a small amount of ferric nitrate to 2700 ml of liquid ammonia and 169.5 g of potassium are added portionwise with stirring and cooling. When initially the blue color has disappeared, i.e. After about 30-1 * 5 minutes, acetylene gas is introduced at 3 1 / min until the dark color of the reaction mixture lightens. The gas flow is then reduced to 2 l / min. and a solution of 12,6321 3,500 g of acetic acid in 1 * 25 ml of absolute ether is added dropwise to the mixture. The acetylene gas is passed with stirring for another hour. 1 * 25 g of ammonium chloride are then added portionwise to the reaction mixture, gradually heated to 30 [deg.] C. over 12 hours with the evaporation of ammonia and extracted with 1600 ml of ether. The ether extract is dried over sodium sulfate and evaporated to dryness in vacuo. The boiling point of the remaining 1 *, 1 * -dimethoxy-3-methylbut-1-yn-3-ol after distillation is 33 ° C / 0.03 torr, n ^ 5 - 1.1 * 1 * 80.

Dissolve 198 g of 1, 1,1 * -dimethoxy-3-methylbut-1-n-3-ol in 960 ml of high-boiling petroleum ether and hydrogenate under normal conditions by adding 19.3 g of 5%. palladium catalyst and 19 * 3 g of quinoline. When 33.5 l of hydrogen have elapsed, the hydrogenation is stopped. The catalyst is removed by filtration. The filtrate is evaporated to dryness in vacuo. The boiling point of the remaining 1, 1,1 * dimethoxy-3-methylbut-1-en-3-ol after distillation is 70 ° -72 ° C / 18 torr.

195 ml of phosgene at -10 [deg.] C. are introduced into 1070 ml of carbon tetrachloride. After adding 213 g of pyridine to the solution, 327 g of N, U-dimethoxy-3-methylethylbut-1-en-3-ol are added dropwise at -10 ° to -20 ° C. The reaction mixture is slowly warmed to 25 ° C with stirring, stirred for a further three hours at room temperature, cooled to 15 ° C and 895 ml of water are added. The aqueous phase is separated and discarded. The organic phase is left to stand for 12 hours in the cold, 1 * 8 ml of 5% sulfuric acid are added, the mixture is stirred for 5 hours, washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The boiling point of the remaining 2-formyl-h-chlorobut-2-ene after distillation is 37 ° -1 * 0 ° C / 1.8 torr, n = 1.1 * 895.

165.7 g of 2-formyl-1 + -chlorobut-2-ene are dissolved in 8U0 ml and 367 g of triphenylphosphine are added. The reaction mixture is heated to reflux for 12 hours under nitrogen and then cooled to 20 ° C. The precipitated 2-formyl-but-2-ene-U-triphenylphosphonium chloride has a melting point of 250 ° -252 ° C after washing with benzene and drying.

212.6 g of 2-formylbut-2-ene-U-triphenylphosphonium chloride and 95 g of 3-formylchrotonic acid ethyl ester are added to 1100 ml of butanol and a solution of 57 g of triethylamine in 60 ml of butanol is added at 5 ° C. The reaction mixture is then stirred for six hours at 25 ° C, cooled, poured into water and extracted thoroughly with hexane. The hexane phase is washed several times with methanol-water (6: 1 *) and water, dried over sodium sulfate and filtered.

The filtrate is isomerized for 12 hours by shaking with iodine. Iodine is removed by adding sodium thiosulfate. The filtrate is washed again with water, dried and evaporated to dryness in vacuo. The remaining 7-formyl-3-methylocta-2,6,6-triene-1-acid ethyl ester can be used without further purification.

6321 3 13

Example 2

39 g of 2,6-dichloro-1 + -methoxybenzyltriphenylphosphonium chloride, 16 g of 7-formyl-3-methyl-octa-2,6, triene-1-acid ethyl ester and heating under reflux at 82 ° -85 ° C for two hours with stirring. Uo g of 1,2-butylene oxide. The reaction mixture is then extracted thoroughly with hexane. The hexane extract is washed several times with methanol-water (60: 100), dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by adsorption on silica gel (hexane as eluent). The melting point of 9- (2,6-dichloro-U-methoxy-phenyl) -3,7'-methylmethyl-2,6,8-tetraene-1-acid ethyl ester obtained from the extract after recrystallization from hexane is 117 ° -18 ° C.

The 2,6-dichloro-U-methoxybenzyltriphenylphosphonium chloride used as the starting compound can be prepared, for example, as follows:

Dissolve 77 g of 3,5 'dichloroanisole in 250 ml of ether. After adding 70 ml of formaldehyde (35 w / v), hydrogen chloride is bubbled in for 8 hours at room temperature with stirring. The reaction solution is then poured onto ice and extracted thoroughly with ether. The ether extract is washed with water until neutral, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oily 2,6-dichloro-N-methoxybenzyl chloride has a refractive index n1 of 1.5730.

23.7 g of 2,6-dichloro-U-methoxybenzyl chloride, 26.2 g of triphenylphosphine and 150 ml of absolute benzene are stirred under reflux for 12 hours. Upon cooling, the precipitated 2,6-dichloro-N-methoxybenzyltriphenylphosphonium chloride is dried in vacuo before further use.

Example 3

Prepared as described in Examples 1 and 2 by reacting 2-chloro-U-methoxy-5,6-dimethylbenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,1 +, 6-triene-1-acid chloride in 9- (2-chloro- U-methoxy (5,6-dimethylphenyl) -3,7'-diethylnino-2,6,6-tetraene-1-acid ethyl ester as yellow crystals, m.p. 108-111 ° C.

Example U

Prepared as described in Examples 1 and 2 by reacting 2,3,6-trichloro-1-methoxybenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,6-triene-1-ethyl ester 9- (2,3,6- trichloro-U-methoxy-phenyl) -3,7-dimethyl-nona-2,6,8-tetraene-1-acid ethyl ester, m.p. 126-128 ° C.

Example 5

Prepared as described in Examples 1 and 2 by reacting 2,2-dimethoxy-3,6-dimethylbenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,6, tri-triene-1-acid ethyl ester 9- (2,2-dimethoxy) -3,6-dimethylphenyl) -3,7-dimethylnona-2,1,6,8-tetraene-1-acid ethyl ester, m.p.

6321 3

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79-80 C.

9- (2,1-dimethoxy-3,6-dimethylphenyl) -3,7'-dinethylnona-2,6,8-tetraene-1-acid formed from the resulting ester by saponification melts at 211-215 ° C.

Example 6

Prepared as described in Examples 1 and 2 by reacting 6-chloro-N-methoxy-2,5-dimethylbenzyltriphenylphosphonium chloride with 7-formyl-3-methyl-octa-2,6-triene-1-acid ethyl ester 9- (6-chloro-N-methoxy) - 2,5-dimethylphenyl) -3,7-dimethylnona-2,6,6-tetraene-1-acid ethyl ester, m.p. 106-107 ° C.

Example 7

1 g of 9 '(6-chloro-U-methoxy-2,5-dimethylphenyl) -3,7-dimethylninone-2,2,6,8-tetraene-1-acid ethyl ester is dissolved in 750 ml of ethanol. To the solution is added 1 g of potassium hydroxide dissolved in 63 ml of water. The mixture is heated to boiling for 30 minutes under a nitrogen atmosphere, cooled, poured into water and acidified with hydrochloric acid. The precipitated 9- (6-chloro-U-methoxy-2,5-dimethylphenyl) -3,7-dimethylninone-2,2,6,8-tetraene-1-acid melts at 231-23 ° C.

Example 8 15 g of 9- (6-chloro-U-methoxy-2,5-dimethylphenyl) -3,7-climethylninone-2,2,6,8-tetraene-1-acid are dissolved in 750 ml of tetrahydrofuran. 2.6 U ml (0.7 mol) of phosphorus trichloride are added to the solution. After 12 hours, the mixture is concentrated under reduced pressure to half its volume. A tetrahydrofuran solution containing 10.6 g of ethylamine is then added dropwise to the mixture at 0-5 ° C. The reaction mixture is stirred for 1 h at room temperature, then the mixture is poured into saturated aqueous sodium chloride solution, followed by extraction with methylene chloride. The extract is washed with brine, dried and evaporated to dryness under reduced pressure. The residue, i.e. 9- (6-chloro-U-methoxy-2,5-dimethylphenyl) -3,7-dimethylnona-2,1 +, 6,8-tetraene-1-acid ethylamide, is purified by adsorption on silica gel (eluent methylene chloride / methanol). After recrystallization from ethyl acetate, the product melts at 202-203 ° C.

Example 9

Prepared as described in Examples 1 and 2 by reacting 2, k-dimethoxy-3-chloro-5,6-dimethylbenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,1,6,6-diphenyl-1-acid ethyl ester 9 ~ (2,1-Dimethoxy-3-chloro-5,6-dimethylphenyl) -3-dimethylnona-2,2,6,6-tetraene-1-acid ethyl ester, m.p. 95-96 ° C.

Example 10

Prepared as described in Examples 1 and 2 by reacting 2,3-dimethyl-L-methoxy-6-bromobenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,6,6-triene-1-acid ethyl ester 9- (2,3 -dimethyl-1 - 15,632 (3-methoxy-6-bromophenyl) -3,7-dimethylnona-2,6,6,8-tetraene-1-acid ethyl ester, m.p. III + 115 ° C.

Example 11

Prepared as described in Examples 1 and 2 by reacting 2-fluoro-1 + -methoxy-5,6-dimethylbenzyltriphenylphosphonium chloride with 7-formyl-3-methylocta-2,1 +, 6-triene-1-acid ethyl ester 9- (2-fluoro -5,6-Dimethyl-1H-methoxyphenyl-N, N-dimethyl-n-N, N, 6,8-tetraene-1-acid ethyl ester, mp 106-107 ° C.

Example 12 36.5 g of ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene-7-triphenylphosphonium bromide are dissolved in 200 ml of dimethylformamide. To the solution is added 10.0 g of U-methoxy-2,6-dichlorobenzaldehyde, cooled to 10 ° C, then a solution of 1.61+ g of sodium and 1 + 0 ml of abs is added dropwise. alcohol, and stirred for 12 h at room temperature. The reaction mixture is poured into 500 ml of a 60: 100 mixture of methanol and water. The methanol / water phase is carefully extracted with hexane. The hexane extract is washed first with a mixture of methanol and water 60 and then with water, dried over sodium sulfate and evaporated to dryness. The residue, i.e. 9- (1 + -methoxy-2,6-dichlorophenyl) -3,7-ylethylninone-2,1 +, 6,8-tetraene-1-acid ethyl ester, melts after recrystallization from hexane at 117-118 ° C.

Example 13 228 g of 5- (2-chloro-1-methoxy-3,5,6-trimethylphenyl) -3-methylpenta-2,1 +-diene-1-triphenylphosphonium bromide are added to 910 ml of dimethylformamide under a nitrogen atmosphere. The mixture is cooled to 5-10 ° C and 17.5 g of a mineral oil suspension of sodium hydride (about 50%) are added over 20 minutes. The mixture is stirred for 1 h at about 10 [deg.] C., then 6.1 g of 3-formylchrotonic acid ethyl ester are added, the mixture is heated to 65 [deg.] C. for 2 hours, poured into 8 liters of ice water, 300 g of sodium chloride are added and extracted thoroughly with 18 l of hexane. The extract is washed 5 times with 1 l of a 1: 11 mixture of methanol and water (6: h) and twice with 1.5 l of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue, i.e. 9- (2-chloro-1 + -methoxy-3,5,6-trimethylphenyl) -3,7-dinethylnona-2,1 +, 6,8-tetraene-1-acid ethyl ester, melts after recrystallization from hexane to 88- O9 ° C.

Claims (3)

A process according to claim 1 in patent application 981/7 ** for the preparation of new polyene compounds of the formula "2" - in R 5 where R 1 is halogen or lower alkyl, R 9 is halogen or lower alkoxy, R 2 is hydrogen, lower is lower alkoxy, is hydrogen or lower alkyl and R 9 is carboxyl, alkoxycarbonyl or mono-lower alkylcarbamoyl, especially their salts, characterized in that a compound of formula I2 is R l | L Jm Π T Ri ft5 is reacted with a compound of formula _ J in which formulas m = 0 and n = 1 or m * 1 and n = 0, one of the symbols A and B is a formyl group and the other a triphenylphosphonium methyl group wherein X is a phenyl radical and Y is an anion of an organic or inorganic acid, R 2, R 9, R 2 that, if desired, an ester of formula I is saponified and, if desired, the obtained acid is converted to a site or an amide of formula I. Process according to Claim 1, characterized in that 9 '(2-chloro-U-methoxy-3,5 »6-trimethylphenyl) -3,7-dimethyl-octa-2, U, 6,8-tetraene is prepared. -L-ethyl ester.