DK170945B1 - Process for Preparation of 13-Cisretinoic Acid and Process for Preparing a Palladium Catalyst for Use in the Process - Google Patents

Abstract

1. A process for the manufacture of 13-cis-retinoic acid, characterized by a) reacting 5-hydroxy-4-methyl-2(5H)-furanone with a salt of the formula see diagramm : EP0111325,P8,F1 wherein R1 , R2 and R3 are aryl or di-(lower-alkyl)-amino and X is halogen, in a lower alkanol in the presence of an alkali metal hydroxide at a temperature of -10 to -50 degrees C, and b) treating the reaction product obtained in step a) in an organic solvent with a compound or a complex of rhodium or palladium other than palladium or rhodium phthalocyanine or a palladium or rhodium compound containing a cyanide ion.

Description

DK 170945 B1

The present invention relates to a particular process for preparing 13-cis-retinoic acid and to a process for preparing a palladium catalyst for use in the process.

13-cis-Retinoic acid (13-cis vitamin A acid) is a valuable drug that can be used to treat acne. However, this isomer is very difficult to prepare. Pattenden and Weedon, J. Chem. Soc.

(C), 1984-1997 (1968) have disclosed a process for the preparation of 13-cis-retinoic acid in which [3-methyl-5- (2,6,6-trimethyl-1-cyclohexen-1-yl)] - 2,4-pentadienyl] triphenylphosphonium salt and 5-hydroxy-4-methyl-2 (5H) -furanone are reacted with a mixture of cis isomers of the retinoic acid. This process has the disadvantage that the yield of the cis isomers of retinoic acid in the mixture is poor. Furthermore, it is difficult to convert this isomer mixture by isomerization to the specific isomer, namely 13-cis-retinoic acid. This is mainly because the 15 isomers obtained by this process have cis configuration at the 11 and 13 positions. It has been found to be very difficult to selectively isomerize the 11-cis double bond without isomerizing the 13-cis double bond. Many of the isomerization techniques used are relatively ineffective in the selective isomerization of the 11-cis double bond. Each isomerization lowers the yield of 13-cis-vitamin-A acid.

Therefore, there has been a need for a process for producing 13-cis-retinoic acid in high yield and in pure form.

According to the invention, it has now been found that 13-cis-retinoic acid can be prepared by

a) Reacts 5-hydroxy-4-methyl-2 (5H) -furanone with a salt of general formula I

X is sp in the 1 1 wherein R 1, R 2 and R 3 represent aryl or di (lower alkyl) amino, and X represents halogen, with a lower alkanol in the presence of an alkali metal hydroxide at a temperature between -10 and - 50 ° C and 5 b) treat the reaction product obtained in step a) in an organic solvent with a compound or complex of rhodium or palladium other than palladium phthalocyanine, rhodium phthalocyanine, a cyanide ion-containing palladium compound and a cyanide ion-containing rhodium.

An aspect of the invention relates to the reaction of the butenolide, 5-hydroxy-4-methyl-2 (5H) -furanone with the Wittig salt of formula 1 to form a mixture containing 13-cis-retinoic acid and 11,13-cis -retin acid. The reaction is carried out under a Wittig reaction conditions. Although the compound of formula I can be any usual Wittig salt, triphenylphosphonium chloride is preferred as the compound of formula I.

In the next process step for preparing 13-cis-retinoic acid, the 11,13-di-cis-retinoic acid is converted either as an isolated compound or in admixture with 13-cis-retinoic acid with yields greater than 90% to 13-cis-retinoic acid. The preferred catalyst for this isomerization is a palladium compound obtained by reacting palladium II nitrate with a tri (lower alkyl) or arylphosphine and tri (lower alkyl) amine. Using this preferred catalyst, the isomerization to 13-cis-retinoic acid is carried out almost immediately at high yield, 25 without recycling.

Furthermore, it has been found that by carrying out the Wittig reaction at temperatures of between -10 and -50 ° C, preferably between -20 and -50 ° C, especially between -30 and -45 ° C, a mixture of 13-cis and 11,13-di-cis isomers with yields of 90% and above. In addition, the use of these temperatures prevents the formation of retinoic acid isomers other than 13-cis or 11,13-di-cis-retinoic acid.

DK 170945 B1 3

In this reaction, a base and an inert organic solvent are generally used. The organic solvent is chosen so that it does not solidify at the low temperatures used for the Wittig reaction. Thus, the choice of a particularly inert solvent depends on the temperature at which the Wittig reaction is carried out. Among the preferred solvents are lower alkanols such as isopropanol, ethanol and methanol, of which isopropanol is particularly preferred.

Preferred bases of the invention are alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. By far the best 10 results in yield and product quality are obtained using potassium hydroxide and isopropanol. In carrying out this reaction, it is generally preferred to operate under an inert gas atmosphere, preferably under nitrogen.

Process step a) of the present invention provides a mixture of the 13-cis and 11,13-di-cis isomers. If desired, this mixture can be converted directly to the 13-cis isomer without isolation of the 11,13-di-cis isomer. On the other hand, if desired, the 11,13-cis isomer can be isolated from the mixture and converted to the 13-cis isomer. When it is desired to decompose the mixture, the usual 20 techniques for cleavage of isomers can be used. A preferred method consists in fractional crystallization.

In general, the Wittig reaction gives a mixture containing ca.

70 - approx. 90% 11,13-di-cis-retinoic acid and ca. 10 - approx. 30% of the 13-cis isomer. When using low temperatures, ie. temperatures of less than 20 ° C and preferably between -30 and -50 ° C are obtained a mixture of retinoic acids with a yield of at least 90%, based on the butenolide used as the starting material.

In the next step of the process of the invention, either 11,13-di-cis-retinoic acid or the mixture containing the 11,13-di-cis and 13-cis isomer is isomerized to pure 13-cis isomer. The isomerization is carried out in an inert solvent, using as a catalyst a compound or complex of palladium or rhodium, except for palladium or rhodium phthalocyanine or a cyanide ion-containing compound or a cyanide ion-containing complex. Generally, the reaction is carried out at temperatures of 10-150 ° C, especially temperatures of 40-65 ° C, especially 45-55 ° C.

It has been found, according to the invention, that these catalysts selectively isomerize the 11-cis double bond to the corresponding trans-double bond, without attacking the 13-cis double bond. Although some rhodium or palladium compounds or complexes do not provide the 13-cis compound with high yield, the fact that they selectively isomerize the 11-cis double bond is of paramount importance.

In such cases, the yields can be improved by recycling the un-converted 11-cis compound and subjecting it to isomerization. If the catalyst was able to isomerize the 13-cis to 13-trans double bond to some extent, a loss of yield would be obtained because the 13-trans double bond cannot be isomerized simply. Since these catalysts in no way attack the 13-cis bond, it is possible to carry out the isomerization, without isolating the 13-cis isomer from the reaction product of the Wittig reaction.

In this way, the reaction product of the isomerization reaction can be subjected to repeated catalytic isomerization to increase the yield without isolating the 13-cis isomer.

Any of the compounds or complexes of palladium disclosed in U.S. Patent No. 4,051,174 can be used for the present invention. Although a homogeneous catalytic system is preferred, a heterogeneous catalytic system may also be used. In the case of heterogeneous catalytic isomerization, the catalyst may be used in the absence of a carrier or it may be applied to a carrier. The carrier can be any conventional carrier, for example, carbon, nickel oxide, alumina, barium sulfate, calcium carbonate and molecular alloy. Certain polymers such as nylon and perlone can also be used as a carrier. The catalyst can be applied to the support by conventional methods.

The palladium or rhodium compounds or complexes used as catalyst of the present invention are preferably salts or complexes of palladium or rhodium. For example, the following palladium salts or complexes may be used: DK 170945 B1 5

PdCl2, PdBr2, PdF2, Pdl2, K2PdCl4, PdS04, K2PdBr4, (CH3CN) 2PdCl2,

Pd (OAC) 2, (benzonitrile) 2PdCl2, (benzonitrile) 2PdBr2, (C3H5PdCl) 2, (cyclohexene-PdCl2) 2, (1,5-cyclooctadiene) PdCl2, (1,5-cyclooctadiene) -PdBr2, (1, 5-cyclooctadiene) Pd12, (cyclooctatetraene) PdBr2, (acrylonitrile) 2PdCl2, Pd (NO3) 4 (NH4) 2, Pd (pyridine) 2 (NO2) 2, [N (CH2) 3benzyl] 2Pd ( NO2) 4, Pd (NH3) 2Cl2, Pd (NH3) 2 (NO2) 2, Pd (2,2-bipyridyl) Cl2, (NH4) 2PdCl4, (NH3) 2PdCl6, PdS2, K2PdCl6, (ethylenediamine) Pd (NO2 ) 3, (amylamino) 2Pd (NO2) 2, (NH3) 4Pd (NO3> 2, Pd (salicylaldoxime) 2, (succinic dinitrile) PdCl2, (cyclooctatetraene) PdCl2, (azobenzene) 2PdCl2, (bipyri-10dyl) Pd (NO2) 2, K2Pd (malonate) 2, (tricyclohexylphosphine) 2PdCl2, (triphenylphosphine) 2PdCl2, tetrakis (triethylphosphite) Pd (0) and tetrakis (triphenylphosphine) Pd (O) The same salts or complexes can also be used.

Furthermore, according to the invention, it has been found that the catalytic isomerization occurs in high yield, without having to be recycled when using a catalyst prepared by reacting a palladium-II salt with a tri (lower alkyl) - or tri (aryl) phosphine, preferably a tri (aryl) phosphine, in the presence of a tri (lower alkyl) amine in an inert organic solvent, preferably acetonitrile. The use of a tri (lower alkyl) amine improves the catalyst and thus the yield obtained by the isomerization.

For best results, it is preferred to use palladium II nitrate as palladium salt. The preferred triarylphosphine is triphenylphosphine. Any usual lower alkylamine can be used to form the complex, and triethylamine is preferred.

In a preferred embodiment of the present invention, palladium II nitrate and the triaryl phosphine are dissolved in acetonitrile. To the acetonitrile solution is added tri (lower alkyl) amine, after which the catalyst precipitates as a precipitate. If desired, the precipitate can be filtered and used to isomerize the 11,13-di-cis isomer, either alone or in admixture with the 13-cis isomer. On the other hand, the solution and the precipitate can be added into the substrate. To prepare the preferred catalyst, 1 mole of palladium II nitrate is reacted with at least 4 moles of triarylphosphine. A greater excess of triphenylphosphine may also be used. However, since it is not particularly advantageous to use larger excess of triphenylphosphine, amounts of more than 10 moles of triphenylphosphine are rarely used per day. moles of palladium salt. For the reaction of the triphenylphosphine with the palladium II nitrate, any usual solvent for triphenylphosphine and palladium II nitrate can be used. The best results are obtained with acetonitrile as the solvent. When using a tri (lower alkyl) amine such as triethylamine to prepare the catalyst, at least 2 moles of triethylamine per m.p. moles of palladium salt or complex. If desired, the tri-10 (lower alkyl ·) amine can be used in greater amounts, e.g. moles of palladium salt or complex. However, with the use of such large quantities, there are only few, if any, advantages.

In carrying out the isomerization, the catalyst is present in catalytic amounts. Generally, the isomerization is carried out in an inert organic solvent. Any usual inert organic solvent may be used. Preferred solvents are ethers such as tetrahydrofuran, nitriles such as acetonitrile and lower alkyl esters of lower alkane carboxylic acids, for example lower alkane carboxylic acid of 2-4 carbon atoms, eg ethyl acetate. It is generally preferred that the catalyst be present in amounts of approx. 0.0001 mol - approx. 0.01 moles per mole of 11,13-di-cis-retinoic acid. The catalyst can be used in excess in an amount of approx. 1 mole pr. mole of 11,13-di-cis-retinoic acid. However, since no benefits are obtained from the use of larger amounts of catalyst, and since these catalysts are expensive, large amounts of catalyst are rarely used. It is generally preferred to use approx. 0.001 - approx. 0.01 mole of catalyst per mole of 11,13-di-cis-retinoic acid.

Following the isomerization, 13-cis-retinoic acid can be isolated from the reaction mixture with high yields by conventional methods such as crystallization. This crystallization can be carried out by adding water to the reaction mixture to form a suspension and cooling the suspension to a temperature between 0 and -5 ° C.

The term "lower alkyl" as used herein refers to straight-chain and branched-chain alkyl groups having 1-7 carbon atoms, e.g., methyl, ethyl, and propyl, preferably methyl. Lower alkoxy includes lower alkoxy groups having 1-7 carbon atoms, for example methoxy and ethoxy.

Lower alkane carboxylic acids contain 2-7 carbon atoms, for example acetic acid, propionic acid and butyric acid. Halogen includes all the halogens, namely fluorine, chlorine, bromine and iodine.

The term "aryl" refers to single-core aromatic hydrocarbon groups such as phenyl which may be unsubstituted or substituted at one or more positions with lower alkylenedioxy, halogen, nitro, lower alkyl or lower alkoxy, and multi-core aryl groups such as naphthyl, anthryl, phenanthryl and azulyl which may be substituted by one or more of the above groups. The preferred aryl groups are substituted and unsubstituted single-core aryl groups, especially phenyl and tolyl.

The process of the invention is illustrated in more detail by the following examples: EXAMPLE 1

A solution of 157.5 g of [3-methyl-5- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4-pentadienyl] triphenylphosphonium chloride (Wittig salt) and 57.0 g of the butenolide, 5-hydroxy-4-methyl-2 (5H) -furanone, in 1000 ml of isopropanol was stirred under a nitrogen atmosphere at -30 ° C. To the solution was added 625 ml of 2N aqueous potassium hydroxide in isopropanol over a period of 1-1.5 hours at a temperature of -30 ± 2 ° C. Then, the reaction mixture was stirred for 10 minutes and poured into 2500 ml of water.

The alkaline (pH 10) solution was extracted with 2 x 500 ml hexane. The combined hexane extracts were washed with 2 x 100 ml methanol-25 water (7: 3 parts by volume) and the wash water added to the original aqueous solution. The combined aqueous solution was acidified (pH 2) by the addition of 250 ml of 4N aqueous sulfuric acid and extracted with 2000 ml and 2 x 1000 ml of ethyl acetate-hexane (2: 8 by volume). The ethyl acetate-hexane extracts were washed separately with 6 x 400 ml methanol-30 water (7: 3 parts by volume) one after the other, using the same washing solution each time. Each methanol-water wash solution was washed successively with 3 x 1000 ml ethyl acetate-hexane (2: 8 by volume), using the same wash solution all the time. For DK 170945 B1 8, a total of 6 organic (ethyl acetate-hexane) extracts and 6 aqueous (methanol-water) extracts were obtained. Thin layer chromatography showed that all triphenylphosphine oxide was in the aqueous phase and that the organic phases contained 11,13-di-cis-retinoic acid and 16.7 wt% 13-cis-retinoic acid. The organic extracts were combined and washed with 7 x 500 ml water. The solvent was evaporated to give 137.2 g (91.5%) of a crystal mixture containing 75.9 wt.% 11,13-di-cis-retinoic acid and 16.7 wt.% 13-cis-retinoic acid.

EXAMPLE 2-35 In Examples 2-35, the Wittig salt and butenolide of Example 1 were reacted with a crystalline mixture of 11,13-di-cis-retinoic acid and 13-cis-retinoic acid. The effect obtained by using different temperatures on the yield is given in the table below. The percentages are by weight. In Examples 2-23 and 26-35, the molar ratio of butenolide to Wittig salt was as in Example 1. Thus, when the amount of butenolide was increased compared to Example 1, the amount of Wittig salt was increased to the same degree so that was the same molar ratio as in Example 1. In Example 24, a 10% molar excess of the Wittig salt was used in comparison with Example 1. In 20 Example 25, a 20% molar excess of the Wittig salt was used in Comparison with Example 1.

Table I

Example No. Mole Butenolide Temperature, ° C% Yield 25 0.02 2 61.5 3 0.02 0 60.0 4 0.02 -20 91.7 5 0.02 0 55.0 30 6 0, 02 -20 81.7 7 0.1 -20 90.0 8 0.1 -20 88.7 9 0.1 -20 84.7 10 0.1 -10 80.7 DK 170945 B1 9

Table 1 continued 11 0.1 -20 91.0 12 0.1 -10 82.3 13 0.1 -30 93.7 5 14 0.1 -30 99.3 15 0.1 -20 86.0 16 0.1 -30 98.3 17 0.1 -30 95.0 18 0.1 -30 95.7 10 19 0.1 -30 96.7 20 0.1 -30 92.3 21 0.1 - 98.7 22 0.1 -30 99.3 23 0.1 -30 92.3 15 24 0.1 -20 93.3 25 0.1 0 91.3 26 0.1 -20 62.0 27 0.5 -25 88.3 28 0.5 -30 91.5 20 29 0.5 -20 90.0 30 0.5 -30 91.7 31 0.5 -30 90.7 32 0.5 - 89.6 33 0.5 -30 93.5 25 34 0.5 -30 93.1 35 0.5 -30 93.2 Example 37

A solution of 137.2 g of the mixture of retinoic acid prepared in Example 1 in 250 ml of tetrahydrofuran and 500 ml of acetonitrile was heated to 50 ° C with vigorous stirring and under a nitrogen atmosphere. A mixture of 111 mg of palladium II nitrate, 509 mg of triphenylphosphine and 98 mg of triethylamine in 25 ml of acetonitrile was added at one time and then rinsed with 25 ml of acetonitrile. The mixture was heated to 50 ° C for 1 hour. Immediately after the addition of the catalyst, the reaction solution became dark. Within 1 minute, crystallization began and within 2 minutes a thick orange suspension was obtained. This was cooled by adding 500 ml of water, kept for 2 hours at 0-5 ° C and filtered. The crystals were washed with 5 x 100 ml cold acetonitrile water (25:75 volume) and dried at room temperature under reduced pressure. 128.5 g of 13-cis-retinoic acid (85.7% by weight based on butenolide) were obtained.

EXAMPLES 38-43 In Examples 38-43, the crystalline mixture of Example 1 containing 75.9% by weight of 11,13-di-cis-retinoic acid and 16.7% by weight of 13-cis-retinoic acid was described in Example 37 process converted to 13-cis-retinoic acid using catalysts other than palladium nitrate and triphenylphosphine. The same conditions were used except that all reactions were carried out for 3 hours at 50 ° C, with 0.1 mole percent catalyst and 2 equivalents of triethylamine, calculated on the catalyst. The isolation of 13-cis-retinoic acid was done by adding an excess amount of water (solvent content at last 62.5% by volume) and filtering. The percentages in Table II are based on the weight 20 of the 13-cis-retinoic acid obtained, based on the weight of the crystalline mixture used as a starting material.

Table II

Example Catalyst Total Analysis 25 No. Yield 13-cis all-trans 11,13-di-cis 38 (PhCN) 2PdCl2 97.0 90.3 4.5 39 (Ph3P) 3RhCl 97.3 58.1 1.8 35.1 30 40 (Ph3P) 2PdCl2 98.0 20.6 - 74.5 41 (Ph3P) RhH (CO) 98.0 66.6 1.1 27.3 42 Pd (NO3) 2 + Ph3P 97.3 91.0 0.6 4.1 43 (Ph2P) 3RuCl2 93.3 15.4 - 78.9 DK 170945 B1 11 EXAMPLES 44-53

Examples 44-53 were carried out by the procedure described in Example 37 using different amounts of catalyst (palladium II nitrate) to convert the crystalline mixture of retinoic acids obtained from Example 1 into 13-cis-retinoic acid.

Table III

Example Mol Catalytic React Yield ^ Yield C Purity No. Butcher, Tension Time, (%) (%) 10 Nolida Mole% Minutes 44 0.1 0.047 30 78.1 70.3 97.2 45 0.1 0.074 30 83.6 78.3 94.0d 46 0.1 0.043 30 91.4 85.3 15 47 0.1 0.070 150 78.5 78.0 48 0.1 0.046 180 84.4 83.0 97.0 49 0.1 0.10 30 86.8 81.0 50 0.5 0.10 60 93.1 82.3 92.7 51 0.5 0.10 60 93.7 85.7 100.5 20 52 0 , 5 0.10 60 94.2 84.8 99.4f

53 0.5 0.10 60 94.5 86.7 99.8S

a. in the preparation of the starting material of Example 1 b. calculated on the isomer mixture used 25 c. calculated on the butenolide (not corrected) used in the preparation of the starting material. d. product contained 1.4% 11,13-di-cis-retinoic acid product containing 0.8% 11,13-di-cis-retinoic acid f. product containing 0.7% all-trans and 0.5% 11,13-di-cis-retinoic acid g. product containing 0 , 7% 11,13-di-cis-retinoic acid.

Example 170

All operations were performed under nitrogen atmosphere. In a 190 liter stainless steel reaction vessel, which was cooled with dry ice-acetone and equipped with a stirrer, was poured 34.3 kg of isopropanol, 5 5.0 kg of 5-hydroxy-4-methyl-2 (5H) - furanone and 23.0 kg of [3-methyl-5- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4-pentadienyl] -triphenylphosphonium chloride. The mixture was stirred until a solution was formed and then cooled to a temperature between -22 and -25 ° C and maintained at this temperature. Then, during 10 1.5 hours, 49.9 kg of a 2.0N potassium hydroxide isopropanol solution (5-10 ° C) was added at a temperature between -22 and -25 ° C. Then, the reaction mixture was stirred for an additional hour at between -22 and -25 ° C and added to 151.4 kg of deionized water and 54.6 kg of hexane at room temperature. The mixture was stirred for 10 minutes and then allowed to settle and the lower phase (containing the material) was separated. The hexane phase was extracted with a mixture of 4.8 kg of methanol and 2.6 kg of deionized water. The methanol-water extract and the product-containing phase were maintained at 0-10 ° C under a nitrogen atmosphere.

The procedure described above was carried out a further 3 times, 20 so that in total in four reactions 20.0 kg of C5-butenolide was used.

The four abutments were combined and acidified to a pH of 4.0-4.5 by the careful addition of 32.5-35.6 kg of 85% by weight aqueous phosphoric acid. The obtained reaction mixture was extracted with a mixture of 115.8 kg of ethyl acetate and 343.9 kg of hexane (extract 25 # 1).

Extract # 1 was washed with 94.6 kg of deionized water and with 6 portions of a mixture of 54.4 kg of methanol and 29.5 kg of deionized water. Each of the washings was successively extracted with 5 portions of a mixture of 44.2 kg of ethyl acetate and 131.3 kg of hexane. The ethyl acetate-hexane extracts were combined and at a pressure of 50-100 mm Hg and an internal temperature of 20-30 ° C reduced to a final volume of approx. 570 1. The vacuum was removed under nitrogen and 2.0 kg of coal was added. The charge was stirred for 30 minutes at 20-25 ° C with the charcoal and filtered through a diatomaceous earth filter. The filter cake was washed with 34.1 kg of ethyl acetate and the wash water was added to the batch. The charge was evaporated as above to a volume of 95 1. Then the charge was added to 34.1 kg of ethyl acetate and again reduced to a volume of 95 1. The temperature of the charge was adjusted to 50 ° C, after which a solution of 2.65 was added. 5 kg of acetonitrile containing 33.7 g of palladium II nitrate, 162.4 g of tri-phenylphosphine and 31.8 g of triethylamine. The solution was added to the batch with an additional 1 L of ethyl acetate. The charge was then stirred at 50 ° C for one hour, cooled to a temperature between -10 and -15 ° C over 2 hours and kept overnight at this temperature.

The crystals of crude 13-cis-retinoic acid were filtered off and washed 3 times with 10.2 kg of ethyl acetate at a temperature between -10 and -15 ° C. The crystals were thrown as dry as possible in the centrifuge.

356.4 kg of ethyl acetate, 39.7 kg of ethyl acetate moist 13-cis-retinoic acid and 2.0 kg of coal were heated to reflux (75-80 ° C).

The mixture was refluxed for 30 minutes. The solution was filtered under pressure through a diatomaceous earth filter. The filter was washed with 68.1 kg of ethyl acetate and the wash water added to the charge.

The charge was evaporated under a nitrogen atmosphere to a volume of 11.5 liters at an internal temperature of 75-80 ° C. The charge was then cooled to a temperature of between -10 and -15 ° C and left at this temperature overnight. The obtained crystals of pure 13-cis-retinoic acid were filtered off and washed with 3 portions of 10.2 kg of ethyl acetate at a temperature between -10 and -15 ° C. The crystals were dried for 24 hours at a pressure of 50-100 mm Hg at 35 ° C under nitrogen atmosphere.

EXAMPLE 55

A solution of 262.5 g of [3-methyl-5- (2,6,6-trimethyl-2-cyclohexen-1-yl) -2,4-pentadienyl] -triphenylphosphonium chloride, 57.0 g of C5 * butenolide (0.500 mole) and 1000 ml of isopropanol were cooled under nitrogen atmosphere to -25 ° C and over 1 hour at a temperature between -20 and -25 ° C was added 625 ml of 2, ON potassium hydroxide isopropanol (1.25 moles ). Then the mixture was stirred for a further 1 hour at -25 ° C and then poured into 2500 ml of deionized water. The obtained mixture was extracted with 2 x 500 ml hexane to remove nonpolar impurities. The combined hexane phases were washed with 2 x 100 ml methanol-water (70-30% by volume). The combined aqueous phases were adjusted to pH 4 by the addition of 55 ml of 85% phosphoric acid, and the resulting suspension was extracted with 2000 ml of ethyl acetate-hexane (20-80% by volume). This extract was washed successively with 6 x 400 ml methanol-water (70-30% by volume). Each wash was stored separately and successively extracted with 5 x 1000 ml ethyl acetate-hexane (20-80% by volume). Then, the 6 ethyl acetate-hexane extracts were combined, washed with 2 x 500 ml deionized water and concentrated under reduced pressure to 130.4 g (86.9% 10%) of a crystalline mixture containing ca. 70-85% by weight of 11,13-di-cis-retinoic acid and ca. 15-30% by weight of 13-cis-retinoic acid.

EXAMPLE 56 130.4 g of the crystalline mixture of Example 55 prepared 15 and 200 ml of ethyl acetate were stirred at 50 ° C under a nitrogen atmosphere and a mixture of 100 mg of palladium II nitrate, 482 mg of triphenylphosphine, 94.4 mg triethylamine and 25 ml of acetonitrile were added. The reaction mixture immediately darkened and crystallized over 1 minute to a thick orange suspension. This mixture was stirred for 20 hours at 50 ° C, cooled for 2 hours to a temperature between -10 and -15 ° C and filtered, and the precipitate was washed with 3 x 50 ml of cold ethyl acetate and dried under reduced pressure. 117.7 g of pure 13-cis-retinoic acid were obtained (90.3% yield of the crystalline mixture prepared according to Example 55, 78.4% total yield calculated on C5-butenolide).

Example 57 121.2 g of the crystalline mixture of 13-cis-retinoic acid and 11,13-di-cis-retinoic acid obtained in Example 55 were dissolved in 500 ml of diethyl ether. From this mixture, 250 ml of ether was distilled off and replaced with the same volume of hexane. An additional 250 ml of hexane was added and the resulting solution was allowed to cool to room temperature and left to stand for approx. 4 hours. The crystals became

Claims (14)

To a solution of 8.0 g of 11,13-di-cis-retinoic acid and 25 ml of ethyl acetate was added under a nitrogen atmosphere a mixture of 10.0 mg of palladium-II nitrate, 60 mg of triphenylphosphine, 9.4 mg triethylamine and 2.5 ml of acetonitrile. Crystallization occurred within 3-5 minutes. The mixture was stirred for 1 hour at 50 ° C, cooled to -10 ° C and filtered. The crystals were washed with 3 x 20 ml of cold (-20 ° C) ethyl acetate and dried under reduced pressure. 7.28 g (91.5%) of 13-cis-retinoic acid were obtained. A process for the preparation of 13-cis-retinoic acid, characterized in that a) reacting 5-hydroxy-4-methyl-2 (5H) -furanone with a salt of the general formula I - x DK 170945 B1 where, R 2 and R 3 represent aryl or di (lower alkyl) amino, and X represents halogen, in a lower alkanol in the presence of an alkali metal hydroxide at a temperature between -10 and -50 ° C and 5 b) treat it in steps a) obtained reaction product in an organic solvent with a compound or complex of rhodium or palladium other than palladium phthalocyanine, rhodium phthalocyanine, a cyanide ion-containing palladium compound and a cyanide ion-containing rhodium compound. 10 Process according to claim 1, characterized in that the reaction is carried out at between -20 and -50 ° C. Process according to claim 1, characterized in that the reaction is carried out at between -30 and 15 -45 ° C. Process according to claim 1, characterized in that the catalyst is prepared by reacting palladium-II nitrate with a triaryl or trialkylphosphine in the presence of a lower alkylamine in a solvent. Wherein R 2 and R 3 are aryl or di (lower alkyl) amino, and X is halogen, in a lower alkanol in the presence of an alkali metal hydroxide at a temperature between -10 and -50 ° C. Process according to claim 4, characterized in that the phosphine is triphenylphosphine and the amine is diethylamine. Process according to claim 5, characterized in that the solvent is acetonitrile. Process for the preparation of 13-cis-retinoic acid, characterized in that 11,13-di-cis-retinoic acid is treated in an inert organic solvent with a catalyst, the catalyst being a compound or a complex of rhodium or palladium, except from palladium phthalocyanine, rhodium phthalocyanine, a cyanide ion-containing palladium compound and a cyanide ion-containing rhodium compound. DK 170945 B1 Process for preparing a mixture containing 13-cis-retinoic acid and 11,13-di-cis-retinoic acid, characterized by reacting 5-hydroxy-4-methyl-2 (5H) -furanone with a salt with the general formula II f ^^ p'Ri ^ Process according to claim 8, characterized in that the reaction is carried out in isopropanol in the presence of an alkali metal hydroxide. Process for preparing a palladium catalyst for use in the process of claim 1, characterized in that one mole of a palladium-II salt, other than palladium-II cyanide and palladium-II-phthalo-cyanine, is reacted with at least 4 moles of a triaryl phosphine in an organic solvent and then adding a tri (lower alkyl) amine in an amount of at least 2 moles of amine per mole of palladium-II salt. Process according to claim 10, characterized in that the triarylphosphine is present in an amount of 4-10 moles per ml. mole of palladium-II salt and the tri (lower alkyl) amine in an amount of 2-20 moles per mole of palladium-II salt. Process according to claim 10, 25, characterized in that the palladium-II salt is palladium-II nitrate and that the phosphine is triphenylphosphine. DK 170945 B1 Process according to claim 12, characterized in that the solvent is acetonitrile. Process according to claim 13, characterized in that the amine is triethylamine.