DE102008002302A1 - Preparing etretinate, useful to treat severe psoriasis and ichthyosis vulgaris, comprises reacting acitretin with active reagent e.g. 1,1'-carbonyldiimidazole, followed by reacting with ethanol and/or alkali or alkaline earth ethanolate - Google Patents

Abstract

Preparation of etretinate (I) comprises: (a) reacting acitretin (II) with an active reagent, which is 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole or thionyl diimidazole to give 1-(3H-imidazole-1-yl)-3,7-dimethyl-9-(2,3,4,6-tetramethyl-phenyl)-nona-2,4,6,8-tetraen-1-one (III); and (b) reacting (III) with ethanol and/or an alkali or alkaline earth ethanolate to give a reaction mixture containing (I). ACTIVITY : Antipsoriatic; Dermatological. MECHANISM OF ACTION : None given.

Description

Technical field of the invention:

The The present invention relates to an improved method of preparation of etretinate by reaction of acitretin with an activating reagent selected from the group 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole and thionyldiimidazole and ethanol as well as the photochemical or metal-catalyzed isomerization of the E / Z isomers of etretinate.

etretinate is a vitamin A derivative, especially in severe psoriasis u. other keratinization disorders of the skin (eg ichthyosis vulgaris) is used.

State of the art:

In DE 24 14 619 and DE 26 36 879 describes the Wittig reaction between an aryl and an alkenyl building block for the construction of the active substance etretinate. The patent CH 616134 describes the Horner reaction between these building blocks. In Scripture WO 02/34710 Mannich reactions and in EP 802180 Aldol-type reactions used to construct the polyene system.

It in all cases are multistep syntheses, in which the starting materials for this purpose on tedious and cumbersome way must be made specifically. Overall yields are generally insufficient.

Also known in the prior art is the reaction of retinoic acid to retinoic acid esters, wherein the alcohol radical is sterically complex, as in WO 2004/65358 includes a glycerol residue as described in CS 225009 and CS 216980, or according to Synth. Commun. 14 (1984) 725 of corticosteroids.

unterscheidet. Beispielsweise besitzen beide Verbindungen deutlich unterschiedliche Löslichkeiten in vielen organischen Lösungsmitteln.The methods have procedural disadvantages, since they involve elaborate, extractive process steps or chromatographic purification procedures. Furthermore, they are based on the retinoic acid, a polyene, which in many physical and chemical properties of the aromatic acitretin of the formula (II)

different. For example, both compounds have distinctly different solubilities in many organic solvents.

After the lesson of EP 644186 For example, 13Z-retinoic acid isomers can be photochemically isomerized to 13Z-retinoic acid.

task It is an object of the present invention to provide an improved process for Preparation of etretinate starting from the commercially available Acitretin to find the said active substance with a possible low total number of stages, in the highest possible overall yield and in an acceptable for pharmaceutical or pharmaceutical products Purity makes accessible.

ausgehend von Acitretin der Formel II

umfassend die Stufen

• a) Umsetzung von Acitretin der Formel (II) mit einem Aktivierungsreagenz ausgewählt aus der Gruppe der Aktivierungsreagenzien 1,1'-Carbonyldiimidazol, 1,1'-Thiocarbonyldiimidazol und Thionyldiimidazol unter Erhalt des Imidazolids der Formel (III)
  
  und
• b) Umsetzung des in Schritt a) erhaltenen Imidazolids der Formel (III) mit Ethanol und/oder einem Alkali- und Erdalkaliethanolat unter Erhalt eines Etretinat der Formel (I) enthaltenden Reaktionsgemisches.

DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS
The object has been achieved according to the invention by providing a process for the preparation of etretinate (ethyl (2E, 4E, 6E, 8E) -9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2, 4,6,8-nonatetraenoate) of the formula I.

starting from acitretin of the formula II

comprising the steps

• a) Reaction of acitretin of the formula (II) with an activating reagent selected from the group of the activating reagents 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole and thionyldiimidazole to give the imidazolide of the formula (III)
  
  and
• b) reacting the imidazolide of the formula (III) obtained in step a) with ethanol and / or an alkali metal and alkaline earth metal ethanolate to obtain a reaction mixture containing etretinate of the formula (I).

When Starting compounds for carrying out the inventive The method is acitretin of formula II (2E, 4E, 6E, 8E) -9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid) in one for starting or intermediate products of drug syntheses usual purity of about 80 to about 100 wt .-% (based on the mixture used), preferably about 95 to about 100 wt .-% can be used.

The Reaction according to step a) can be solvent-free or preferably in the presence of a suitable aprotic, under the reaction conditions inert solvent performed become. Preference is given to using such solvents or mixtures one in which the starting material acitretin of the formula (II) soluble is readily soluble, for example, dichloromethane, dichloroethane, Tetrahydrofuran (THF), dioxane, dimethyl sulfoxide, dimethylformamide, Dimethylacetamide, N-methylpyrrolidone. As part of a preferred Embodiment leads step a) of the invention Procedure in dichloromethane as a solvent by.

beschrieben, wobei im Falle von 1,1'-Carbonyldiimidazol Z Sauerstoff und im Fall von 1,1'-Thiocarbonyldiimidazol Z Schwefel bedeutet. Thionyldiimidazol weist die Formel (V) auf.The reaction according to the invention in step a) is moreover carried out in the presence, ie using an activating reagent selected from the group of the activating reagents 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole and thionyldiimidazole. The said activating reagents can be used individually or in the form of mixtures with one another. The activating reagents 1,1'-carbonyldiimidazole and 1,1'-thiocarbonyldiimidazole are represented by formula (IV)

in the case of 1,1'-carbonyldiimidazole Z oxygen and in the case of 1,1'-thiocarbonyldiimidazole Z sulfur. Thionyldiimidazole has the formula (V).

in the Framework of a preferred embodiment leads one step a) of the method according to the invention in the presence of 1,1'-carbonyldiimidazole (CDI) or 1,1'-thiocarbonyldiimidazole, most preferably in the presence of 1,1'-carbonyldiimidazole.

The Sequence for the addition of the stated starting materials and reagents to the reaction mixture is usually not critical. Usually It is preferable to apply acitretin with solvent at temperatures from 0 to 78 ° C before and then offset with the selected Activation reagent of the formula (IV) (1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole) or (V) thionyldiimidazole).

The Aktivierungsreagenzien mentioned in commercial Qualities and purities of about 90 to 100 wt .-% used usually require no special prior to use Purification. Thionyldiimidazole is prepared by those skilled in the known Methods z. From thionyl chloride and imidazole (Takahashi, Shimizu, Ogata, Heterocycles (1985) 1483).

wird gemäß Schritt b) des erfindungsgemäßen Verfahrens mit Ethanol und/oder einem Alkali- und Erdalkaliethanolat unter Erhalt eines Etretinat der Formel (I) enthaltenden Reaktionsgemisches umgesetzt.The imidazolide of the formula (III) obtained according to step a)

is reacted according to step b) of the process according to the invention with ethanol and / or an alkali and Erdalkaliethanolat to obtain a etretinate of the formula (I) containing reaction mixture.

Leads Step a) in the presence of a suitable solvent By, it is recommended that this first of the as an intermediate imidazolide of the formula (III) obtained, for example by distillation and then the imidazolide of the formula (III) with ethanol and / or an alkali and Erdalkaliethanolat to move.

For the esterification according to step b) of the invention Process are the common qualities of ethanol suitable. Small amounts of water are not critical. Also disturb usually the usual denaturants not the reaction. Nevertheless, a preferred embodiment the reaction with pure, undiluted alcohol.

The Implementation according to step b) can also be used of alkali and or alkaline earth alcoholates of ethanol such as Sodium, potassium or calcium ethoxide, preferably with use be carried out by sodium or potassium ethanolate.

The Amount ratio of the invention used Starting materials can be varied within wide limits. Considering From the economic point of view, acitretin of the formula (II) and the selected activating reagent as well as acitretin and the chosen ethanolate in a molar ratio from about 1: 1 to about 1: 3, preferably in a molar ratio from about 1: 1 to about 1: 2. The molar ratio of used acitretin of the formula (II) to ethanol is preferably in a range from about 1: 1 to about 1: 100, preferably from about 1:10 to about 1:30 elected.

The Addition of the chosen alcoholate may optionally be before or after that of the solvent. The reaction takes place when using alcoholates usually in the temperature range from 20 ° C to 78 ° C. A preferred temperature range is 10 ° C to 30 ° C. If you perform the procedure according to step b) without the addition of said ethanolates usually by working at higher temperatures, preferably under reflux.

For a successful implementation of step b) of the invention Manufacturing process is not necessarily the use of a catalyst required, but can be influenced advantageous. In particular, the use of nucleophilic catalysts has become proved to be advantageous. A preferred in this respect according to the invention Catalyst is 4- (N, N-dimethylamino) -pyridine (DMAP). A preferred embodiment the process according to the invention is accordingly characterized in that step b) in the presence of 4- (N, N-dimethylamino) pyridine as a catalyst.

After reaching the desired reaction progress is advantageously cooled, the resulting, Et Retinat of formula (I) containing reaction mixture, preferably to temperatures of about -20 to about + 40 ° C, wherein usually the desired etretinate of the formula (I) crystallized in pure form according to step c) of the method according to the invention. The term etretinate in pure form is to be understood as meaning that has a content of etretinate in the form of the all-trans isomer of 80 to 100 wt .-%, preferably from 90 to 100 wt .-%.

Next the said etretinate in pure form is obtained according to the optional step c) of the method according to the invention an etretinate of the formula (I) and isomers of etretinate-containing Mother liquor. Under the term isomers of etretinate are included Double bond isomers with respect to the E / Z configuration of individual ethylenic double bonds of etretinate such. B. (11Z) -Etretinat to understand.

The in the reaction mixture obtained in step b), especially in reaction at elevated Temperature, or in according to step c) after Separation of the etretinate of the formula (I) obtained in pure form Mother liquor-containing isomers of etretinate can by Isomerization at least partially converted into etretinate of formula (I) become. According to a preferred embodiment Accordingly, one carries out the inventive Method by reacting the reaction mixture obtained in step b) and / or the mother liquor obtained according to step c) in an additional step d) of a thermal or photochemical Subject to isomerization. Preference is given only in step c) mother liquor obtained isomerization. By doing so leaves the achievable yield of etretinate increase significantly.

Leads the optional isomerization is irradiated photochemically the reaction mixture or said mother liquor advantageously with light in the wavelength range from 200 to 650 nm. As light source For example, mercury lamps come in different pressure levels (High, medium and low pressure lamps) into consideration. Furthermore is also monochromatic laser light in the wavelength range from 200 to 650 nm.

Leads the mentioned isomerization is photochemically through proved to be advantageous that isomerization a Add photosensitizer. As photosensitizers come both colored as well as fluorescent compounds in question. As examples of his cited: triphenylpyrylium salts, perylene dyes, quinizarin, Quinophthalene, fluorescein, eosin, rose bengal, erythrosin, Euchrysin orange, Rhodamines, diethylsafrinine, astraphloxin, cyanine dyes and theirs Metal complexes with Mg, Zn, Sn, Fe, Ni, Cu and Co, quinoline red, Basacrylbrilliantrot, Malachite green, methylene blue, crystal violet, carotene, zeaxanthin, lycopene, Astaxantin, Canthaxanthin, Lutein, Tetraphenylporphin and his Metal complexes with Mg, Zn, Sn, Fe, Ni, Cu and Co and chlorophyll. Furthermore, mixtures of two or more Photosensitizers are used. Preferred sensitizers are erythrosin, eosin or rose bengal, more preferably erythrosin.

alternative can be said isomerization of double bond isomers of etretinate to etretinate of formula (I) also thermally perform. As a rule, all such isomerizations are general known solvents into consideration.

by virtue of the associated procedural advantages, in particular in the crystallization of the process product, is a preferred Solvent ethanol.

The Thermal isomerization can be done both with the reaction mixture also with the mother liquor in the temperature range from 0 to 140 ° C be performed. If necessary, you lead the thermal isomerization under elevated pressure. Of the Pressure range from 0 to 20 bar is common. A preferred Driving style is under self-pressure. In addition to isomerizations in solution are also possible in suspension.

When Catalysts for thermal isomerization can the commonly used for such reactions metal catalysts be used. A preferred embodiment is the use of palladium catalysts. Are suitable for it both homogeneous palladium catalysts of oxidation state 0, such as tetrakistriphenylphosphinepalladium, as well as the oxidation state 2, such as palladium (II) acetate, palladium (II) nitrate or palladium (II) chloride, as well as heterogeneous palladium catalysts, like palladium on charcoal.

It may recommend the mentioned reactions according to the Steps a) to d), in particular according to the steps a) and b) under an inert protective gas atmosphere, using as protective gases nitrogen, carbon dioxide or argon can come.

It may also be advisable to carry it out by crystallization as desired leading step c) of the process according to the invention and to combine the etretinate obtained from the optionally also be carried out isomerization according to step d) and recrystallize from ethanol or an ethanol-water mixture in a mass ratio of 1: 2 to 2: 1.

The Response times of the individual steps are usually directed after the reaction temperature at which the components used, d. H. Starting materials and reagents are reacted with each other. The completion of the implementation can each with usual Methods, for example capillary zone electrophoresis, ion exchange chromatography, Thin layer chromatography or HPLC can be determined.

The inventive method is different, the expert Expert clearly superior to conventional esterification methods. For example, one finds no sales in the attempt acitretin with ethanol in the presence of thionyl chloride and triethylamine too esterified. The activation of acitretin with pivaloyl chloride and Reaction with ethanol only yields incomplete sales. The esterification with triethyl orthoformate is incomplete. The reaction of acitretin with triethyl orthoacetate is after 40 Hours of reflux completely. The value product However, does not crystallize from the reaction mixture. Only after elaborate work-up and cleaning could finally a solid, but containing a number of impurities contained.

The in contrast, the process according to the invention opens a procedurally simple and powerful Access to etretinate of the formula (I). As procedural and economical It is particularly advantageous to assess the fact that the inventive process product by a one-step implementation, d. H. without isolation or purification of Intermediates can be obtained. As a result, elaborate processing, Saved cleaning and insulation measures and a achieved higher yield.

Examples:

The following examples are illustrative of the invention without restricting it in any way:

Example 1:

acitretin (99 g, 300 mmol) was extracted with dichloromethane (600 mL) at 20 ° C initially charged under nitrogen and carbonyldiimidazole (60 g, 360 mmol) suspended in dichloromethane (150 ml). After 1.5 h was Distilled off dichloromethane (590 ml) and DMAP (3.75 g, 30 mmol) and ethanol (750 ml). It was at a transition temperature of 78 ° C within 4.5 h solvent (900 ml) distilled off. The reaction mixture was refluxed for a further 3 h heated and then cooled to 3 ° C. The suspension was filtered off, with ethanol (2 × 75 ml) washed and dried the filter cake in a stream of nitrogen. etretinate (78.4 g, HPLC: 99.7 wt.%, 74%) became as yellow, crystalline Obtained solid.

Example 2:

177 g of the mother liquor obtained by filtration in Example 1 were diluted with 443 g of ethanol, and 1 ml of a 1% solution of erythrosin in ethanol was added. The solution was irradiated for 2 hours with a mercury lamp. The following changes in the isomer distribution compiled in Table 1 were observed: TABLE 1 Bestr.last [h] (11Z) -tretinate (HPLC FI.%) Etretinate (HPLC FI.%) 0.00 61.9 26.1 0.50 58.7 29.1 0.55 57.8 30.1 0.75 49.9 36.5 1.50 38.7 46.0 2.00 34.6 49.8 3.50 30.3 53.6 4.50 29.2 54.4

Example 3:

acitretin (33g, 100mmol) was washed with dichloromethane (200ml) at 20 ° C submitted under nitrogen and carbonyldiimidazole (20 g, 120 mmol) suspended in dichloromethane (50 ml). After 1 h, dichloromethane distilled off and ethanol (250 ml) was added. It was at a Internal temperature of 21 ° C and a pressure of 300 to 100 mbar solvent up to a level of Distilled off 200 ml. Subsequently, DMAP (1.25 g, 10 mmol) and sodium ethoxide (34 g, 500 mmol) was added and over Night stirred. After the addition of water (100 g) was added the suspension was filtered off, washed with ethanol (2 × 50 ml) and the filter cake dried in a stream of nitrogen. Etretinate (32.9 g, HPLC: 94.2 wt%, 83%) as a yellow, crystalline solid receive.

Example 4:

etretinate (31.3 g) from Example 3 was refluxed in ethanol (156 g) solved. The solution was clear filtered and then slowly cooled to 0 ° C. The suspension was filtered off and the filter cake washed twice with 55 ml of ethanol. The filter cake was dried overnight in a stream of nitrogen. etretinate (23.7 g, 75%) was in analytically pure form as yellow, crystalline Obtained solid.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 2414619 [0003]
• - DE 2636879 [0003]
• - CH 616134 [0003]
• WO 02/34710 [0003]
• - EP 802180 [0003]
• WO 2004/65358 [0005]
• EP 644186 [0007]

Claims (12)

Process for the preparation of etretinate of the formula I

starting from acitretin of the formula II

comprising the steps a) reaction of acitretin of the formula (II) with an activating reagent selected from the group of the activating reagents 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole and thionyldiimidazole to give the imidazolide of the formula (III)

and b) reacting the imidazolide of the formula (III) obtained in step a) with ethanol and / or an alkali metal and alkaline earth metal hanolate to obtain a reaction mixture containing etretinate of the formula (I). Method according to claim 1, characterized in that that step a) in dichloromethane as solvent performs. Method according to claim 1 or 2, characterized that step b) is carried out in ethanol as solvent and in an additional step c) etretinate of the formula (I) from the reaction mixture obtained in step b) by crystallization to obtain pure etretinate of the formula (I) and an etretinate of the formula (I) and isomers of the etretinate-containing mother liquor isolated. Method according to one of claims 1 to 3, characterized in that the reaction according to step b) in the presence of 4- (N, N-dimethylamino) -pyridine as a catalyst performs. Method according to one of claims 1 to 4, characterized in that the one obtained in step b) Reaction mixture and / or according to step c) obtained mother liquor in an additional step d) subjected to thermal or photochemical isomerization. Method according to claim 5, characterized in that that the isomerization is photochemically with light in the wavelength range from 200 to 650 nm. Method according to one of claims 5 or 6, characterized in that the photochemical isomerization Add a photosensitizer. Method according to claim 7, characterized in that that as a photosensitizer erythrosin, eosin or rose bengal used. Method according to claim 5, characterized in that that the isomerization according to step d) thermally performs. A method according to claim 9, characterized in that one for thermal isomerization Metal catalyst added. Method according to claim 10, characterized in that that as a metal catalyst homogeneous or heterogeneous palladium catalysts used. Method according to one of claims 5 to 11, characterized in that one from the crystallization according to step c) and that of the isomerization obtained according to step d) etretinate and in ethanol or an ethanol-water mixture in mass ratio recrystallized from 1: 2 to 2: 1.