WO2025021674A2

WO2025021674A2 - Process for the preparation of tapinarof

Info

Publication number: WO2025021674A2
Application number: PCT/EP2024/070514
Authority: WO
Inventors: Thierry LEÓN SERRANO; Francisco De Asís MARQUILLAS OLONDRIZ
Original assignee: Interquim, S.A.
Priority date: 2023-07-21
Filing date: 2024-07-19
Publication date: 2025-01-30

Abstract

The present invention relates to a process for the preparation of tapinarof, as well as to new co-crystals and solvates of tapinarof, process for preparation thereof and their use to obtain pure tapinarof and with high yield.

Description

Process for the preparation of tapinarof

This application claims the benefit of European Patent Application n° 23382752.6 filed on July 21st, 2023, and European application n° 24382445.5 filed on April 24th, 2023.

Technical Field

Background Art

Tapinarof, also known as benvitimod, is 3,5-dihydroxy-4-isopropylstilbene, also known as (E)-2-isopropyl-5- styrylbenzene-1 ,3-diol, and it has the following chemical structure of formula (I):

Tapinarof, market as Vtama®, is a therapeutic aryl hydrocarbon receptor (AhR) modulating agent (TAMA), and has been developed for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells and has critical roles in the regulation of skin homeostasis.

Clinical tests show that Vtama® is safe and effective in treating psoriasis, and part of curative effect indexes are superior to those of "Gold Standard" that are recognized worldwide, has the advantages of quick effect, lasting effect, low recurrence rate after drug withdrawal, long remission period and the like, embody the excellent clinical value of the drug and have obvious advantages compared with the existing therapeutic drugs.

Several synthetic routes have been reported to prepare tapinarof. The Witting-Horner condensation route is considered the best in terms of yield and the configuration obtained of the double bond. However, the demethylation step used as the final reaction in the Wittig-Horner condensation route, which is the key step of the whole product quality, has still room for improvement. Several demethylation methods have been reported in the current literature.

PCT patent WC200142231 uses BBra/dichloromethane as a demethylation reagent, and since BBra is easy to volatilize, it must be added dropwise at low temperature between -70 and - 80 °C, the reaction conditions are extreme, and the operation is difficult.

Chinese patent CN101648851 B uses pyridine hydrochloride as a demethylation reagent and require a reflux reaction at 175°C, while the pyridine has a large toxicity and harms the human body and the environment.

Chinese patent CN103265412B has an improved process, and the method of combining the demethylation reagent and microwave technology is used to reduce the reaction temperature, shorten the reaction time, and reduce the generation of by-products, but the industrial production application of the microwave method is limited, and the cost is high.

Chinese patent CN103992212B performs cis-tapinarof synthesis, and performs a large amount of demethylation reagent attempts, including commonly used demethylation reagent such as trimethylsilane, concentrated HI, 40% HBr/acetic acid and sodium dodecyl mercaptan/DMF which result in that the product purity is poor, with low yield, and harsh reaction conditions. Finally, it was found that products with high purity and high yield can be obtained by demethylation with N, N-dimethylaniline and anhydrous aluminium trichloride. It was found that the product purity was average, and the appearance of the product was dark green. The colour is extremely difficult to remove which affects the product quality attributes. In addition, the post-treatment with dilute hydrochloric acid quenching process is violent and results in large heat release and poses a safety hazard.

CN112811985 A discloses a demethylation method for preparing tapinarof that uses aluminium trichloride and triethylamine at room temperature. However, these conditions had still problems with product purity and colour of the final solid.

In view of the processes disclosed in the prior art, there is a need in the art for alternative processes for preparing tapinarof providing better yields, higher purity, and which are cost-effective and easy to scale-up to an industrial level.

Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid-state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favourable direction, or improving stability (polymorph as well as chemical stability) and shelflife. These variations in the properties of different salts and solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid-state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents may not be completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process.

Discovering new solid-state forms and solvates of useful intermediates may yield pharmaceutical products having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other crystalline forms. New solid-state forms of useful intermediates compounds can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability).

In order to overcome the defects in the prior art, the present invention provides a demethylation method for preparing tapinarof, which improves the product quality, optimizes the post-treatment operation, high yields are obtained, and reduces the risk of coloured material resulting in a final solid is off-white.

Summary of Invention

The inventors have found a new process for the preparation of tapinarof that overcomes the drawbacks of the processes disclosed in the prior art. Furthermore, the process allows having a final product in high yield, off-white, high purity and easy to industrialize.

Therefore, a first aspect of the invention relates to a process for the preparation of a compound of formula (I), which is tapinarof,

comprising the following steps: a) reacting a compound of formula (II)

with a cycloalkyl amine and aluminium trichloride in the presence of first solvent to give a compound of formula (I) or a co-cry stal or a salt or a solvate thereof, and b) optionally isolating the obtained compound of formula (I).

In particular, the inventors have developed a process for the preparation of tapinarof which use crystalline intermediates that allow having a final product in high yield, off-white, in high purity and easy to industrialize. In particular, the cocrystal compound of formula (III)

and the co-crystal compound of formula (IV)

The isolation of these synthesis intermediates in co-crystal form is very advantageous, especially on an industrial scale, and contributes to obtaining the final product tapinarof with high yield and purity and off-white. It has been found tapinarof can form stable co-crystals when cycloalkyl amine in the demethylation reaction is N-cyclohexyl-N- methylcyclohexanamine (DCHMA).

A second aspect of the invention relates to a co-crystal compound of formula (III),

A third aspect of the invention relates to a co-crystal compound of formula (IV)

In a fourth aspect, the present invention relates to the use of the compound of formula (III) of the second aspect claims for the preparation of the compound (I).

In a fifth aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula

(III) of the second aspect and a pharmaceutically acceptable excipient.

In a sixth aspect, the present invention relates to a compound of formula (III) of the second aspect for use as a pharmaceutical.

In a seventh aspect, the present invention relates to a compound of formula (III) of the second aspect for use in the topical treatment of plaque psoriasis in adults.

In an eight aspect, the present invention relates to the use of the compound or formula (IV) of the third aspect for the preparation of the compound (I).

In a ninth aspect, the present invention relates to a pharmaceutical composition comprising the compound or formula

(IV) of the third aspect and a pharmaceutically acceptable excipient.

In a tenth aspect, the present invention relates to a compound of formula (IV) of the third aspect for use as a pharmaceutical.

In an eleventh aspect, the present invention relates to a compound of formula (IV) of the third aspect for use in the topical treatment of plaque psoriasis in adults.

In a twelfth aspect, the present invention relates to a crystalline compound of formula (I), tapinarof, in the form of an organic acid solvate selected from the group consisting of butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

In a thirteenth aspect, the present invention relates to a crystalline butyric acid solvate of tapinarof. In a fourteenth aspect, the present invention relates to a crystalline isobutyric acid solvate of tapinarof.

In a fifteenth aspect the present invention relates to the use of the organic acid solvate compound of the twelfth, thirteenth and fourteenth aspect for the preparation of the compound (I), tapinarof.

In a sixteenth aspect the present invention relates to a pharmaceutical composition comprising the organic acid solvate compound of the twelfth, thirteenth and fourteenth aspect and a pharmaceutically acceptable excipient.

In a seventeenth aspect the present invention relates to an organic acid solvate compound of the twelfth, thirteenth and fourteenth aspect for use as a pharmaceutical.

In an eighteenth aspect the present invention relates to an organic acid solvate compound of the twelfth, thirteenth and fourteenth aspect for use in the topical treatment of plaque psoriasis in adults.

Brief Description of the Figures

Figure 1 : FTIR of co-crystal compound of formula (III) prepared in Example 1.

Figure 2: DSC of co-crystal compound of formula (III) prepared in Example 1 showing an endotherm peak at 176.1 °C due to the melting of the solid.

Figure 3: TGA of co-crystal compound of formula (III) prepared in Example 1.

Figure 4: PXRD of co-crystal compound of formula (III) prepared in Example 1.

Figure 5: Structure of the unit cell of co-crystal compound of formula (III) (1 :1) prepared in Example 1 obtained by SCXRD analysis.

Figure 6: FTIR of co-crystal compound of formula (IV) prepared in Example 2.

Figure 7: DSC of co-crystal compound of formula (IV) prepared in Example 2 showing an endotherm peak at 187.5 °C.

Figure 8: TGA of co-crystal compound of formula (IV) prepared in Example 2.

Figure 9: PXRD of co-crystal compound of formula (IV) prepared in Example 2.

Figure 10: Structure of the unit cell of co-crystal compound of formula (IV) (2:1) prepared in Example 2 obtained by SCXRD analysis.

Figure 11 : PXRD of butyric acid solvate of tapinarof prepared in Example 4.

Figure 12: PXRD of isobutyric acid solvate of tapinarof prepared in Example 4.

Detailed description of the invention

As mentioned above, the present invention relates to a new process for the preparation of tapinarof that overcomes the drawbacks of the processes disclosed in the prior art. Furthermore, the process allows having a final product in high yield, off-white, high purity and easy to industrialize. All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

For the purposes of the invention, any ranges given include both the lower and the upper endpoints of the range.

For the purposes of the invention, room temperature is 20-25 °C.

The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. Solvates may involve non-aqueous solvents such as propionic acid, acetic acid, butyric acid, isobutyric acid or they may involve water as the solvent that is incorporated into the crystalline lattice. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

"Co-crystal" as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the co-crystal includes two molecules which are in natural state.

The processes of the invention are schematically represented in the following scheme:

(2:1) (IV)

Scheme 1 The beneficial effects of the present invention are as follows:

- In the present invention, a high quality tapinarof can be obtained, and the product is an off-white solid.

- The post-treatment is mild and controllable, which reduces the risk of large heat release and facilitates industrial scale-up.

- The isolation of these synthesis intermediates in co-crystal form is very advantageous, especially on an industrial scale, and contributes to obtaining the final product tapinarof with high yield and purity and off-white.

In another particular embodiment of the present invention, the process for the preparation of a compound of formula (I) according to the first aspect, the cycloalkyl amine is selected from the group consisting of N-cyclohexyl-N- methylcyclohexanamine (DCHMA), N,N-dimethylcyclohexanamine, N-cyclohexyl-N-ethylcyclohexanamine, dicyclohexylamine (DOHA) and N,N-diethylcyclohexylamine.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the cycloalkyl amine is N-cyclohexyl-N-methylcyclohexanamine.

In another particular embodiment, in combination with any of the embodiments of the invention, the amount of N- cyclohexyl-N-methylcyclohexanamine is from 1 to 6 equivalents in relation to compound (II). In a further embodiment, the amount of N-cyclohexyl-N-methylcyclohexanamine is from 1 to 5 equivalents in relation to compound (II). In a further embodiment, the amount of N-cyclohexyl-N-methylcyclohexanamine is from 2 to 3 equivalents in relation to compound (II).

In another particular embodiment, in combination with any of the embodiments of the invention, the first solvent in step a) is selected from the group consisting of toluene, chlorobenzene, xylene, anisole, methyl benzoate, nitrobenzene, dichloromethane, and mixtures thereof. In a further embodiment, the first solvent in step a) is chlorobenzene.

In another particular embodiment, in combination with any of the embodiments of the invention, the amount of aluminium trichloride is from 1 to 8 equivalents. In another particular embodiment, the amount of aluminium trichloride is from 2 to 6 equivalents. In a further embodiment, the amount of aluminium trichloride is from 2.5 to 4 equivalents.

In another particular embodiment, in combination with any of the embodiments of the invention, the step a) is carried out at a temperature above 60 °C. In another particular embodiment, the step a) is carried out at a temperature comprised from 90 to 130 °C. In a further embodiment, the step a) is carried out at a temperature comprised from 100 to 120 °C.

In another particular embodiment, in combination with any of the embodiments of the invention, the process of step a) further comprises:

I) adding a second solvent and treatment with an acid ii) isolating the compound of formula (III) from the reaction medium:

As used herein, the term "isolated" in reference to of tapinarof or its co-crystals of the present disclosure corresponds to a tapinarof or its co-crystals that is physically separated from the reaction mixture in which it is formed.

In another particular embodiment, in combination with any of the embodiments of the invention, wherein the acid used in step I) is HCI.

In another particular embodiment, in combination with any of the embodiments of the invention, the second solvent of step I) is selected from the group consisting of 1 ,4-dioxane, chloroform, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), isopropyl acetate (IPrOAc), acetonitrile (ACN), n-butanol or combinations thereof. In another particular embodiment, in combination with any of the embodiments of the invention, the second solvent of step I) is selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN). In a further embodiment, the second solvent of step I) is acetonitrile (ACN).

In another particular embodiment, in combination with any of the embodiments of the invention, the step I) is carried out at a temperature comprised from 20 to 25 °C.

In another particular embodiment, in combination with any of the embodiments of the invention, the step ii) comprises evaporating part of the solvent and further crystallization or precipitation.

In another particular embodiment, in combination with any of the embodiments of the invention, the process for the preparation of a compound of formula (I) according to the first aspect, further comprises step ill) of slurrying or recrystallizing compound of formula (III) in water to yield compound of formula (IV).

In another particular embodiment, in combination with any of the embodiments of the invention, the step iii) is carried out at a temperature comprised from 20 to 100 °C. In another particular embodiment, the step iii) is carried out at a temperature comprised from 40 to 70 °C. In further embodiment, the step iii) is carried out at a temperature comprised from 50 to 60 °C.

In another particular embodiment, in combination with any of the embodiments of the invention, the process for the preparation of a compound of formula (I) according to the first aspect, the step b) further comprises slurrying compound of formula (III) or (IV) in a third solvent and water to isolate compound of formula (I).

In another particular embodiment, in combination with any of the embodiments of the invention, the third solvent or mixture of solvents is selected from the group consisting of toluene, 1 ,4-dioxane, diethyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), methyltetrahydrofuran, ethyl acetate (EtOAc), isopropyl acetate (IPrOAc), methyl ethyl ketone (MEK), acetonitrile (ACN), n-butanol, or combinations thereof. In another particular embodiment, the third solvent or mixture of solvents is selected from the group consisting of toluene, THF, methyltetrahydrofuran, MTBE or combinations thereof.

In another particular embodiment, in combination with any of the embodiments of the invention, the step b) further comprises crystallization or precipitation in a fourth solvent.

In another particular embodiment, in combination with any of the embodiments of the invention, the fourth solvent or mixture of solvents is selected from the group consisting of toluene, chlorobenzene, 1 ,4-dioxane, diethyl ether, MTBE, THF, methyltetrahydrofuran, EtOAc, IPrOAc, MEK, ACN, n-butanol, methylcyclohexane, cyclohexane, n-heptan, n- octane, isooctane, nonane or combinations thereof. In another particular embodiment, the fourth solvent or mixture of solvents is selected from the group consisting of toluene, THF, methyltetrahydrofuran, MTBE, n-heptane or combinations thereof.

In another particular embodiment, in combination with any of the embodiments of the invention, the process for the preparation of a compound of formula (I) according to the first aspect,

comprising the following steps: a) reacting a compound of formula (II)

with N-cyclohexyl-N-methylcyclohexanamine (DCHMA) and aluminium trichloride in the presence of a first solvent to give a co-crystal of the compound of formula (III).

I) adding a second solvent and optionally treatment with an acid,

II) isolating the compound of formula (III) from the reaction medium:

and b) subsequently slurrying the compound of formula (III) in a third solvent or mixture of solvents and water and adding a fourth solvent to isolate compound of formula (I).

In another particular embodiment, in combination with any of the embodiments of the invention, for the preparation of a compound of formula (I) according to the first aspect, after step II) further comprises the following steps of: ill) slurrying or recrystallizing the compound of formula (III) in water to yield compound of formula (IV)

and b) slurrying the compound of formula (IV) in a third solvent or mixture of solvents and water and adding a fourth solvent to isolate compound of formula (I).

The above described process of the invention has the advantage that avoids colour problems thanks to the isolation of compound of formula (III) which is solid off-white. The colour remains in the mother liquor and results in obtaining tapinarof with high purity and improved yield. Further, the reaction of the compound (II) and DCHMA offers a better control in the carry-over of the genotoxic by-products such as methyl chloride (MeCI) and also allows a potential access to any polymorphic form of tapinarof, such as Form I, Form II, III and IV. As used herein Form I, II, III and IV of tapinarof are as defined in the International Publication No. WO 2019/063002.

In another particular embodiment, in combination with any of the embodiments of the invention, for the preparation of a compound of formula (I) according to the first aspect the process further comprises the formation of an organic acid solvate of the compound of formula (I), tapinarof.

In another particular embodiment, in combination with any of the embodiments of the invention, the process for the formation of an organic acid solvate of tapinarof comprises: c) providing compound of formula (I), tapinarof, in an organic acid solvent or a mixture of organic acid solvent and one or more solvents; d) optionally heating the reaction mixture to a temperature of about 60 °C to about 80 °C to obtain dissolution; e) cooling to a temperature of about 0 °C to about 50 °C; f) optionally stirring the reaction mixture for about 0,5 hour to about 3 hours; and g) optionally separating the precipitate.

In another particular embodiment, in combination with any of the embodiments of the invention, the organic acid solvent is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid. In another particular embodiment, in combination with any of the embodiments of the invention, the starting material provided in step c) is tapinarof crystalline form I or tapinarof crystalline form IV o tapinarof crystalline form III or mixtures thereof.

In another particular embodiment, in combination with any of the embodiments of the invention, a slurry is obtained in step (c).

In another particular embodiment, in combination with any of the embodiments of the invention, one or more solvents are polar solvents. In another particular embodiment, the solvent is water.

In another particular embodiment, in combination with any of the embodiments of the invention, the step e) is cooling to a temperature of about 0 °C to 40 °C. In another particular embodiment, wherein the step e) is cooling to a temperature of about 15 °C to about 30 °C.

In another particular embodiment, in combination with any of the embodiments of the invention, the step f) is for about 1 hour to about 2 hours.

In another particular embodiment, in combination with any of the embodiments of the invention, the precipitate is separated by centrifuge. In another particular embodiment, the precipitate is separated by filtration.

In another particular embodiment, in combination with any of the embodiments of the invention, after step g) further comprises drying the precipitate to obtain compound of formula (I).

The above described process of the invention, in particular, the use of an organic acid solvate of tapinarof has the advantage that avoids the problem of having residual solvents in the isolated tapinarof. Thus, tapinarof is obtained as a solid off-white with hight purity and high yield. Particulary, it has been found crystalline organic acid solvates of tapinarof can be obtained .

As mentioned above, the present invention also relates to co-crystals of Tapinarof, processes for preparation thereof and pharmaceutical compositions thereof. These co-crystals can be used to prepare other solid-state forms of tapinarof.

(HI)

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (III) according to the second aspect, is in a crystalline form characterized by a DSC with one endotherm peak at 176.1 ±4 °C.

"DSC” refers to Differential Scanning Calorimetry. "TGA” refers to Thermo Gravimetric Analysis. DSC and TGA experiments are performed between 30 and 350 °C at 10 °C/min under N2 flux.

In another particular embodiment of the present invention, the co-crystal compound of formula (III) according to the second aspect is characterized by an FTIR comprising the following peaks: 3139, 2934, 2866, 1605, ± 5 cm -¹. In another particular embodiment of the present invention, the co-crystal compound of formula (III) according to the second aspect is characterized by an FTIR comprising the following peaks: 3139, 2934, 2866, 1605, 1581 , 1421 , 1199, 989, 833, 630, 570 ±5 cm ¹.

"FTIR” refers to Fourier-Transform Infra-Red spectroscopy.

In another particular embodiment of the present invention, the co-crystal compound of formula (III) according to the second aspect is characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 4.

In another particular embodiment of the present invention, the co-crystal compound of formula (III) according to the second aspect is characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 7.7, 16.8, 17,5, 18.4 and 22.5 ± 0.2 degrees 29. In another particular embodiment, the co-crystal compound of formula (III) is characterized by a PXRD pattern comprising the following peaks: 7.2, 7.7, 14.3, 15.8, 16.5, 16.8, 17,5, 18.7, 20.3, 21.8, 22.5, 23.4, 24.1, 25.3, 29.3 and 29.5 ± 0.2 degrees 29. In further particular embodiment, the co-crystal compound of formula (III) is characterized by a PXRD pattern comprising the following peaks: 7.2, 7.7, 11.1 , 11.5, 13.1 , 13.9, 14.3, 15.8, 16.5, 16.8, 17.5, 17.9, 18.4, 18.7, 19.7, 20.3, 21.2, 21.5, 21.8, 22.5, 23.4, 23.7, 24.1 , 25.3, 25.9, 26.4, 27.1 , 28.0, 29.3, 29.5, 31.2, 32.2, 32.6, 34.3, 35.1 , 36.8, 37.7, 39.4, 44.5 and 46.0 ± 0.2 degrees 29.

"PXRD” refers to Powder X-Ray Diffraction. "SCXRD” refers to single crystal X-Ray Diffraction

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (III) according to the second aspect, is characterized in that it has a monoclinic unit cell with the following dimensions: a = 12.249(3) A b = 10.435(2) A c = 22.988(5) A a = 90° P = 95.165(5)° y = 90°

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (IV) according to the third aspect, is in a crystalline form characterized by a DSC with one endotherm peak at 187.5 ±4 °C.

In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (IV) is characterized by an FTIR comprising the following peaks: 3227, 3081 , 2939, 2866, 1606 cm ¹ ±5 cm ¹. In another particular embodiment of the present invention, the co-crystal compound of formula (IV) is characterized by an FTIR comprising the following peaks: 3227, 3081 , 2939, 2866, 1606, 1580, 1448, 1364, 1270, 1013, 970, 821 , 690 cm-¹ ±5 crrr¹.

In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (IV) is characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 9.

In another particular embodiment of the present invention, the co-crystal compound of formula (IV) is characterized by an PXRD pattern comprising the following peaks: 7.3, 19.3, 20.6 and 21.2 ± 0.2 degrees 2e. In another particular embodiment of the present invention, the co-crystal compound of formula (IV) is characterized by a PXRD pattern comprising the following peaks: 7.3, 12.7, 13.8, 14.4, 14.6, 16.2, 17.0, 17.3, 18.7, 19.0, 19.3, 20.3, 20.6, 21.2, 21.7 and 22.2, ± 0.2 degrees 2e. In a further embodiment, the co-crystal compound of formula (IV) is characterized by a PXRD pattern comprising the following peaks: 7.2, 9.6, 10.3, 10.8, 12.0, 12.7, 13.8, 14.4, 14.6, 15.3, 16.2, 17.0, 17.3, 17.9, 18.1 , 18.7, 19.3, 20.3, 20.6, 21.2, 21.7, 22.2, 22.8, 23.3, 24.4, 24.8, 25.3, 26.2, 26.7, 27.9, 28.3, 28.7, 29.1 , 30.1 , 31 .3, 33.9, 35.3, 37.2, 40.0, 42.0 and 43.6 ± 0.2 degrees 29.

In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the co-crystal compound of formula (IV) is characterized in that it has a monoclinic unit cell with the following dimensions: a = 9.913(3) A b = 18.339(5) A c = 24.197(6) A a = 90°

P = 92.519(6)° y = 90°

"Pharmaceutically acceptable excipient” refers to any substance, other than the pharmacologically active drug or prodrug, that is useful in preparing a pharmaceutical composition, which is generally safe and non-toxic and that is approved or approvable by a regulatory agency.

(III) of the second aspect and a pharmaceutically acceptable excipient.

(IV) of the third aspect and a pharmaceutically acceptable excipient.

In an eleventh aspect, the present invention relates to a compound of formula (IV) of the third aspect for use in the topical treatment of plaque psoriasis in adults. As mentioned above, the present invention also relates to solvates of tapinarof, processes for preparation thereof and pharmaceutical compositions thereof. These solvates can be used to prepare other solid-state forms of tapinarof.

In a thirteenth aspect, the present invention relates to a crystalline butyric acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the butyric acid solvate of tapinarof in a crystalline form is characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 11.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the crystalline butyric acid solvate of tapinarof is characterized by an PXRD pattern comprising the following peaks: 6.5, 9.9, 12.9, 14.9 and 24.3 ± 0.2 degrees 2e. In another particular embodiment, the crystalline butyric acid solvate of tapinarof is characterized by a PXRD pattern comprising the following peaks: 6.5, 9.9, 12.9, 14.9, 19.5, 24.0, 24.3 and 26.0 ± 0.2 degrees 2e.

In a fourteenth aspect, the present invention relates to a crystalline isobutyric acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the isobutyric acid solvate of tapinarof in a crystalline form is characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 12.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the crystalline isobutyric acid solvate of tapinarof is characterized by an PXRD pattern comprising the following peaks: 6.4, 9.7, 12.9, 14.8, 15.9 and 23.4 ± 0.2 degrees 2e. In another particular embodiment, the crystalline isobutyric acid solvate of tapinarof is characterized by a PXRD pattern comprising the following peaks: 6.4, 9.7, 10.9, 12.9, 14.8, 15.9, 16.8, 23.4 and 25.2 ± 0.2 degrees 2e.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention,

In a fifteenth aspect the present invention relates to the use of the organic acid solvate compound of the twelfth aspect, thirteenth and fourteenth aspects for the preparation of the compound (I), tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the organic acid solvate compound of the fifteenth aspect is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid. In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the organic acid solvate compound is acetic acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the organic acid solvate compound is butyric acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the organic acid solvate compound is isobutyric acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the present invention also relates to the use of acetic acid solvate of tapinarof or the butyric acid solvate of tapinarof or the isobutyric acid solvate of tapinarof for the preparation of crystalline form I of tapinarof.

The compound of formula (I), tapinarof, may be prepared in the form of an acetic acid solvate of tapinarof or butyric acid solvate of tapinarof or isobutyric acid solvate of tapinarof thereof. It has been found that formation of the acetic acid solvate of tapinarof or butyric acid solvate of tapinarof or isobutyric acid solvate of tapinarof provides impurity and colour purging capabilities to the process of the invention. The acetic acid solvate of tapinarof or butyric acid solvate of tapinarof or isobutyric acid solvate of tapinarof can thereafter be converted into crystalline form I of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the organic acid solvate compound is propionic acid solvate of tapinarof.

In a particular embodiment of the present invention, in combination with any of the embodiments of the invention, the present invention also relates to the use of propionic acid solvate of tapinarof for the for the preparation of crystalline form III of tapinarof.

The compound of formula (I), tapinarof, may be prepared in the form of a propionic acid solvate of tapinarof thereof. It has been found that formation of the propionic acid solvate of the compound of formula (I) provides impurity and colour purging capabilities to the process of the invention. The propionic acid solvate of tapinarof can thereafter be converted into crystalline form III of tapinarof.

As already mentioned above, the use of an organic acid solvate of tapinarof has the advantage that avoids the problem of having residual solvents in the isolated tapinarof. Thus, tapinarof is obtained as a solid off-white with high purity and high yield. Furthermore, the use of a specific organic acid solvate of tapinarof can be useful to modulate which crystalline form of tapinarof may be obtained.

In a sixteenth aspect the present invention relates to a pharmaceutical composition comprising the organic acid solvate compound of the twelfth aspect, thirteenth and fourteenth aspects for the preparation of the compound (I), tapmarof and a pharmaceutically acceptable excipient.

In a seventeenth aspect the present invention relates to an organic acid solvate compound of the twelfth aspect, thirteenth and fourteenth aspects for use as a pharmaceutical.

In an eighteenth aspect the present invention relates to an organic acid solvate compound of the twelfth aspect, thirteenth and fourteenth aspects for use in the topical treatment of plaque psoriasis in adults.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise” encompasses the case of "consisting of'. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention.

The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Clauses

Further aspects and embodiments of the present invention are described in the following clauses below:

1 . A process for the preparation of a compound of formula (I), which is tapinarof,

comprising the following steps: a) reacting a compound of formula (II)

with a cycloalkyl amine and aluminium trichloride in the presence of first solvent to give a compound of formula (I) or a co-crystal or a salt or a solvate thereof, and b) optionally isolating the obtained compound of formula (I). The process according to clause 1, wherein the cycloalkyl amine is selected from the group consisting of N- cyclohexyl-N-methylcyclohexanamine (DCHMA), N,N-dimethylcyclohexanamine, N-cyclohexyl-N- ethylcyclohexanamine, dicyclohexylamine (DOHA) and N,N-diethylcyclohexylamine. The process according to any of the clauses 1 to 2, wherein the cycloalkyl amine is N-cyclohexyl-N- methylcyclohexanamine. The process according to clause 3, wherein the amount of N-cyclohexyl-N-methylcyclohexanamine is from 1 to 6 equivalents in relation to compound (II), particularly from 1 to 5 equivalents in relation to compound (II), particularly from 2 to 3 equivalents in relation to compound (II). The process according to any of the clauses 1 to 4, wherein the first solvent in step a) is selected from the group consisting of toluene, chlorobenzene, xylene, anisole, methyl benzoate, nitrobenzene, dichloromethane, and mixtures thereof, particularly chlorobenzene. The process according to any of the clauses 1 to 5, wherein the amount of aluminium trichloride is from 1 to 8 equivalents, particularly from 2 to 6 equivalents, particularly from 2.5 to 4 equivalents. The process according to any of the clauses 1 to 6, wherein step a) is carried out at a temperature above 60 °C, particularly at a temperature comprised from 90 to 130 °C, particularly at a temperature comprised from 100 to 120 °C. The process according to any of the clauses 3 to 7, wherein the process of step a) further comprises: i) adding a second solvent and treatment with an acid ii) isolating the compound of formula (III) from the reaction medium:

The process according to the preceding clause, wherein the acid used in step i) is HCI. The process according to clause 8, wherein the second solvent of step i) is selected from the group consisting of 1,4-dioxane, chloroform, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), isopropyl acetate (IPrOAc), acetonitrile (ACN), n-butanol or combinations thereof, particularly, dichloromethane (DOM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), particularly acetonitrile (ACN).

11 . The process according to any of the clauses 8 to 10, wherein step I) is carried out at a temperature comprised from 20 to 25 °C.

12. The process according to any of the clauses 8 to 11, wherein step II) comprises evaporating part of the solvent and further crystallization or precipitation.

13. The process according to any of the clauses 8 to 12, further comprising step ill) of slurrying or recrystallizing compound of formula (III) in water to yield compound of formula (IV).

14. The process according to clause 13, wherein step ill) is carried out at a temperature comprised from 20 to 100 °C, more particularly at a temperature comprised from 40 to 70 °C, preferably at a temperature comprised from 50 to 60 °C.

15. The process according to any of the clauses 8 to 14, wherein step b) further comprises slurrying compound of formula (III) or (IV) in a third solvent and water to isolate compound of formula (I).

16. The process according to the previous clause, wherein the third solvent or mixture of solvents is selected from the group consisting of toluene, 1 ,4-dioxane, diethyl ether, MTBE, THF, methyltetrahydrofuran, EtOAc, IPrOAc, MEK, ACN, n-butanol, or combinations thereof; particularly, is toluene, THF, methyltetrahydrofuran, MTBE or combinations thereof.

17. The process according to any of the clauses 15 to 16, wherein step b) further comprises crystallization or precipitation in a fourth solvent. The process according to the previous clause, wherein the fourth solvent or mixture of solvents is selected from the group consisting of toluene, chlorobenzene, 1 ,4-dioxane, diethyl ether, MTBE, THF, methyltetrahydrofuran, EtOAc, IPrOAc, MEK, , ACN, n-butanol, methylcyclohexane, cyclohexane, n-heptan, n-octane, isooctane, nonane or combinations thereof; particularly, in toluene, THF, MTBE, n-heptane or combinations thereof. The process according to any of the clauses 3 to 18, for the preparation of a compound of formula (I),

comprising the following steps: a) reacting a compound of formula (II)

with N-cyclohexyl-N-methylcyclohexanamine (DCHMA) and aluminium trichloride in the presence of a first solvent to give a co-crystal of the compound of formula (III). i) adding a second solvent and optionally treatment with an acid, ii) isolating the compound of formula (III) from the reaction medium:

and b) subsequently slurrying the compound of formula (III) in a third solvent or mixture of solvents and water and adding a fourth solvent to isolate compound of formula (I). The process according to clause 19, wherein after step ii) further comprises the following steps of: iii) slurrying or recrystallizing the compound of formula (III) in water to yield compound of formula (IV)

and b) slurrying the compound of formula (IV) in a third solvent or mixture of solvents and water and adding a fourth solvent to isolate compound of formula (I). The process according to any of the clauses 1 to 20, wherein the process further comprises the formation of an organic acid solvate of the compound of formula (I), tapinarof. The process according to the previous clause, wherein the process comprises: c) providing compound of formula (I), tapinarof, in an organic acid solvent or a mixture of organic acid solvent and one or more solvents; d) optionally heating the reaction mixture to a temperature of about 60 °C to about 80 °C to obtain dissolution; e) cooling to a temperature of about 0 °C to about 50 °C; f) optionally stirring the reaction mixture for about 0,5 to about 3 hours; and g) optionally separating the precipitate. The process according to any of the clauses 21 to 22, wherein the organic acid solvent is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid. The process according to any of the clauses 21 to 23, wherein the starting material provided in step c) is tapinarof crystalline form I or tapinarof crystalline form IV o tapinarof crystalline form III or mixtures thereof. The process according to any of the clauses 21 to 24, wherein a slurry is obtained in step c). The process according to any of the clauses 21 to 25, wherein one or more solvents are polar solvents. The process according to any of the clauses 21 to 26, wherein the solvent is water; 28. The process according to any of the clauses 21 to 27, wherein the step e) is cooling to a temperature of about 0 °C to 40 °C.

29. The process according to any of the clauses 21 to 28, wherein the step e) is cooling to a temperature of about 15 °C to about 30 °C.

30. The process according to any of the clauses 21 to 29, wherein the step f) is for about 1 hour to about 2 hours.

31 . The process according to any of the clauses 21 to 30, wherein the precipitate is separated by centrifuge.

32. The process according to any of the clauses 21 to 31, wherein the precipitate is separated by filtration.

33. The process according to any of the clauses 21 to 32, wherein after step g) further comprises drying the precipitate to obtain compound of formula (I), tapinarof.

34. A co-crystal compound of formula (III),

35. The co-crystal compound of formula (III) of clause 34 is in a crystalline form characterized by a DSC with one endotherm peak at 176.1 ±4 °C.

36. The co-crystal compound of formula (III) of any of the clauses 34 to 35 characterized by an FTIR comprising the following peaks: 3139, 2934, 2866, 1605, ±5 cm ¹.

37. The co-crystal compound of formula (III) of any of the clauses 34 to 36 characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 4.

38. The co-crystal compound of formula (III) of any of the clauses 34 to 37 characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 7.7, 16.8, 17,5, 18.4 and 22.5 ± 0.2 degrees 2e.

39. The co-crystal compound of formula (III) of the previous clause characterized by a PXRD pattern comprising the following peaks: 7.2, 7.7, 14.3, 15.8, 16.5, 16.8, 17.5, 18.7, 20.3, 21.8, 22.5, 23.4, 24.1, 25.3, 29.3 and 29.5 ± 0.2 degrees 2e. 40. The co-crystal compound of formula (III) of the previous clause characterized by a PXRD pattern comprising the following peaks: 7.2, 7.7, 11.1 , 11.5, 13.1 , 13.9, 14.3, 15.8, 16.5, 16.8, 17.5, 17.9, 18.4, 18.7, 19.7, 20.3, 21.2, 21.5, 21.8, 22.5, 23.4, 23.7, 24.1 , 25.3, 25.9, 26.4, 27.1 , 28.0, 29.3, 29.5, 31.2, 32.2, 32.6, 34.3, 35.1 , 36.8, 37.7, 39.4, 44.5 and 46.0 ± 0.2 degrees 2e.

41 . The co-crystal compound of formula (III) of any of the clauses 34 to 40 characterized in that it has a monoclinic unit cell with the following dimensions: a = 12.249(3) A b = 10.435(2) A c = 22.988(5) A a = 90°

P = 95.165(5)° y = 90°

42. A co-crystal compound of formula (IV),

43. The co-crystal compound of formula (IV) of clause 42 in a crystalline form characterized by a DSC with one endotherm peak at 187.5 ±4 °C.

44. The co-crystal compound of formula (IV) of clause 42 to 43 characterized by an FTIR comprising the following peaks: 3227, 3081 , 2939, 2866, 1606 cm ¹ ±5 cm ¹.

45. The co-crystal compound of formula (IV) of any of the clauses 42 to 44 characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 9.

46. The co-crystal compound of formula (IV) of any of the clauses 42 to 45 characterized by an PXRD pattern comprising the following peaks: 7.3, 19.3, 20.6 and 21.2 ± 0.2 degrees 2e.

47. The co-crystal compound of formula (IV) of the previous clause characterized by a PXRD pattern comprising the following peaks: 7.3, 12.7, 13.8, 14.4, 14.6, 16.2, 17.0, 17.3, 18.7, 19.0, 19.3, 20.3, 20.6, 21.2, 21.7 and 22.2 ± 0.2 degrees 2e.

48. The co-crystal compound of formula (IV) of the previous clause characterized by a PXRD pattern comprising the following peaks: 7.2, 9.6, 10.3, 10.8, 12.0, 12.7, 13.8, 14.4, 14.6, 15.3, 16.2, 17.0, 17.3, 17.9, 18.1 , 18.7, 19.3, 20.3, 20.6, 21.2, 21.7, 22.2, 22.8, 23.3, 24.4, 24.8, 25.3, 26.2, 26.7, 27.9, 28.3, 28.7, 29.1 , 30.1 , 31.3, 33.9, 35.3, 37.2, 40.0, 42.0 and 43.6 ± 0.2 degrees 2e.

49. The co-crystal compound of formula (IV) of any of the clauses 42 to 48 characterized in that it has a monoclinic unit cell with the following dimensions: a = 9.913(3) A b = 18.339(5) A c = 24.197(6) A a = 90°

P = 92.519(6)° y = 90°

50. Use of the compound of formula (III) as defined in any one of clauses 34 to 41 for the preparation of the compound (I).

51. A pharmaceutical composition comprising the compound of formula (III) as defined in any one of clauses 34to 41 and a pharmaceutically acceptable excipient.

52. A compound of formula (III) as defined in any one of clauses 34 to 41 for use as a pharmaceutical.

53. A compound of formula (III) as defined in any one of clauses 34 to 41 for use in the topical treatment of plaque psoriasis in adults.

54. Use of the compound or formula (IV) as defined in any one of clauses 42 to 49 for the preparation of the compound (I).

55. A pharmaceutical composition comprising the compound or formula (IV) as defined in any one of clauses 42 to 49 and a pharmaceutically acceptable excipient.

56. A compound of formula (IV) as defined in any one of clauses 42 to 49 for use as a pharmaceutical.

57. A compound of formula (IV) as defined in any one of clauses 42 to 49 for use in the topical treatment of plaque psoriasis in adults. 58. A crystalline compound of formula (I), tapinarof, in the form of an organic acid solvate selected from the group consisting of butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

59. A crystalline butyric acid solvate of tapinarof.

60. The butyric acid solvate of tapinarof of the previous clause in a crystalline form characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 11 .

61 . The butyric acid solvate of tapinarof of any of the clauses 59 to 60 characterized by an PXRD pattern comprising the following peaks: 6.5, 9.9, 12.9, 14.9 and 24.3 ± 0.2 degrees 2e.

62. The butyric acid solvate of tapinarof of any of the clauses 59 to 61 characterized by a PXRD pattern comprising the following peaks: 6.5, 9.9, 12.9, 14.9, 19.5, 24.0, 24.3 and 26.0 ± 0.2 degrees 2e.

63. A crystalline isobutyric acid solvate of tapinarof.

64. The isobutyric acid solvate of tapinarof of the previous clause in a crystalline form characterized by a powder X- Ray diffraction pattern substantially as depicted in Figure 12.

65. The isobutyric acid solvate of tapinarof of any of the clauses 63 to 64 characterized by an PXRD pattern comprising the following peaks: 6.4, 9.7, 12.9, 14.8, 15.9 and 23.4 ± 0.2 degrees 2e.

66. The isobutyric acid solvate of tapinarof of any of the clauses 63 to 65 characterized by a PXRD pattern comprising the following peaks: 6.4, 9.7, 10.9, 12.9, 14.8, 15.9, 16.8, 23.4 and 25.2 ± 0.2 degrees 2e.

67. Use of the organic acid solvate compound as defined in any one of clauses 58 to 61 for the preparation of the compound (I), tapinarof.

68. Use of the organic acid solvate compound according to the previous clause, wherein the organic acid solvate compound is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

69. Use of the organic acid solvate compound according to any of the clauses 67 to 68, wherein the organic acid solvate compound is acetic acid solvate of tapinarof.

70. Use of the organic acid solvate compound according to any of the clauses 67 to 68, wherein the organic acid solvate compound is butyric acid solvate of tapinarof.

71 . Use of the organic acid solvate compound according to any of the clauses 67 to 68, wherein the organic acid solvate compound is isobutyric acid solvate of tapinarof. 72. Use of the organic acid solvate compound according to any of the clauses 69 to 71 for the preparation of crystalline form I of tapinarof.

73. Use of the organic acid solvate compound according to any of the clauses 67 to 68, wherein the organic acid solvate compound is propionic acid solvate of tapinarof.

74. Use of the organic acid solvate compound according to the preceding clause for the preparation of crystalline form III of tapinarof.

75. A pharmaceutical composition comprising the organic acid solvate compound as defined in any one of clauses 58 to 61 and a pharmaceutically acceptable excipient.

76. An organic acid solvate compound as defined in any one of clauses 58 to 61 for use as a pharmaceutical.

77. An organic acid solvate compound as defined in any one of clauses 58 to 61 for use in the topical treatment of plaque psoriasis in adults.

Examples

HPLC method:

Chromatographic column: Zorbax Eclipse Plus Phenyl-Hexyl 150x3mmx3.5pim; Column temperature: 30° C; Mobile phase: A: phosphoric acid 0.10%, B: Acetonitrile

Gradient elution conditions:

The chromatograph is programmed as follows:

Main peak retention time: around 10.3 min; Sample volume 3pL; Detection wavelength: 215 nm; running time: 32 min; Test solution: 0.25mg/mL, Solvent: Acetonitrile; Column flow: 0.5ml/min.

Test 1. Powder X-Ray Diffraction Analysis (PXRD) analysis are performed as follows:

Data acquisition: Powder diffraction patterns were acquired with a Siemens D5000 diffractometer using Cu radiation (CuKo = 1.5418 A, 40 kV, 40 mA) in Bragg-Brentano geometry typically at room temperature. The diffraction patterns were recorded in the range of 20 values from 2 to 50° with a sampling rate of 0.02° per second and a step time of 1 second per step. The equipment was periodically calibrated using corundum.

Single Crystal X-Ray Diffraction (SC-XRD) Resolution

Single crystals of compounds of formula (III) and (IV) obtained from methanol were selected for single crystal X-ray diffraction experiments and mounted at the tip of a nylon CryoLoop on a Bruker Smart Apex-Il CCD diffractometer using graphite monochromated Mo-Ka radiation ( = 0.71073 A). Crystallographic data for compounds of formula (III) and (IV)- were collected at 295(2) K, respectively. Data reduction was performed using SAINT v6.45A and SORTAV in the diffractometer package, Blessing, R. H., "An empirical correction for absorption anisotropy, Acta Crystallogr., Sect. A: Found. Adv. 1995, 51 , 33-38. Data were corrected for Lorentz and polarization effects and for absorption by SADABS (SAINT, Bruker, A. X. S., Ed.; Inc.: Madison, Wisconsin, USA). The structural resolution procedure was made using SHELXT (Sheldrick, G. M., "SHELXT - Integrated space-group and crystal-structure determination”, Acta Crystallogr., Sect. A: Found. Adv. 2015, 71 , 3-8). Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were introduced in calculated positions and refined riding on their parent atoms. Selected crystal and data collection parameters are reported in the corresponding Table 1 and Table 2. Mercury 2021.1.0 software was also used to calculate the PXRD powder patterns of the new cocrystals based on the single-crystal X-ray structures: Macrae, CF. et al., "New Features for the Visualization and Investigation of Crystal Structures”, J. Appl. Crystallogr. 2008, 41, 466— 470.

Example 1. Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound cocrystallized with N-cyclohexyl- N,N-dimethylcyclohexanammonium chloride (1 :1) (compound of formula (III))

A jacketed laboratory reactor of 2 L was purged with nitrogen and then charged with (E)-2-isopropyl-1 ,3-dimethoxy-5- styrylbenzene (50 g, 177 mmol, 1 equiv.), chlorobenzene (0.35 L), N-cyclohexyl-N-methylcyclohexanamine (86 g, 443 mmol, 2.5 equiv.) and aluminium trichloride (70.8 g, 531 mmol, 3 equiv.). The mixture was protected from light and was heated to 105-110 °C for 2 hours. The product mixture was then cooled to 55-65 °C and was diluted with acetonitrile (0.2 L). The resulting solution was slowly treated with aqueous hydrochloric acid (4%, 0.26 L) and the resulting mixture was allowed to stir for additional 10 minutes. The resulting biphasic system was allowed to decant at room temperature and the aqueous phase was disposed of. The organic phase was treated with charcoal for 30 minutes and the purified solution was concentrated under reduced pressure until collecting ca. 0.3 L. The resultant slurry was allowed to cool at room temperature and was then allowed to stir for 30 minutes. The crude mass was cooled at 0-5 °C and was then stirred for 1 additional hour. The suspension was filtered and the solid washed with cold chlorobenzene (0.1 L). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol compound co-crystal I i zed with N-cyclohexyl-N,N-dimethylcyclohexanammonium chloride (1 :1) (compound of formula (III)) as an off-white powder solid (76.2 g, 89%).

1 H-NMR (400 MHz, MeOD) 5 7.53 - 7.47 (m, 2H), 7.37 - 7.31 (m, 2H), 7.26 - 7.20 (m, 1 H), 7.05 - 6.90 (m, 2H), 6.51 (s, 2H), 3.50 (m, 3H), 2.84 (s, 6H), 2.18 - 2.11 (m, 4H), 2.02 - 1 .91 (m, 4H), 1 .74 - 1 .66 (m, 2H), 1 .58 - 1 .35 (m, 8H), 1 .33 (d, J = 7.1 Hz, 6H), 1.21 (m, 2H).

13C-NMR (100 MHz, MeOD) 5 157.7, 138.9, 136.8, 129.9, 129.7, 128.4, 127.3, 122.0, 106.5, 72.0, 71.9, 71.9, 44.2, 44.1 , 44.1 , 27.2, 26.5, 26.0, 25.6, 21.0.

FTIR (ATR, Figure 1): 3137, 2934, 2866, 1605, 1581 , 1421 , 1199, 989, 833, 630, 570 cm ¹

MS (m/z, ESI+): 210.3 (M)

MS (m/z, ESI-): 253.1 (M-1)

HPLC purity (%area): 100.0

DSC (onset): 176.1 °C, as shown in Figure 2

PXRD co-crystal compound of formula (III) as shown in Figure 3 with the following peaks:

Angle (20) Intensity (Counts) d Value (A) Angle (26) Intensity (Counts) d Value (A)

7.2 510 12.22 28.0 182 3.18

7.7 2311 11.49 28.3 109 3.15

11.1 63 7.99 28.6 96 3.12

11.5 76 7.66 29.3 309 3.05

13.2 122 6.72 29.5 263 3.02

13.9 64 6.37 30.2 106 2.96

14.3 258 6.18 30.4 99 2.93

15.8 378 5.60 30.9 135 2.89

16.5 273 5.37 31.2 111 2.87

16.8 988 5.28 32.2 213 2.78

17.5 714 5.06 32.6 111 2.75

17.9 146 4.94 32.8 87 2.73

18.4 584 4.81 33.4 81 2.68

18.7 468 4.74 34.3 153 2.61

19.0 79 4.66 34.6 94 2.59

19.7 251 4.49 35.1 118 2.55

20.3 404 4.38 35.6 89 2.52

21.2 220 4.20 36.0 73 2.49

21.5 219 4.14 36.8 125 2.44

21.8 276 4.07 37.0 97 2.43

22.5 1757 3.95 37.7 107 2.38

23.4 461 3.79 38.4 107 2.34

23.7 241 3.75 39.4 83 2.29

24.1 420 3.69 40.5 144 2.23

24.7 93 3.60 41.3 95 2.18

25.3 275 3.52 44.5 124 2.04

25.9 109 3.44 45.3 73 2.00

26.4 179 3.38 46.0 104 1.97

27.1 213 3.29 46.6 60 1.95

27.7 152 3.21 48.0 94 1.89

Crystal data and structure refinement for (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol with N-cyclohexyl-N,N- dimethylcyclohexanammonium chloride (1 :1) co-crystal (compound of formula (III)) is given in the table 1. Table 1 : Most relevant structural data of the SCXRD analysis of co-crystal.

The crystal structure is depicted in Figure 4

Example 2. Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound cocrystallized with N-cyclohexyl- N,N-dimethylcyclohexanammonium chloride (2:1) (IV)

A jacketed laboratory reactor of 0.25 L was purged with nitrogen and then charged with (E)-2-isopropyl-5- styrylbenzene-1 ,3-diol compound cocrystallized with N-cyclohexyl-N,N-dimethylcyclohexanammonium chloride (1 : 1) (compound (III)) (37 g, 76 mmol, 1 equiv.) and water (0.19 L). The suspension was protected from light and was heated to 50-60 °C for 2 hours with vigorous stirring. The resulting suspension was then directly filtered in hot. The suspension was filtered and the solid washed with water (0.1 L). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol compound cocristallized with N-cyclohexyl-N,N- dimethylcyclohexanammonium chloride (2: 1) (compound (IV)) as an off-white powder solid (27.3 g, 74%).

1 H-NMR (400 MHz, MeOD) 5 7.53 - 7.47 (m, 2H), 7.37 - 7.31 (m, 2H), 7.26 - 7.20 (m, 1 H), 7.05 - 6.90 (m, 2H), 6.51 (s, 2H), 3.50 (m, 2H), 2.84 (s, 3H), 2.18 - 2.11 (m, 2H), 2.02 - 1.91 (m, 2H), 1.74 - 1.66 (m, 1 H), 1.58 - 1.35 (m, 4H), 1 .33 (d, J = 7.1 Hz, 6H), 1.21 (m, 1 H).

FTIR (ATR, Figure 5): 3227, 3081 , 2939, 2866, 1606, 1580, 1448, 1364, 1270, 1013, 970, 821 , 690 cm ¹

DSC (onset): 187.5 °C, as shown in Figure 6

MS (m/z, ESI+): 210.3 (M)

MS (m/z, ESI-): 253.1 (M-1)

HPLC purity (%area): 99.0

PXRD co-crystal compound of formula (IV) as shown in Figure 7 with the following peaks: Angle (20) Intensity (Counts) d Value (A) Angle (26) Intensity (Counts) d Value (A)

7.3 1753 12.17 22.8 217 3.89

8.7 66 10.19 23.3 203 3.81

9.6 73 9.23 24.4 169 3.65

10.3 74 8.60 24.8 136 3.59

10.8 114 8.15 25.3 294 3.52

12.0 204 7.40 26.2 207 3.40

12.7 439 6.98 26.4 213 3.37

13.8 300 6.41 26.7 188 3.34

14.4 417 6.15 27.9 159 3.20

14.6 376 6.06 28.3 275 3.15

15.3 114 5.78 28.7 296 3.10

16.2 531 5.48 29.1 245 3.06

17.0 443 5.22 30.1 206 2.97

17.3 471 5.12 30.6 122 2.92

17.9 130 4.96 31.3 131 2.86

18.1 210 4.89 32.1 107 2.79

18.7 622 4.74 33.1 81 2.71

19.0 486 4.66 33.9 117 2.64

19.3 1631 4.60 35.3 107 2.54

19.6 145 4.52 36.2 98 2.48

20.3 403 4.36 37.2 118 2.41

20.6 661 4.30 40.0 137 2.25

21.2 1099 4.20 42.0 110 2.15

21.7 308 4.10 43.6 115 2.08

22.2 451 4.00

Crystal data and structure refinement for (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol with N-cyclohexyl-N,N- dimethylcyclohexanammonium chloride (2: 1) co-crystal (compound of formula (IV)) is given in table 2. Table 2: Most relevant structural data of the SCXRD analysis of co-crystal compound of formula (IV).

The crystal structure is depicted in Figure 8 Example 3. Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol, compound (I), tapinarof.

A two-necked flask of 100 mL was charged with compound of formula (III) (10 g, 20 mmol, 1 equiv.), 2- methyltetrahydrofuran (40 mL) and water (20 mL). The suspension was protected from light. After 10 minutes at room temperature, the solids dissolved, and a clear biphasic system was obtained. The mixture was allowed to decant at room temperature and the aqueous phase was disposed of. The organic phase was treated with additional water (20 mL) and was stirred for 10 minutes. The resulting biphasic system was allowed to decant. The resulting aqueous phase was disposed of, and toluene (50 mL) was added to the organic phase and 2-methyltetrahydrofuran solvent was distilled. The resulting mixture was cooled at room temperature. A precipitate appeared and then the mixture was cooled to 0-5°C and was aged at this temperature for 1 hour. The suspension was filtered and the solid washed with cold toluene (10 mL). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2-isopropyl- 5-styryl benzene- 1 ,3-diol, tapinarof, as an off-white powder solid (4.2 g, 82%).

1 H-NMR (400 MHz, MeOD) 5 7.53 - 7.47 (m, 2H), 7.37 - 7.31 (m, 2H), 7.26 - 7.20 (m, 1 H), 7.05 - 6.90 (m, 2H), 6.51 (s, 2H), 3.50 (hept, J= 7.1 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 6H).

13C-NMR (100 MHz, MeOD) 5 157.7, 139.0, 136.9, 129.9, 129.7, 128.3, 128.2, 127.3, 122.0, 106.5, 25.6, 21.0.

DSC (onset, °C): 147.3°C

HPLC purity (%area): 99.9

Example 4. Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol, compound (I), tapinarof.

A two-necked flask of 100 mL was charged with compound (IV) (5 g, 6.63 mmol, 1 equiv.), 2-methyltetrahydrofuran (20 mL) and water (10 mL). The suspension was protected from light. After 10 minutes at room temperature, the solids dissolved, and a clear biphasic system was obtained. The mixture was allowed to decant at room temperature and the aqueous phase was disposed of. The organic phase was treated with additional water (10 mL) and was stirred for 10 minutes. The resulting biphasic system was allowed to decant. The resulting aqueous phase was disposed of, and toluene (50 mL) was added to the organic phase and 2-methyltetrahydrofuran solvent was distilled. The resulting mixture was cooled at room temperature. A precipitate appeared and then the mixture was cooled to 0-5°C and was aged at this temperature for 1 hour. The suspension was filtered and the solid washed with cold toluene (10 mL). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2-isopropyl-5-styrylbenzene-1 ,3-diol, tapinarof, as an off-white powder solid (2.7 g, 81 %).

1 H-NMR (400 MHz, MeOD) 5 7.53 - 7.47 (m, 2H), 7.37 - 7.31 (m, 2H), 7.26 - 7.20 (m, 1 H), 7.05 - 6.90 (m, 2H), 6.51 (s, 2H), 3.50 (hept, J= 7.1 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 6H). 13C-NMR (100 MHz, MeOD) 5 157.7, 139.0, 136.9, 129.9, 129.7, 128.3, 128.2, 127.3, 122.0, 106.5, 25.6, 21.0.

DSC (onset, °C): 147.3°C

HPLC purity (%area): 99.9

Example 4. Synthesis of wet (E)-2-isopropyl-5-styrylbenzene-1,3-diol organic acid solvate compound

A laboratory 0.1-liters flask was purged with nitrogen and then charged with (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol, tapinarof, (10 g) and organic acid solvent (40-50 mL). The mixture was protected from light and was heated to 65-75 °C until complete dissolution. The resulting solution was then cooled to 0 °C and a precipitate appeared. The resulting slurry was aged at 0 °C for 1-2 hours. The suspension was filtered at 0°C. The isolated wet white solid was analysed by XRPD being (E)-2-isopropyl-5-styrylbenzene-1 ,3-diol organic acid solvate compound.

Acetic acid solvate obtained was the same as described in WO2019094934

Propionic acid solvate obtained was the same as WO2021236709

Butyric acid solvate of tapinarof characterization

PXRD butyric acid solvate of tapinarof as shown in Figure 11 with the following peaks:

3.2 104 27.72 24.3 5277 3.66

6.5 27308 13.67 25.6 363 3.48

7.2 119 12.23 26.0 1001 3.42

9.9 4760 8.90 26.2 678 3.39

10.9 228 8.14 27.0 425 3.29

11.3 183 7.82 27.8 419 3.21

12.9 15016 6.83 27.9 324 3.19

13.8 248 6.42 28.5 334 3.13

14.9 7355 5.90 29.4 101 3.03

15.7 101 5.63 30.1 261 2.97

16.4 339 5.39 31.4 135 2.84

17.0 675 5.21 32.7 486 2.73

18.6 268 4.76 34.7 130 2.58

19.1 612 4.64 36.1 121 2.49

19.5 904 4.55 36.9 336 2.43

19.9 283 4.45 37.9 181 2.37

20.9 564 4.24

21.3 82 4.17

22.9 180 3.88

24.0 2254 3.70

I sobuty ric acid solvate of tapinarof characterization.

PXRD isobutyric acid solvate of tapinarof as shown in Figure 12 with the following peaks:

6.4 8916 13.73 22.8 440 3.89

7.2 142 12.18 23.4 9157 3.79

9.7 4497 9.12 24.4 252 3.64

10.9 1091 8.12 24.9 558 3.56

11.1 444 7.98 25.2 1537 3.52

11.6 78 7.62 25.9 120 3.44

12.9 4042 6.87 26.3 230 3.39

13.5 92 6.55 26.7 31 3.33

14.5 606 6.10 27.3 379 3.26

14.8 3263 5.99 27.7 481 3.22

15.0 726 5.89 28.3 115 3.15

15.9 2126 5.58 28.7 70 3.10

16.3 181 5.44 29.2 100 3.05

16.8 909 5.27 29.5 143 3.02

17.8 291 4.97 30.4 149 2.94

18.3 184 4.84 31.4 102 2.84

18.8 636 4.69 32.0 104 2.79

19.3 278 4.58 32.5 138 2.75

20.1 278 4.42 33.1 87 2.70

20.4 187 4.35 33.6 107 2.66

20.7 99 4.29 35.4 71 2.53

21.4 116 4.15 37.4 103 2.40

22.4 249 3.97 38.5 68 2.33 Example 5. De-solvation of organic acid solvate to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol, compound (I), tapinarof.

Wet (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol organic acid solvate compound was placed in an oven and was dried under vacuum at 80 °C for 16 hours to provide (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol, compound (I), tapinarof, as white powder solid and showing a single polymorph by XRPD analysis.

Example 6. Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol, tapinarof, Form I

A laboratory 0.1 -liters flask was purged with nitrogen and then charged with (E)-2-isopropyl-5-styrylbenzene-1 ,3-diol (10 g) and organic acid solvent (40-50 mL). The mixture was protected from light and was heated to 65-75 °C until complete dissolution. The resulting solution was then cooled to 0 °C and a precipitate appeared. The resulting slurry was aged at 0 °C for 1-2 hours. The suspension was filtered at 0°Cand a wet white solid was isolated.

Wet white solid was placed in an oven and was dried under vacuum at 80 °C for 16 hours to provide (E)-2-isopropyl- 5-styryl benzene- 1 ,3-diol, compound (I), tapinarof, as white powder solid and showing a single polymorph by XRPD analysis.

Comparative Example 1 : Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol, compound (I), tapinarof

A round-bottom flask of 250 mL was purged with nitrogen and then charged with (E)-2-isopropyl-1 ,3-dimethoxy-5- styrylbenzene (2.7 g, 9.56 mmol, 1 equiv.) and toluene (38 mL). The resulting solution was cooled at 0-5°C. Then, N,N- dimethylaniline (5.8 g, 47.9 mmol, 5 equiv.) was charged and the resulting solution was stirred for 10 minutes. Then, aluminium chloride (7.67 g, 57.5 mmol, 6 equiv.) was charged portionwise in three times every 10 minutes. Once the reagent charged, the resulting suspension was stirred for 15 minutes. The crude mass was heated at 105-110°C and was allowed to react for 2 hours. The product mixture was then cooled and hydrochloric acid 10% was slowly charged (about 14 mL) and the resulting mixture was allowed to stir for 15 minutes. Then, ethyl acetate (19 mL) was charged and a biphasic system was obtained. The aqueous phase was re-extracted up to two times more with ethyl acetate (19 mL). Subsequently, the organic phases were merged and extracted three times with water (13.5 mL each). The resulting organic phase was concentrated to dryness and the resulting solid was suspended in toluene (7.5 mL) and was then heated to 70°C until total dissolution. The resulting clear solution was cooled at 0-5°C in 1 hour. The resulting suspension was filtered and the solid washed with cold toluene twice (1 mL each). The isolated solid was then dried under vacuum at 50 °C for 16 hours to provide (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol compound, tapinarof, as a brown solid (1 .8 g, 74%), along with the corresponding impurities obtained from the coupling of tapinarof with toluene and N,N-dimethylaniline, respectively, and their isomers.

HPLC purity (%area): 94.9

Brown colour did not comply with specifications for the release of the API, therefore several recrystallizations in toluene were performed. However, even after several recrystallizations, brown colour persisted reducing dramatically the yield of the process.

Comparative Example 2: Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound, tapinarof

Comparative Example 1 was repeated at a higher scale of (E)-2-isopropyl-1 ,3-dimethoxy-5-styrylbenzene (10 g, 35.4 mmol, 1 equiv.).

The isolated solid obtained was (E)-2-isopropyl-5-styryl benzene- 1 ,3-diol compound, tapinarof, as a grey-brown solid (7.7 g, 85%), along with the corresponding impurities obtained from the coupling of tapinarof with toluene and N,N- dimethylaniline, respectively, and their isomers.

HPLC purity (%area): 97.5

References List

Blessing, R. H., "An empirical correction for absorption anisotropy”, Acta Crystallogr., Sect. A: Found. Adv. 1995, 51 , 33-38.

Sheldrick, G. M., "SHELXT - Integrated space-group and crystal-structure determination”, Acta Crystallogr., Sect. A: Found. Adv. 2015, 71 , 3-8.

Macrae, CF. et al., "New Features for the Visualization and Investigation of Crystal Structures”, J. Appl. Crystallogr. 2008, 41 , 466-470.

Claims

comprising the following steps: a) reacting a compound of formula (II)

with a cycloalkyl amine and aluminium trichloride in the presence of a first solvent to give a compound of formula (I) or a co-crystal or a salt or a solvate thereof, and b) optionally isolating the obtained compound of formula (I).

2. The process according to claim 1, wherein the cycloalkyl amine is selected from the group consisting of N- cyclohexyl-N-methylcyclohexanamine, N,N-dimethylcyclohexanamine, N-cyclohexyl-N-ethylcyclohexanamine, dicyclohexylamine and N, N-diethylcyclohexylamine.

3. The process according to any of the claims 1 to 2, wherein the cycloalkyl amine is N-cyclohexyl-N- methylcyclohexanamine.

4. The process according to claim 3, wherein the amount of N-cyclohexyl-N-methylcyclohexanamine is from 1 to 6 equivalents in relation to compound (II).

5. The process according to any of the claims 3 to 4, wherein the process of step a) further comprises:

I) adding a second solvent and treatment with an acid, and

II) isolating the compound of formula (III) from the reaction medium:

6. The process according to the preceding claim, wherein the acid used in step i) is HCI.

7. The process according to any of the claims 5 to 6, further comprising step ill) of slurrying or recrystallizing compound of formula (III) in water to yield compound of formula (IV).

8. The process according to any of the claims 5 to 7, wherein step b) further comprises slurrying compound of formula (III) or (IV) in a third solvent and water to isolate compound of formula (I).

9. The process according to any of the claims 3 to 8, for the preparation of a compound of formula (I),

comprising the following steps: a) reacting a compound of formula (II)

with N-cyclohexyl-N-methylcyclohexanamine and aluminium trichloride in the presence of a first solvent to give a co-crystal of the compound of formula (III),

I) adding a second solvent and optionally treatment with an acid,

II) isolating the compound of formula (III) from the reaction medium,

10. The process according to the previous claim, wherein after step II) further comprises the following steps of: ill) slurrying or recrystallizing the compound of formula (III) in water to yield compound of formula (IV)

11 . The process according to any of any of the claims 1 to 10, wherein the process further comprises the formation of an organic acid solvate of the compound of formula (I), tapinarof.

12. The process according to the previous claim, wherein the process comprises: c) providing compound of formula (I), tapinarof, in an organic acid solvent or a mixture of organic acid solvent and one or more solvents; d) optionally heating the reaction mixture to a temperature of about 60 °C to about 80 °C to obtain dissolution; e) cooling to a temperature of about 0 °C to about 50 °C; f) optionally stirring the reaction mixture for about 0,5 to about 3 hours; and g) optionally separating the precipitate.

13. The process according to any of the claims 11 to 12, wherein the organic acid solvent is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

14. The process according to any of the clauses 11 to 13, wherein after step g) further comprises drying the precipitate to obtain compound of formula (I), tapinarof.

15. A co-crystal compound of formula (III),

16. The co-crystal compound of formula (III) of the previous claim characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 7.7, 16.8, 17.5, 18.4 and 22.5 ± 0.2 degrees 2e.

17. A co-crystal compound of formula (IV),

18. The co-crystal compound of formula (IV) of the previous claim characterized by an PXRD pattern comprising the following peaks: 7.3, 19.3, 20.6 and 21.2 ± 0.2 degrees 2e.

19. Use of the compound of formula (III) as defined in any one of claims 15 to 16 or the compound or formula (IV) as defined in any one of claims 17 to 18 for the preparation of the compound (I), tapinarof.

20. A crystalline compound of formula (I), tapinarof, in the form of an organic acid solvate selected from the group consisting of butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

21 . A crystalline butyric acid solvate of tapinarof.

22. The butyric acid solvate of tapinarof of the previous claim characterized by an PXRD pattern comprising the following peaks: 6.5, 9.9, 12.9, 14.9 and 24.3 ± 0.2 degrees 2e.

23. A crystalline isobutyric acid solvate of tapinarof.

24. The isobutyric acid solvate of tapinarof of any of the previous claim characterized by an PXRD pattern comprising the following peaks: 6.4, 9.7, 12.9, 14.8, 15.9 and 23.4 ± 0.2 degrees 2e.

25. Use of the organic acid solvate compound as defined in any one of claims 20 to 24 for the preparation of the compound (I), tapinarof.

26. Use of the organic acid solvate compound according to the previous claim, wherein the organic acid solvate compound is selected form the group consisting of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid and 2-methylbutyric acid.

27. Use of the organic acid solvate compound according to any of the claims 25 to 26, wherein the organic acid solvate compound is acetic acid solvate of tapinarof.

28. Use of the organic acid solvate compound according to any of the clauses 25 to 26, wherein the organic acid solvate compound is butyric acid solvate of tapinarof.

29. Use of the organic acid solvate compound according to any of the clauses 25 to 26, wherein the organic acid solvate compound is isobutyric acid solvate of tapinarof.

30. Use of the organic acid solvate compound according to any of the clauses 27 to 29 for the preparation of crystalline form I of tapinarof.

31 . Use of the organic acid solvate compound according to any of the clauses 25 to 26, wherein the organic acid solvate compound is propionic acid solvate of tapinarof.

32. Use of the organic acid solvate compound according to the preceding claim for the preparation of crystalline form III of tapinarof.