Process for preparing the polymorphic form iii of tapinarof

Abstract

The present invention concerns a process for preparing tapinarof and its polymorphic form III, which provides for the obtaining of tapinarof through an optimized process, which is then heated to obtain the polymorphic form III. The process according to the present invention is therefore very simple, effective, and industrially applicable.

Description

[0001] “PROCESS FOR PREPARING THE POLYMORPHIC FORM III OF TAPINAROF”

[0002] ***** ***** *****

[0003] DESCRIPTION

[0004] FIELD OF THE INVENTION

[0005] The present invention concerns a process for preparing tapinarof and its polymorphic form III.

[0006] STATE OF THE ART

[0007] The compound tapinarof, (E)-3,5-dihydroxy-4-isopropylstilbene, also known as benvitimod, has the following chemical formula:

[0008] Tapinarof is an active ingredient approved by the Food and Drug Administration (FDA) and it is an aryl hydrocarbon receptor-modulating agent (TAMA) used for the treatment of psoriasis and atopic dermatitis thanks to its immunomodulatory effect. By binding directly to the receptor, it induces a downregulation of inflammatory cytokines, regulates the expression of proteins involved in the skin barrier formation, and also acts as an antioxidant.

[0009] Tapinarof has been described in numerous publications including Paul, V.J., Frautschy, S., Fenical, W. et al. Antibiotics in microbial ecology. J Chem Ecol 7, 589-597 (1981 ) and in the International Patent Applications WO2001042231 and W02004031117.

[0010] The International Patent Application No. WO2019094934 describes a process for the synthesis of tapinarof and the process for obtaining the polymorphic form I. CN101648851 describes a route for the synthesis of tapinarof through the Homer- Wadsworth-Emmons reaction. WO2021236709 describes nine different solvated forms of tapinarof and the processes for obtaining them.

[0011] The polymorphic form III of tapinarof, and the process for preparing it, is described in the International Patent Application WO2019 / 063002, and is characterized by an X-ray diffraction spectrum having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.4°, 23.7°, 24.4°, 28.3°, 30.6°, 40.8°, 42.4°(± 0.2° 20). The processes known in the art, for obtaining both tapinarof and its polymorphic form III, have critical issues especially related to the applicability on an industrial scale.

[0012] For example, some of the processes known for obtaining tapinarof, such as those described in WO2001042231 , CN101830764, CN101838173, CN101531571 , and CN104003848 proceed through a reaction intermediate corresponding to Compound 5.

[0013] As described in CN104003848, the synthesis of Compound 5 may involve the use of MnO2, which is suspended in the mixture comprising the reagents. The mixture thus obtained is then filtered. The filtration step is very slow and difficult; this has a significant impact on the efficiency of the process and on the costs, especially when it involves industrial scale production.

[0014] The object of the present invention is therefore to provide an efficient process for the synthesis of tapinarof, and its polymorphic form III, that overcomes the drawbacks of the prior art while being at the same time advantageous from an industrial point of view. SUMMARY OF THE INVENTION

[0015] The above-mentioned object has been achieved by means of a process that allows to obtain Compound 5, avoiding the slow and difficult filtration step, and using reproducible and scalable isolation techniques to obtain tapinarof and its polymorphic form III.

[0016] In a first aspect, therefore, the present invention relates to a process for preparing the compound tapinarof, (E)-3,5-dihydroxy-4-isopropylstilbene, comprising the steps of: i) reacting Compound 1 with a methylating agent and an organic or inorganic base, in an appropriate solvent, to obtain Compound 2; ii) reacting Compound 2 with an isopropylating agent in the presence of a Lewis acid, and subsequently methylating it with a methylating agent in the presence of a base to obtain Compound 3; iii) reacting Compound 3 with a reducing reagent to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing MnCX, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from

[0017] 60°C to 80°C, to obtain Compound 5; vi) reacting Compound 5 with diethyl benzylphosphonate in the presence of a base to obtain Compound 6; vii) reacting Compound 6 with a mixture of AlCh and a tertiary amine to obtain tapinarof.

[0018] Advantageously and surprisingly, the process of the invention which provides for the synthesis of Compound 5 using the column containing solid Mn02 through which the solution of Compound 4 is eluted, allows to significantly reduce times and costs with respect to the processes described in the prior art, such as CN104003848. Once the reaction is finished, in fact, the column can be easily disposed of, thus avoiding the step of removing the solid from the reaction environment through a difficult filtration.

[0019] In a second aspect, the present invention relates to a process for obtaining the polymorphic form III of tapinarof characterized by an X-ray spectrum having peak s at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4°± 0.2° 20, comprising the steps of: a) adding a solvent selected from the group consisting of toluene, DMSO, n- heptane, chlorobenzene, to the compound tapinarof, crude or amorphous, or in any other crystalline form; b) heating the solution to a temperature in the range from 30°C to 100°C, preferably from 40°C to 100°C, more preferably from 80°C to 100°C; c) optionally adding a second solvent and cooling the solution to a temperature in the range from 20°C to 45°C, preferably from 35°C to 45°C, to initiate crystallization; d) slowly cooling until reaching a temperature equal to or lower than 4°C, preferably a temperature of 0°C; e) isolating the solid obtained in step d); f) heating the solid isolated in step e) to a temperature in the range from 70°C to 90°C, preferably from 70°C to 80°C, until the polymorphic form III of tapinarof is obtained.

[0020] Advantageously, with the process of the invention, the tapinarof obtained by crystallization from various appropriate solvents completely converts into the polymorphic form III, when subjected to heating at a temperature in the range from 70°C to 90°C. The object of the present invention is therefore to provide an efficient process for the synthesis of tapinarof and its polymorphic form III that overcomes the drawbacks of the prior art, while being at the same time advantageous from an industrial point of view.

[0021] DESCRIPTION OF THE FIGURES

[0022] Figure 1 shows the XRPD diffractogram of the polymorph form III of the compound tapinarof, having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4°± 0.2° 28.

[0023] Figure 2 shows the DSC thermogram of the polymorphic form III of the compound tapinarof.

[0024] Figure 3 shows the thermogravimetric curve of the polymorphic form III of the compound tapinarof

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] In the present invention, when using:

[0027] -“solid state form” or “polymorph”, it is intended to mean a pure form or one substantially free of other polymorphic forms. Tapinarof described below is considered free of other polymorphs when it contains more than 90% (w / w) of the polymorphic form under examination.

[0028] - “solvate” is intended to mean a crystalline form that incorporates a solvent into the crystalline structure. When the solvent is water, it may be referred to as a “hydrate”. The solvent in a solvate may be either stoichiometric or non-stoichiometric. The term “isolated” with reference to the polymorphic crystalline form of tapinarof, in the following invention, refers to a polymorphic crystalline form of tapinarof that is physically separated from the reaction mixture in which it is formed.

[0029] - “reduced pressure” is intended to mean a pressure lower than the atmospheric pressure, usually a pressure between 500 and 2000 Pa.

[0030] - “any other crystalline form of tapinarof” is intended to mean any other polymorphic form of tapinarof other than form III, such as the known forms I, II, IV, and all solvated forms;

[0031] The present invention relates to an efficient process for the synthesis of the compound tapinarof and its polymorphic form III.

[0032] In a first aspect, the present invention relates to a process for preparing the compound tapinarof, comprising the steps of: i) reacting Compound 1 with a methylating agent and an organic or inorganic base in an appropriate solvent to obtain Compound 2; ii) reacting Compound 2 with an isopropylating agent in the presence of a Lewis acid, and subsequently methylating it with a methylating agent in the presence of a base to obtain Compound 3; iii) reacting Compound 3 with a reducing reagent to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing MnO2, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from 60°C to 80°C, to obtain Compound 5; vi) reacting Compound 5 with diethyl benzylphosphonate in the presence of a base to obtain Compound 6;

[0033] vii) reacting Compound 6 with a mixture of AlCh and a tertiary amine to obtain tapinarof.

[0034] According to a preferred embodiment of the invention, the methylating agent of step i) is selected from the group consisting of dimethyl sulfate, methyl iodide, and dimethyl carbonate. Preferably the methylating agent of step i) is dimethyl sulfate.

[0035] According to a preferred embodiment of the invention, the organic or inorganic base of step i) is selected from the group consisting of potassium carbonate, sodium hydride, and potassium tert-butoxide. Preferably the inorganic base of step i) is potassium carbonate.

[0036] According to a preferred embodiment of the invention, the isopropylating agent of step ii) is selected from the group consisting of isopropyl bromide, isopropyl chloride, isopropyl methanesulfonate, isopropyl trifluoromethanesulfonate, isopropyl tosylate, and isopropanol. Preferably the isopropylating agent of step ii) is isopropyl bromide.

[0037] According to a preferred embodiment of the invention, the Lewis acid of step ii) is selected from the group consisting of aluminum trichloride, boron tribromide, aluminum tribromide, boron trichloride, boron trifluoride, tin tetrachloride.

[0038] According to a preferred embodiment of the invention, the methylating agent of step ii) is selected from the group consisting of dimethyl sulfate, methyl iodide, and dimethyl carbonate. Preferably the methylating agent of step ii) is dimethyl sulfate.

[0039] According to a preferred embodiment of the invention, the organic or inorganic base of step ii) is selected from the group consisting of potassium carbonate, sodium hydride, and potassium tert-butoxide. Preferably the inorganic base of step ii) is potassium carbonate.

[0040] According to a preferred embodiment of the invention, the reducing agent of step iii) is selected from the group consisting of sodium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane, and di-iso-butyl aluminum hydride. Preferably the reducing agent of step iii) is sodium borohydride.

[0041] According to a preferred embodiment of the invention, the base of step vi) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, and potassium hydride. Preferably the base of step vi) is sodium tert-butoxide. According to a preferred embodiment of the invention, the tertiary amine of step vii) is selected from the group consisting of DIPEA, TEA, N,N-dimethylaniline. Preferably the tertiary amine of step vii) is TEA.

[0042] According to a preferred embodiment of the invention, in step v) the flow is adjusted to ensure a residence time comprised between 5 and 60 minutes, preferably between 10 and 30 minutes, even more preferably between 10 and 20 minutes.

[0043] Advantageously and surprisingly, the process of the invention that involves the synthesis of Compound 5 using the column containing solid Mn02 through which the solution of Compound 4 is eluted, allows to significantly reduce times and costs with respect to the processes described in the prior art.

[0044] Once the reaction is finished, in fact, the column can be easily disposed of, thus avoiding the step of removing the solid from the reaction environment by filtration.

[0045] According to an even more preferred embodiment of the invention, the process for preparing tapinarof comprises the steps of: i) reacting Compound 1 with dimethyl sulfate and potassium carbonate in acetone to obtain Compound 2; ii) reacting Compound 2 with isopropyl bromide in the presence of a Lewis acid, and subsequently methylating it with dimethyl sulfate and potassium carbonate in acetone to obtain Compound 3; iii) reacting Compound 3 with sodium borohydride in the presence of MeOH or BF3 to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing Mn02, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from 60°C to 80°C, to obtain Compound 5; vi) reacting Compound 5 with diethyl benzylphosphonate in the presence of sodium tert-butoxide to obtain Compound 6; vii) reacting Compound 6 with a mixture of AICI3 and TEA to obtain tapinarof.

[0046]

[0047] The polymorphic form III of tapinarof characterized by an X-ray spectrum having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4°± 0.2° 20 may be obtained by a process comprising the steps of: a) adding a solvent selected from the group consisting of toluene, DMSO, n- heptane, chlorobenzene, to the compound tapinarof, crude or amorphous, or in any other crystalline form; b) heating the solution to a temperature in the range from 30°C to 100°C, preferably from 40°C to 100°C, more preferably from 80°C to100 °C; c) optionally adding a second solvent and cooling the solution to a temperature in the range from 20°C to 45°C, preferably from 35°C to 45°C, to initiate crystallization; d) slowly cooling until reaching a temperature equal to or lower than 4°C, preferably a temperature of 0°C; e) isolating the solid obtained in step d); f) heating the solid isolated in step e) to a temperature in the range from 70°C to 90°C, preferably from70°C to 80°C, until the polymorphic form III of tapinarof is obtained.

[0048] According to a preferred embodiment of the invention, the tapinarof of step a) is obtained according to steps i)-vii).

[0049] According to the invention, the solvent of step c) is selected from the group consisting of n-heptane and water.

[0050] According to a preferred embodiment of the invention, the solvent of step a) is toluene, and the solvent of step c) is n-heptane.

[0051] According to a even more preferred embodiment of the invention, when the solvent of step a) is toluene, and the solvent of step c) is n-heptane, the solution in step b) is heated to a temperature in the range from 80°C to 100°C.

[0052] According to a preferred embodiment of the invention, the solvent of step a) is DMSO and the solvent of step c) is water.

[0053] According to an even more preferred embodiment of the invention, when the solvent of step a) is DMSO and the solvent of step c) is water, the solution in step b) is heated to a temperature in the range from 40°C to 60°C.

[0054] According to a preferred embodiment of the invention, the solvent of step a) is n- heptane.

[0055] According to a preferred embodiment of the invention, when the solvent of step a) is n-heptane, the solution in step b) is heated to a temperature in the range from 80°C to 100°C.

[0056] Advantageously, with the process of the invention, the tapinarof obtained by crystallization from different appropriate solvents completely converts into the polymorphic form III once subjected to heating at a temperature comprised in the range from 70°C to 90°C.

[0057] EXPERIMENTAL PART

[0058] The invention is now illustrated by means of some examples intended for illustrative and non-limiting purposes.

[0059] Abbreviations - Meaning

[0060] DMSO: dimethyl sulfoxide

[0061] MTBE: methyl-tert-butyl ether

[0062] Mn02: manganese dioxide

[0063] TEA: triethylamine

[0064] DIPEA: N,N-Diisopropylethylamine

[0065] AlCh: aluminum trichloride

[0066] THF: tetrahydrofuran

[0067] MeOH: methanol tBuONa: sodium tert-butoxide

[0068] HCI: hydrochloric acid

[0069] EtOH: ethanol

[0070] AcOEt: ethyl acetate

[0071] NMR: Nuclear Magnetic Resonance

[0072] TGA: Thermogravimetric Analysis

[0073] XRPD: X-Ray Powder Diffraction

[0074] DSC: Differential Scanning Calorimetry Analytical Methods

[0075] X-Ray Diffraction (XRPD)

[0076] Diffractograms were acquired with an XPert PRO X-ray powder diffractometer equipped with a CuK a irradiation source, A = 1 .54060 A (Angstrom) and a X’Celerator detector (0.518° 29). Scanning parameters: angle range 3-50 deg, step size 0.0167, time per step 20 s, continuous scanning.

[0077] Differential Scanning Calorimetry (DSC)

[0078] Differential scanning calorimetry was performed on a Perkin Elmer DSC7 calorimeter by heating a 3 mg sample from 25°C to 200°C in a perforated aluminum capsule. The sample compartment was conditioned with nitrogen.

[0079] Thermoqravimetric Analysis (TGA)

[0080] Thermogravimetric analysis was performed with a Perkin Elmer Pyris 1 TGA by heating a 6 mg sample from 30°C to 200°C in an open ceramic crucible. The sample compartment was conditioned with nitrogen.

[0081] Examples

[0082] Example 1 : Preparation of Compound 2

[0083] A suspension of 3,5-hydroxybenzoic acid (Compound 1 , 100.0 g), dimethyl sulfate (3.5 eq), and potassium carbonate (3.9 eq) in acetone was brought to reflux to 55°C for 12 h. The reaction mixture was diluted with water and stirred at 55°C for 1 h. Acetone was removed by distillation under reduced pressure. The residue was cooled down to 25°C and filtered through a Buchner filter to recover Compound 2 as a white solid.

[0084] Example 2: Preparation of Compound 3

[0085] To a suspension of AlCh (42 g, 315 mmol) in dichloromethane (150 mL) under a nitrogen atmosphere, isopropyl bromide (38.8 g, 315 mmol) was added while maintaining the temperature between 10 and 15 °C, and the resulting mixture was left under stirring at this temperature for 30 minutes. At this point, a solution of methyl 3,5- dimethoxybenzoate (Compound 2, 30 g, 153 mmol) in DCM (50 mL) was added in a single portion, the temperature was raised to 38°C and the reaction mixture was left under stirring for 18 hours. The reaction mixture was added to an aqueous solution of 2 M HCI and ice at 0°C; the layers were separated, and the organic layer was washed with saturated Rochelle salt solution, then with a saturated sodium bicarbonate solution, followed by water and brine. The solvent was removed under reduced pressure. If necessary, the residue obtained can be methylated according to the procedure described for Compound 2 to increase the yield of Compound 3.

[0086] Example 3: Preparation of Compound 4

[0087] Methyl 4-isopropyl-3,5-dimethoxybenzoate (Compound 3, 100.0 g, 419.7 mmol) and sodium borohydride (81 .3 g, 2.31 mol) were suspended in THF (1 .0 L), and the reaction mixture was heated to reflux. MeOH (500 mL) was added slowly. Water was added, and extraction was performed with toluene to obtain Compound 4.

[0088] Alternatively, Compound 4 was obtained by suspending methyl 4-isopropyl-3,5- dimethoxybenzoate (Compound 3, 100.0 g, 419.7 mmol) and sodium borohydride (17.5 g, 461.6 mmol) in THF (420 mL). BF3THF (60.1 mL, 545.6 mmol) was slowly added dropwise into the reaction mixture, heating at reflux. A solution of MeOH in THF, an aqueous solution of NaHCOs, and toluene were added in succession. The two layers formed were separated, and the organic layer was washed with an aqueous solution of NaCI. Compound 4 was isolated by evaporating the solvent.

[0089] Example 4: Preparation of Compound 5 (4-lsopropyl-3,5-dimethoxyphenyl)methanol (Compound 4, 90 g, 428.02 mmol) was solubilized in toluene. The solution was heated to 80°C and eluted on a column previously packed with MnO2, for a residence time of 15 min. The toluene solution containing Compound 5 was then concentrated to dryness, and the product crystallized from an EtOH / water mixture.

[0090] Example 5: Preparation of Compound 6

[0091] 4-lsopropyl-3,5-dimethoxybenzaldehyde (Compound 5, 62.0 g, 297.7 mmol) and diethyl benzylphosphonate (68.6 g, 297.7 mmol) were solubilized in THF (400 mL). tBuONa (35.4 g, 357.3 mmol) was added, and the mixture was allowed to react at 40°C. An aqueous 2M HCI solution was then added, and the mixture was extracted with AcOEt. The product was then crystallized from MeOH.

[0092] Example 6: Preparation of the Compound Tapinarof

[0093] (E)-2-isopropyl-1 ,3-dihydroxy-5-styrylbenzene (Compound 6, 65.7 g, 232.6 mmol) was solubilized in chlorobenzene (66 mL), and the solution was added to a mixture of AlCh (125.3 g, 930.5 mmol) and TEA (142.7 g, 1.4 mol) in chlorobenzene (328 mL) and heated to 110°C. After dilution with water, the mixture was extracted with AcOEt and the crude compound tapinarof was obtained.

[0094] Example 7: Preparation of the Polymorphic Form III of Tapinarof by Crystallization from Toluene / n-Heptane Toluene (10 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 80-100°C with stirring for 20-30 minutes, until completely dissolved. Heptane (20 mL) was added over 15-30 minutes, and then the mixture was cooled down to room temperature to obtain crystallization. The mixture was left at 0°C for 1 -3 hours, and the crystal obtained was recovered by filtration and washed with heptane. The white solid obtained was placed in an oven at reduced pressure at 80°C, overnight, to obtain the polymorphic form III. To demonstrate that form III was obtained, the product taken from the oven was subjected to XRPD, TGA, and DSC analysis. The graphs in Figures 1 , 2 and 3, which confirmed that the polymorphic form III had been formed, were obtained.

[0095] Example s: Preparation of Tapinarof Polymorph III by Crystallization from DMSO / Water DMSO (10 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 40-60°C with stirring for 20-30 minutes, until completely dissolved. Water (20 mL) was then added over 15-30 minutes, and the mixture was cooled down to room temperature to achieve crystallization. The mixture was left at 4°C for 1 -3 hours, and the crystal was recovered by filtration and washed with water. The resulting white solid was placed in a vacuum oven at 80°C, overnight, to obtain polymorph III. To demonstrate that form III was obtained, the product taken from the oven was subjected to XRPD, TGA, and DSC analysis. The same graphs as in Figures 1 , 2 and 3 of Example 7, which confirmed that the polymorphic form III had been formed, were obtained.

[0096] Example 9: Preparation of Polymorphic Form III of Tapinarof by Crystallization from n- Heptane n-Heptane (400 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 80-100°C with stirring for 20-30 minutes, until completely dissolved. The mixture was cooled down to room temperature to achieve crystallization. The mixture was then left at 0°C for 1 -3 hours, and the crystal was recovered by filtration and washed with n-heptane. The resulting white solid was placed in a vacuum oven at 80°C, overnight, to obtain the polymorphic form III. To demonstrate that form III was obtained, the product taken from the oven was subjected to XRPD, TGA, and DSC analysis. The same graphs as in Figures 1 , 2 and 3 of Example 7, which confirmed that the polymorphic form III had been formed, were obtained.

Claims

CLAIMS1 . A process for preparing the compound tapinarof, comprising the steps of: i) reacting Compound 1 with a methylating agent and an organic or inorganic base, in an appropriate solvent to obtain Compound 2;ii) reacting Compound 2 with an isopropylating agent, in the presence of a Lewis acid, and subsequently methylating it with a methylating agent in the presence of a base to obtain Compound 3;iii) reacting Compound 3 with a reducing reagent to obtain Compound 4;iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing Mn02, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from 60°C to 80°C, to obtain Compound 5;vi) reacting Compound 5 with diethyl benzylphosphonate in the presence of a base to obtain Compound 6;vii) reacting Compound 6 with a mixture of AlCh and a tertiary amine to obtain tapinarof.

2. The process of claim 1 , wherein the flow of step (v) is adjusted to ensure a residence time in the range from 5 to 60 minutes, preferably from 10 to 30 minutes.

3. The process of claims 1 and 2, wherein the methylating agent of step (i) is selected from the group consisting of dimethyl sulfate, methyl iodide, and dimethyl carbonate.

4. The process of any one of claims 1 to 3, wherein the organic or inorganic base of step (i) is selected from the group consisting of potassium carbonate, sodium hydride, and potassium tert-butoxide.

5. The process of any one of claims 1 to 4, wherein the isopropylating agent of step (ii) is selected from the group consisting of isopropyl bromide, isopropyl chloride, isopropyl methanesulfonate, isopropyl trifluoromethanesulfonate, isopropyl tosylate, and isopropanol. .

6. The process of any one of claims 1 to 5, wherein the reducing agent of step (iii) is selected from the group consisting of sodium borohydride, lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, borane, and di-iso-butyl aluminium hydride.

7. The process of any one of claims 1 to 6, wherein the base of step (vi) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, sodiumhydride, and potassium hydride.

8. The process of any one of claims 1 to 7, wherein the tertiary amine of step (vii) is selected from the group consisting of DIPEA, TEA, N,N-dimethylaniline.

9. A process for obtaining the polymorphic form III of tapinarof characterized by an X- ray spectrum having peaks at 5.6°, 11 .3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4°± 0.2° 28, comprising the steps of: a) adding a solvent selected from the group consisting of toluene, DMSO, n- heptane, chlorobenzene, to the compound tapinarof, crude or amorphous, or in any other crystalline form; b) heating the solution to a temperature in the range from 30°C to 100°C, preferably from 40°C to 100°C, more preferably from 80°C to100 °C; c) optionally adding a second solvent and cooling the solution to a temperature in the range from 20°C to 45°C, preferably from 35°C to 45°C, to initiate crystallization; d) slowly cooling until reaching a temperature equal to or lower than 4°C, preferably a temperature of 0°C; e) isolating the solid obtained in step d); f) heating the solid isolated in step e) to a temperature in the range from 70°C to 90°C, preferably from 70°C to 80°C, until polymorphic form III of tapinarof is obtained.

10. The process of claim 9, wherein tapinarof is obtained according to steps i)-vii).

11. The process of claim 9, wherein the solvent of step c) is selected from the group consisting in n-heptane and water.12 The process of claims 9 and 11 , wherein the solvent of step a) is toluene, and the solvent of step c) is n-heptane.

13. The process of claims 9 and 11 , wherein the solvent of step a) is DMSO and the solvent of step c) is water.

14. The process of claim 9, wherein the solvent of step a) is n-heptane.

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