Process for the preparation of intermediates useful for the preparation of tapinarof

Abstract

The present invention relates to a new process for the preparation of synthesis intermediate products useful for the preparation of tapinarof and to new intermediates thus obtained.

Description

[0001] Process for the preparation of intermediates useful for the preparation of tapinarof

[0002] This application claims the benefit of European Patent Application no. 23383371 filed December 22nd, 2023.

[0003] Technical Field

[0004] The present invention relates to a new process for the preparation of synthesis intermediate products useful for the preparation of tapinarof and to new intermediates thus obtained.

[0005] Background Art

[0006] Tapinarof, also known as benvitimod, is 3,5-dihydroxy-4-isopropylstilbene and it has the following chemical structure of formula (I):

[0007] 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.

[0008] 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. It has the advantages of quick effect, lasting effect, low recurrence rate after drug withdrawal, long remission period and the like, which embodies the excellent clinical value of the drug and has obvious advantages compared with the existing therapeutic drugs.

[0009] Several synthetic routes have been reported to prepare tapinarof. The Wittig-Horner condensation route is considered the best in terms of yield and the configuration obtained of the double bond. However, the oxidation step used to obtain the aldehyde intermediate of formula (III) has still room for improvement. Several oxidation methods have been reported in the literature.

[0010] EP1248774B1 discloses an oxidation reaction for preparing the aldehyde intermediate (III) using pyridinium chlorochromate (PCC). However, this reaction is associated with problems when the aldehyde is isolated, yield was very low, and many impurities appear. Furthermore, the PCC reagent cannot be used on an industrial scale.

[0011] CN 101830764 relates to a method that uses reaction Albright-Goldman oxidation and Wittig-Horner condensation for the synthesis of stilbene compounds. Specifically, dimethylsulfoxide (DMSO) and acetic anhydride as oxidative agent are used to obtain aldehyde intermediate (III) for the preparation of tapinarof. This reaction has several drawbacks since many impurities appear during the process.

[0012] IPCOM000270726D describes intermediate aldehyde (III) obtained by oxidation of the alcohol (II) using iodobenzene diacetate / TEMPO in a solvent. This process is not easy to scale-up to industrial scale due to the large amounts of iodobenzene byproducts obtained, which raises environmental issues.

[0013] 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.

[0014] In order to overcome the problems in the prior art, the present invention provides an oxidation method for preparing key synthetic intermediate for the preparation of tapinarof, which avoids the use of toxic metals, such as chromium, and can be carried out under very mild conditions improving the product quality and optimizing the post-treatment operation resulting in high yield as well as high purity tapinarof.

[0015] Summary of Invention

[0016] The inventors have found that by modifying certain parameters of reaction in the route of synthesis of tapinarof some of the synthesis intermediates can be prepared in a large scale, with high yields and purity, in particular the compound of formula (III), 4-isopropyl-3,5-dimethoxybenzaldehyde:

[0017] And the compound of formula (IV), (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene:

[0018] Therefore, a first aspect of the invention relates to a process for the preparation of a compound of formula (III), comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and an alkyl methyl sulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III) or a solvate thereof, and b) optionally isolating the obtained compound of formula (III).

[0019] In particular, the inventors have developed a process for the preparation of compound of formula (IV) which uses a bisulfite adduct (BA) crystalline intermediate that allows having an intermediate product in high yield and purity, and results in a process easy to industrialize. In particular, the adduct used is the compound of formula (lll-BA- M):

[0020] (lll-BA M) The isolation of this synthesis intermediate bisulfite adduct is very advantageous, especially on an industrial scale, and contributes to obtaining the intermediate compound of formula (IV) with high yield and purity and as a white powder. This reaction is useful for the separation and purification the aldehyde intermediate of formula (III). The bisulfite adducts are charged and so are more soluble in polar solvents. M is Na, K or Cs.

[0021] A second aspect of the invention relates to a process for the preparation of a compound of formula (IV), comprising the following steps: c) reacting a compound of formula (lll-BA M)

[0022] (lll-BA M) wherein M is Na, K or Cs, with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV), or d) slurrying the compound of formula (lll-BA- M) in water and aqueous hydrochloric acid, filtering the solid and drying the compound of formula (III) and e) reacting a compound of formula (III) with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

[0023] A third aspect of the invention relates to a compound of formula (I ll-BA- M),

[0024] (lll-BA M) wherein M is Na, K or Cs.

[0025] In a fourth aspect, the present invention relates to the use of the compound of formula (lll-BA M) of the third aspect as an intermediate for the preparation of the compound of formula (I), tapinarof.

[0026] Brief Description of the Figures

[0027] Figure 1 : FTIR of compound of formula (lll-BA Na) prepared in Example 1.

[0028] Figure 2: DSC of compound of formula (lll-BA- Na) prepared in Example 1 showing an endotherm peak at 90 °C due to the melting of the solid.

[0029] Figure 3: PXRD of compound of formula (lll-BA- Na) prepared in Example 1.

[0030] Detailed description of the invention

[0031] As mentioned above, the present invention relates to a new process for the preparation of synthesis intermediate products useful in the preparation of tapinarof that overcomes the drawbacks of the processes disclosed in the prior art. Furthermore, the process is easy to industrialize and allows having intermediate products in high yield and high purity.

[0032] 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.

[0033] For the purposes of the invention, any ranges given include both the lower and the upper endpoints of the range.

[0034] For the purposes of the invention, room temperature is 20-25 °C.

[0035] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. 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. The processes of the invention are schematically represented in the following scheme:

[0036] Scheme 1

[0037] The beneficial effects of the present invention are as follows:

[0038] - In the present invention, high quality tapinarof intermediates such as compound of formula (Ill-AB- M) and compound of formula (III) can be obtained, and the compound of formula (IV) is a white solid.

[0039] - The process is easy to industrialize and allows having an intermediate product of formula (IV) in high yield and high purity, easy to industrialize and avoids several impurities of the synthetic process.

[0040] In a particular embodiment of the present invention, the process for the preparation of a compound of formula (I II) according to the first aspect, the alkyl group of the alkyl methyl sulfoxide comprises a carbon chain length from 1 to 16 carbon.

[0041] In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the amount of alkyl methyl sulfoxide is from 1 to 5 equivalents. In a further embodiment, the amount of alkyl methyl sulfoxide is from 2 to 4 equivalents.

[0042] In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the alkyl methyl sulfoxide is dimethyl sulfoxide.

[0043] The expression "alkyl methyl sulfoxides" is intended to define but is not limited to such sulfoxides as dimethyl sulfoxide, ethyl methyl sulfoxide, methyl propyl sulfoxide, butyl methyl sulfoxide, methyl n-pentyl sulfoxide, heptyl methyl sulfoxide, methyl octyl sulfoxide, decyl methyl sulfoxide, methyl undecyl sulfoxide, dodecyl methyl sulfoxide, methyl tetradecyl sulfoxide, hexadecyl methyl sulfoxide. In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylpyrrolidine and N- ethylpyperidine.

[0044] In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the amount of base is from 1 to 8 equivalents. In another particular embodiment, the amount of base is from 2 to 6 equivalents. In a further embodiment, the amount of base is from 3 to 5 equivalents.

[0045] In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the base is triethylamine.

[0046] In another particular embodiment, in combination with any of the embodiments of the invention, the first organic solvent is selected from the group consisting of toluene, chlorobenzene, xylene, anisole, tetrahydrofuran, acetonitrile, dichloromethane, and mixtures thereof. In another particular embodiment, the first solvent is dichloromethane.

[0047] In another particular embodiment, in combination with any of the embodiments of the invention, the amount of oxalyl chloride is from 1 to 4 equivalents. In another particular embodiment, the amount of oxalyl chloride is from 1 to 2 equivalents.

[0048] In another particular embodiment, in combination with any of the embodiments of the invention, the reaction is carried out at a temperature below -50 °C, particularly at a temperature comprised from -60 to -80 °C.

[0049] In another particular embodiment, in combination with any of the embodiments of the invention, a compound of formula (III) is converted by reacting with a bisulfite compound to compound of formula (lll-BA-M)

[0050] (lll-BA M) wherein M is Na, K or Cs.

[0051] As used herein, the term "isolated" in reference to intermediate products useful for the preparation of tapinarof of the present disclosure corresponds to an intermediate product 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, the step a) further comprises:

[0052] I) adding water and treatment with an acid; ii) washing the organic phase with water; ill) treating the organic phase with aqueous solution containing bisulfite compound; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the reaction mixture; v) heating the mixture obtained in step iv) to a temperature of between 30 °C and the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and vi) optionally isolating and drying a compound of formula (I ll-BA- M) thus obtained

[0053] (lll-BA M) wherein M is Na, K or Cs.

[0054] In another particular embodiment, in combination with any of the embodiments of the invention, the acid used in step i) is hydrochloric acid (HCI), hydrobromic acid (HBr), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), particularly hydrochloric acid.

[0055] In another particular embodiment, in combination with any of the embodiments of the invention, the bisulfite compound is selected from the group consisting of sodium metabisulfite, sodium bisulfite, potassium metabisulfite, potassium bisulfite, caesium metabisulfite and caesium bisulfite. In another particular embodiment, the bisulfite compound is sodium metabisulfite.

[0056] As used herein, the term "bisulfite compound” refers to a mixture of salts that dissolve in water to give solutions composed of a metal (M) and bisulfite ions.

[0057] In another particular embodiment, in combination with any of the embodiments of the invention, the step iv) is performed before step ill).

[0058] In another particular embodiment, in combination with any of the embodiments of the invention, the steps I) to ill) are 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 second organic solvent of step iv) is selected from the group consisting of 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), 2-propanol or combinations thereof, particularly tetrahydrofuran (THF).

[0059] In another particular embodiment, in combination with any of the embodiments of the invention, the step vi) comprises evaporating part of the solvent and further crystallization or precipitation.

[0060] In another particular embodiment, in combination with any of the embodiments of the invention, the process after step v) further comprises slurrying the wet material in aqueous acid and stirring the mixture at room temperature, filtering the solid and drying the compound of formula (III)

[0061] In another particular embodiment, in combination with any of the embodiments of the invention, the acid used is hydrochloric acid (HCI), hydrobromic acid (HBr), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), particularly wherein the acid is hydrochloric acid.

[0062] In another particular embodiment, in combination with any of the embodiments of the invention, the process further comprises several steps to obtain tapinarof.

[0063] A second aspect of the invention relates to a process for the preparation of a compound of formula (IV), comprising the following steps: c) reacting a compound of formula (lll-BA- M)

[0064] (lll-BA M) wherein M is Na, K or Cs, with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV), or d) slurrying the compound of formula (lll-BA- M) in water and aqueous hydrochloric acid, filtering the solid and drying the compound of formula (III) and e) reacting a compound of formula (III) with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

[0065] The expression " phosphorous-based reagent " is intended to define but is not limited to such reagents as phosphonium halide, phosphonate or phosphine oxide for Wittig reaction or Wittig-Horner reaction (also known as Horner- Wadsworth-Emmons reaction).

[0066] In a particular embodiment of the present invention, the process for the preparation of a compound of formula (IV) according to the second aspect, the phosphorous-based reagent is selected from the group consisting of phosphonium halide, phosphonate or phosphine oxide, particularly phosphonate .

[0067] In another particular embodiment, in combination with any of the embodiments of the invention, the phosphorous- based reagent is selected from the group consisting of benzytriphenyphosphonium chloride, benzytriphenyphosphonium bromide, dimethyl benzylphosphonate, diethyl benzylphosphonate or benzyldiphenylphosphine oxide. In another particular embodiment, the phosphorous-based reagent is diethyl benzylphosphonate.

[0068] In another particular embodiment, in combination with any of the embodiments of the invention, the amount of diethylbenzylphosphonate is from 1 to 4 equivalents. In another particular embodiment, the amount of diethylbenzylphosphonate is from 1 to 3 equivalents. In a further embodiment, the amount of diethylbenzylphosphonate is from particularly from 1 to 2 equivalents.

[0069] In another particular embodiment, in combination with any of the embodiments of the invention, the base is selected from the group consisting of potassium tert-butoxide, sodium methoxide, sodium hydride, 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), butyllithium (BuLi), lithium bis(trimethylsilyl)amide (LHMDS) and isopropylmagnesium bromide (IPrMgBr). In another particular embodiment, the base is potassium tert-butoxide.

[0070] In another particular embodiment, in combination with any of the embodiments of the invention, the amount of potassium tert-butoxide is from 1 to 4 equivalents. In another particular embodiment, the amount of potassium tert- butoxide is from 1 .5 to 3 equivalents. In a further embodiment, the amount of potassium tert-butoxide is from 1 .5 to 2.5 equivalents.

[0071] In another particular embodiment, in combination with any of the embodiments of the invention, the suitable organic solvent is selected from the group consisting of 1 ,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2- MeTHF), acetonitrile (ACN), DMF or combinations thereof, particularly, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN). In another particular embodiment, the suitable organic solvent is tetrahydrofuran.

[0072] In another particular embodiment, in combination with any of the embodiments of the invention, the reaction is carried out at a temperature comprised from 10 to 100 °C. In another particular embodiment, the reaction is carried out at a temperature comprised from 30 to 70 °C. In a further embodiment, the reaction is carried out at a temperature comprised from 40 to 60 °C.

[0073] In another particular embodiment, in combination with any of the embodiments of the invention, the process for the preparation of a compound of formula (IV) according to the second aspect, comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III), solution (III)

[0074] I) adding water and treatment with an acid;

[0075] II) extracting the organic phase with water; ill) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and vi) optionally isolating and drying the compound of formula (lll-BA- Na) thus obtained

[0076] (lll-BA Na) and b) subsequently reacting a compound of formula (lll-BA- Na) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

[0077] In another particular embodiment, in combination with any of the embodiments of the invention, the process for the preparation of a compound of formula (IV) according to the second aspect, comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III), solution (III) i) adding water and treatment with an acid; ii) extracting the organic phase with water; ill) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and d) slurrying the wet material in water and aqueous hydrochloric acid and allowing the mixture to stir at room temperature, filtering the solid and drying the compound of formula (III) and e) subsequently reacting a compound of formula (III) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

[0078] In another particular embodiment, in combination with any of the embodiments of the invention, the process further comprises several steps to obtain tapinarof.

[0079] A third aspect of the invention relates to a compound of formula (lll-BA M), i OMe

[0080] .. ^JL J\ / SO3M

[0081] MeOJ

[0082] OH

[0083] (lll-BA M) wherein M is Na, K or Cs.

[0084] In a particular embodiment, in combination with any of the embodiments of the invention, the compound of formula (III- BA'M) according to the third aspect, wherein M is Na, namely compound of formula (lll-BA Na)

[0085] (lll-BA Na)

[0086] In another particular embodiment, in combination with any of the embodiments of the invention, the compound of formula (lll-BA- Na) according to the third aspect is characterized by a water content stoichiometry between 1 and 4. In another particular embodiment, characterized by a water content stoichiometry between 2 and 3. In a further embodiment, characterized by a water content stoichiometry of 3.

[0087] In another particular embodiment of the present invention, in combination with any of the embodiments of the invention, the compound of formula (lll-BA- Na) according to the third aspect is in a crystalline form characterized by a DSC with one endotherm peak 90 ±3 °C.

[0088] "DSC” refers to Differential Scanning Calorimetry.

[0089] In another particular embodiment, in combination with any of the embodiments of the invention, the compound of formula (lll-BA- Na) according to the third aspect is characterized by an FTIR comprising the following peaks: 3514, 3249, 2959, 1368, 1035, 970, 667 ±5 cm1.

[0090] "FTIR” refers to Fourier-Transform Infra-Red spectroscopy.

[0091] In another particular embodiment, in combination with any of the embodiments of the invention, the compound of formula (lll-BA- Na) according to the third aspect is characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 3.

[0092] In another particular embodiment, in combination with any of the embodiments of the invention, the compound of formula (lll-BA Na) according to the third aspect is characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 4.5, 12.2, 14.6, 15.5, 17.8 and 27.0 ± 0.2 degrees 2e. In another particular embodiment, the compound of formula (lll-BA-Na) is characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 4.5, 9.0, 12.2, 13.3, 14.6, 15.5, 17.8, 21.0, 22.6, 24.8, and 27.0 ± 0.2 degrees 2e.

[0093] "PXRD” refers to Powder X-Ray Diffraction.

[0094] 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.

[0095] Clauses

[0096] Further aspects and embodiments of the present invention are described in the following clauses below:

[0097] 1. A process for the preparation of a compound of formula (III), comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and an alkyl methyl sulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III) or a solvate thereof, and b) optionally isolating the obtained compound of formula (III).

[0098] 2. The process according to clause 1, wherein the alkyl group of the alkyl methyl sulfoxide comprises a carbon chain length from 1 to 16 carbon.

[0099] 3. The process according to clause 1 to 2, wherein the amount of alkyl methyl sulfoxide is from 1 to 5 equivalents.

[0100] 4. The process according to any of the clauses 1 to 3, wherein the amount of alkyl methyl sulfoxide is from 2 to 4 equivalents.

[0101] 5. The process according to any of the clauses 1 to 4, wherein the alkyl methyl sulfoxide is dimethyl sulfoxide. 6. The process according to any of the clauses 1 to 5, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylpyrrolidine and N-ethylpyperidine.

[0102] 7. The process according to any of the clauses 1 to 6, wherein the amount of base is from 1 to 8 equivalents.

[0103] 8. The process according to any of the clauses 1 to 7, wherein the amount of base is from 2 to 6 equivalents.

[0104] 9. The process according to any of the clauses 1 to 8, wherein the amount of base is from 3 to 5 equivalents.

[0105] 10. The process according to any of the clauses 1 to 9, wherein the base is triethylamine.

[0106] 11 . The process according to any of the clauses 1 to 10, wherein the first organic solvent is selected from the group consisting of toluene, chlorobenzene, xylene, anisole, tetrahydrofuran, acetonitrile, dichloromethane, and mixtures thereof.

[0107] 12. The process according to any of the clauses 1 to 11, wherein the first solvent is dichloromethane.

[0108] 13. The process according to any of the clauses 1 to 12, wherein the amount of oxalyl chloride is from 1 to 4 equivalents.

[0109] 14. The process according to any of the clauses 1 to 13, wherein the amount of oxalyl chloride is from 1 to 2 equivalents.

[0110] 15. The process according to any of the clauses 1 to 14, wherein the reaction is carried out at a temperature below - 50 °C, particularly at a temperature comprised from -60 to -80 °C.

[0111] 16. The process according to any of the clauses 1 to 15, wherein a compound of formula (III) is converted by reacting with a bisulfite compound to compound of formula (lll-BA- M)

[0112] (lll-BA M) wherein M is Na, K or Cs.

[0113] 17. The process according to any of the clauses 1 to 16, wherein step a) further comprises: i) adding water and treatment with an acid; ii) washing the organic phase with water; ill) treating the organic phase with aqueous solution containing a bisulfite compound; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the reaction mixture; v) heating the mixture obtained in step iv) to a temperature of between 30 °C and the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature; and vi) optionally isolating and drying a compound of formula (I ll-BA- M) thus obtained

[0114] (lll-BA M) wherein M is Na, K or Cs.

[0115] 18. The process according to the preceding clause, wherein the acid used in step i) is hydrochloric acid (HCI), hydrobromic acid (HBr), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), particularly hydrochloric acid.

[0116] 19. The process according to any of the clauses 17 to 18, wherein the bisulfite compound is selected from the group consisting of sodium metabisulfite, sodium bisulfite, potassium metabisulfite, potassium bisulfite, caesium metabisulfite and caesium bisulfite.

[0117] 20. The process according to any of the clauses 17 to 19, wherein the bisulfite compound is sodium metabisulfite.

[0118] 21 . The process according to any of the clauses 17 to 20, wherein step iv) is performed before step ill).

[0119] 22. The process according to any of the clauses 17 to 21, wherein steps I) to ill) are independently carried out at a temperature comprised from 20 to 25 °C.

[0120] 23. The process according to any of the clauses 17 to 22, wherein the second organic solvent of step iv) is selected from the group consisting of 1 ,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), 2-propanol or combinations thereof, particularly tetrahydrofuran (THF).

[0121] 24. The process according to any of the clauses 17 to 23, wherein step vi) comprises evaporating part of the solvent and further crystallization or precipitation. The process according to any of the clauses 17 to 23, wherein the process after step v) further comprises slurrying the wet material in aqueous acid and stirring the mixture at room temperature, filtering the solid and drying the compound of formula (III)

[0122] (HI). The process according to the preceding clause, wherein the acid used is hydrochloric acid (HCI), hydrobromic acid (HBr), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), particularly wherein the acid is hydrochloric acid. The process according to any of the clauses 1 to 26, wherein the process further comprises several steps to obtain tapinarof. A process for the preparation of a compound of formula (IV), comprising the following steps: c) reacting a compound of formula (lll-BA- M) wherein M is Na, K or Cs, with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV), or d) slurrying the compound of formula (lll-BA- M) in water and aqueous hydrochloric acid, filtering the solid and drying the compound of formula (III) and e) reacting a compound of formula (III) with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

[0123] 29. The process according to the preceding clause, wherein the phosphorous-based reagent is selected from the group consisting of phosphonium halide, phosphonate, or phosphine oxide, particularly phosphonate.

[0124] 30. The process according to any of the clauses 28 to 29, wherein the phosphorous-based reagent is selected from the group consisting of benzytriphenyphosphonium chloride, benzytriphenyphosphonium bromide, dimethyl benzylphosphonate, diethyl benzylphosphonate or benzyldiphenylphosphine oxide.

[0125] 31. The process according to any of the clauses 28 to 30, wherein the phosphorous-based reagent is diethyl benzylphosphonate.

[0126] 32. The process according to any of the clauses 28 to 31 , wherein the amount of diethylbenzylphosphonate is from 1 to 4 equivalents.

[0127] 33. The process according to any of the clauses 28 to 32, wherein the amount of diethylbenzylphosphonate is from 1 to 3 equivalents.

[0128] 34. The process according to any of the clauses 28 to 33, wherein the amount of diethylbenzylphosphonate is from 1 to 2 equivalents.

[0129] 35. The process according to any of the clauses 28 to 34, wherein the base is selected from the group consisting of potassium tert-butoxide, sodium methoxide, sodium hydride, 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), butyllithium (BuLi), lithium bis(trimethylsilyl)amide (LHMDS) and isopropylmagnesium bromide (IPrMgBr).

[0130] 36. The process according to any of the clauses 28 to 35, wherein the base is potassium tert-butoxide.

[0131] 37. The process according to any of the clauses 35 to 36, wherein the amount of potassium tert-butoxide is from 1 to 4 equivalents. 38. The process according to any of the clauses 35 to 37, wherein the amount of potassium tert-butoxide is from 1 .5 to 3 equivalents.

[0132] 39. The process according to any of the clauses 35 to 38, wherein the amount of potassium tert-butoxide is from 1 .5 to 2.5 equivalents.

[0133] 40. The process according to any of the clauses 28 to 39, wherein the suitable organic solvent is selected from the group consisting of 1 ,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), DMF or combinations thereof, particularly, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN).

[0134] 41 . The process according to any of the clauses 28 to 40, wherein the suitable organic solvent is tetrahydrofuran.

[0135] 42. The process according to any of the clauses 28 to 41 , wherein the reaction is carried out at a temperature comprised from 10 to 100 °C.

[0136] 43. The process according to any of the clauses 28 to 42, wherein the reaction is carried out at a temperature comprised from 30 to 70 °C.

[0137] 44. The process according to any of the clauses 28 to 43, wherein the reaction is carried out at a temperature comprised from 40 to 60 °C.

[0138] 45. The process according to any of the preceding clauses, for the preparation of a compound of formula (IV), comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III), solution (III) i) adding water and treatment with an acid; ii) extracting the organic phase with water; iii) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and vi) optionally isolating and drying the compound of formula (lll-BA- Na) thus obtained

[0139] (lll-BA Na) and c) subsequently reacting a compound of formula (lll-BA' Na) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV). The process according to any of the preceding clauses, for the preparation of a compound of formula (IV), comprising the following steps: a) reacting a compound of formula (II) with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III), solution (III) i) adding water and treatment with an acid; ii) extracting the organic phase with water; ill) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and d) slurrying the wet material in water and aqueous hydrochloric acid and allowing the mixture to stir at room temperature, filtering the solid and drying the compound of formula (III) and e) subsequently reacting a compound of formula (III) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV). The process according to any of the clauses 1 to 46, wherein the process further comprises several steps to obtain tapinarof. A compound of formula (lll-BA M), i OMe

[0140] .. ^JL J\ / SO3M

[0141] MeOJ

[0142] OH

[0143] (lll-BA M) wherein M is Na, K or Cs. The compound of formula (lll-BA M) according to the preceding clause wherein M is Na, namely compound of formula (lll-BA-Na)

[0144] (lll-BA Na)

[0145] 50. The compound of formula (lll-BA- Na) according to of any of the clauses 48 to 49 characterized by a water content stoichiometry between 1 and 4.

[0146] 51. The compound of formula (lll-BA Na) according to any of the clauses 48 to 50 characterized by a water content stoichiometry between 2 and 3.

[0147] 52. The compound of formula (lll-BA Na) according to any of the clauses 48 to 51 characterized by a water content stoichiometry of 3.

[0148] 53. The compound of formula (lll-BA' Na) according to any of the clauses 48 to 52 is in a crystalline form characterized by a DSC with one endotherm peak 90 ±3 °C.

[0149] 54. The compound of formula (lll-BA' Na) according to any of the clauses 48 to 53, characterized by an FTIR comprising the following peaks: 3514, 3249, 2959, 1368, 1035, 970, 667 ±5 cm1.

[0150] 55. The compound of formula (lll-BA' Na) according to any of the clauses 48 to 54 characterized by a powder X-Ray diffraction pattern substantially as depicted in Figure 3.

[0151] 56. The compound of formula (lll-BA' Na) according to any of the clauses 48 to 55 characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 4.5, 12.2, 14.6, 15.5, 17.8 and 27.0 ± 0.2 degrees 2e.

[0152] 57. The compound of formula (lll-BA' Na) according to any of the clauses 48 to 56 characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 4.5, 9.0, 12.2, 13.3, 14.6, 15.5, 17.8, 21.0, 22.6, 24.8, and 27.0 ± 0.2 degrees 2e.

[0153] 58. Use of the compound of formula (lll-BA) as defined in any one of clauses 48 to 57 as an intermediate for the preparation of the compound of formula (I), tapinarof.

[0154] Examples HPLC method for compound of formula (III)

[0155] Chromatographic column: Zorbax Eclipse Plus Phenyl-Hexyl 150x3mmx3.5pim; Column temperature: 30° C; Mobile phase: A: phosphoric acid 0.10%, B: Acetonitrile

[0156] Gradient elution conditions: The chromatograph is programmed as follows:

[0157] Main peak retention time: around 11.9 min; Sample volume 3pL; Detection wavelength: 215 nm; running time: 20 min; Test solution: 0.20 mg / mL, Solvent: Acetonitrile: water Milli Q (7:3); Column flow: 0.5ml / min. HPLC method for compound of formula (IV)

[0158] Chromatographic column: Zorbax Eclipse Plus Phenyl-Hexyl 150x3mmx3.5pim; Column temperature: 30° C; Mobile phase: A: phosphoric acid 0.10%, B: Acetonitrile

[0159] Gradient elution conditions:

[0160] The chromatograph is programmed as follows:

[0161] Main peak retention time: around 21.4 min; Sample volume 3pL; Detection wavelength: 215 nm; running time: 32 min; Test solution: 0.4 mg / mL, Solvent: Acetonitrile; Column flow: 0.5ml / min.

[0162] P owder X-Ray Diffraction (PXRD) Analysis conditions:

[0163] Powder diffraction patterns were acquired with a Panalytical X'Pert Powder 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 3 to 40° 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.

[0164] Example 1. Synthesis of sodium hydroxy(4-isopropyl-3,5-dimethoxyphenyl)methanesulfonate trihydrate (compound of formula (lll-BA-Na))

[0165] A jacketed laboratory reactor of 2 L was purged with nitrogen and then charged with dichloromethane (450 mL), oxalyl chloride (86 g, 1.59 equiv.). The mixture was cooled to between -60 and -80 °C. Dimethylsulfoxide (114 g, 3.42 equiv.) in dichloromethane (99 mL) was carefully added at the same temperature and was allowed to stir for 10 minutes. 4- isopropyl-3,5-dimethoxyphenyl)methanol (compound of formula (II) (90 g, 1.00 equiv.) in dichloromethane (414 mL) was then added dropwise in 1 hour. The resulting crude mass was allowed to stir for 30 minutes and then triethylamine (188 g, 4.34 equiv.) was added dropwise in 2 hours. The resulting reaction mass was allowed to stir for 2 hours. Water (360 mL) was then charged allowing temperature to reach 25 °C and the mixture was stirred another 15 minutes. The pH of the resulting biphasic system was adjusted at 6.5 with hydrochloric acid and was then allowed to equilibrate for

[0166] 15 minutes. The resulting biphasic mass was allowed to settle, and organic phase was washed with water (360 mL) thrice. The resulting organic phase was treated with charcoal and sodium metabisulfite (65.1 g, 0.8 equiv.) in water (306 mL) was then added. The resulting biphasic system was stirred for 15 minutes and then dichloromethane was removed by distillation. Tetrahydrofuran (540 mL) was charged, and the resulting crude was stirred for 4 hours at 50 °C. Then, the resultant slurry was allowed to cool at room temperature and the solids were filtered and washed with water (270 mL) twice and finally with tetrahydrofuran (180 mL). The isolated solid was then dried under vacuum at 40 °C for

[0167] 16 hours to provide sodium hydroxy(4-isopropyl-3,5-dimethoxyphenyl)methanesulfonate trihydrate (compound of formula (I I l-BA- Na)) as a white powder solid (120.4 g, 77%).

[0168] 1 H-NMR (400 MHz, DMSO-d6) 5 6.73 (s, 2H), 5.86 (d, J= 5.40 Hz, 1 H), 4.92 (d, J= 5.42 Hz, 1 H), 3.71 (s, 6H), 3.50 (hept, J= 7.07 Hz, 1 H), 1.20 (d, J= 7.08 Hz, 6H).

[0169] 13C-NMR (100 MHz, DMSO-d6) 5 156.9, 138.4, 121.4, 104.6, 85.1 , 55.6, 23.3, 20.8 FTIR (ATR, Figure 1): 3514, 3249, 2959, 1368, 1035, 970, 667 cm-1 as shown in Figure 1

[0170] DSC (onset, °C): 90 (broad signal) as shown in Figure 2

[0171] KF: 15.4%

[0172] PXRD crystalline compound of formula (lll-BA- Na) as shown in Figure 3 with the following peaks:

[0173] Angle (26) Intensity (Counts) d Value (A) Angle (26) Intensity (Counts) d Value (A)

[0174] 4.5 4316 19.72 25.5 126 3.50

[0175] 6.0 14 14.85 25.8 402 3.46

[0176] 7.6 22 11.67 26.4 148 3.37

[0177] 8.9 267 9.91 27.0 1329 3.31

[0178] 9.5 47 9.35 27.6 113 3.22

[0179] 10.5 34 8.42 28.8 79 3.10

[0180] 12.1 1329 7.28 30.0 170 2.98

[0181] 13.3 642 6.63 30.5 76 2.93

[0182] 14.6 784 6.06 30.9 107 2.89

[0183] 15.5 2413 5.72 31.8 35 2.81

[0184] 16.4 126 5.40 33.0 28 2.71

[0185] 17.5 201 5.07 33.7 235 2.65

[0186] 17.8 745 4.98 34.4 112 2.60

[0187] 18.5 161 4.78 35.4 75 2.53

[0188] 20.9 335 4.24 35.8 173 2.50

[0189] 22.6 377 3.93 36.8 55 2.44

[0190] 23.2 235 3.83 37.5 47 2.4.0

[0191] 23.7 190 3.75 38.2 88 2.35

[0192] 24.0 99 3.70 38.7 182 2.32

[0193] 24.8 698 3.60 39.2 136 2.3.

[0194] 25.0 253 3.56 Example 2. Synthesis of 4-isopropyl-3,5-dimethoxybenzaldehyde (compound of formula (III))

[0195] A jacketed laboratory reactor of 2 L was purged with nitrogen and then charged with dichloromethane (450 mL), oxalyl chloride (86 g, 1.59 equiv.). The mixture was cooled to between -60 and -80 °C. Dimethylsulfoxide (114 g, 3.42 equiv.) in dichloromethane (99 mL) was carefully added at the same temperature and was allowed to stir for 10 minutes. 4- isopropyl-3,5-dimethoxyphenyl)methanol (compound of formula (II)) (90 g, 1.00 equiv.) in dichloromethane (414 mL) was then added dropwise in 1 hour. The resulting crude mass was allowed to stir for 30 minutes and then triethylamine (188 g, 4.34 equiv.) was added dropwise in 2 hours. The resulting reaction mass was allowed to stir for 2 hours. Water (360 mL) was then charged allowing temperature to reach 25 °C and the mixture was stirred another 15 minutes. The pH of the resulting biphasic system was adjusted at 6.5 with hydrochloric acid and was then allowed to equilibrate for 15 minutes. The resulting biphasic mass was allowed to settle, and organic phase was washed with water (360 mL) thrice. The resulting organic phase was treated with charcoal and sodium metabisulfite (65.1 g, 0.8 equiv.) in water (306 mL) was then added. The resulting biphasic system was stirred for 15 minutes and then dichloromethane was removed by distillation. Tetrahydrofuran (540 mL) was charged, and the resulting crude was stirred for 4 hours at 50 °C. Then, the resultant slurry was allowed to cool at room temperature and the solids were filtered and washed with water (270 mL) twice. The resulting wet material was charged in a jacketed laboratory reactor of 2 L together with water (1.26 L) and aqueous hydrochloric acid (270 mL, 18%). The suspension was allowed to stir at room temperature for 6 hours. Then the suspension was filtered and the solid obtained was washed with water (270 mL). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide 4-isopropyl-3,5-dimethoxybenzaldehyde (compound of formula (III)) as a white powder solid (78.4 g, 88%).

[0196] 1 H-NMR (400 MHz, MeOD) 5 9.85 (s, 1 H), 7.11 (s, 2H), 3.79 (s, 6H), 3.54 (hept, J= 7.07 Hz, 1 H), 1.17 (d, J= 7.08 Hz, 6H).

[0197] 13C-NMR (100 MHz, MeOD) 5 192.4, 158.9, 135.5, 131.2, 105.1 , 54.9, 24.3, 19.2.

[0198] DSC (onset, °C): 57.5

[0199] HPLC purity (%area): 99.6

[0200] Example 3. Synthesis of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene (compound of formula (IV))

[0201] Route a:

[0202] A jacketed laboratory reactor of 0.5 L was purged with nitrogen and then charged with sodium hydroxy (4-isopropy I- 3,5-dimethoxyphenyl)methanesulfonate trihydrate (compound of formula (III AET Na) (29.1 g, 1.00 equiv.), tetrahydrofuran (252 mL) and diethyl benzylphosphonate (27.2 g, 1.5 equiv.). The resulting suspension was cooled at 10 °C and potassium tert-butoxide (17.8 g 2.0 equiv.) was added cropwise. The crude mass was allowed to stir for 10 minutes at 10 °C. The crude mass was heated at 50 °C and was allowed to stir for 2 hours. Then, the resulting crude mass was cooled at room temperature and water (88 mL) was slowly added. The biphasic system obtained was allowed to settle, the aqueous phase was disposed of, and then additional water (16 mL) was added. The tetrahydrofuran was distilled, and isopropanol (37 mL) was charged. The resulting suspension was heated at 60°C until observing total dissolution. Then, the resulting solution was cooled to 44 °C and was seeded with TPN-4. Solids rapidly appeared and the resulting suspension was cooled to 5 °C. Then, the solids were filtered and washed with a cold mixture of isopropanol / water 7:3 (35 mL). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2- isopropy I- 1 ,3-dimethoxy-5-styrylbenzene (compound of formula (IV)) as a white powder solid (21 .49 g, 96%).

[0203] Route b:

[0204] A jacketed laboratory reactor of 0.5 L was purged with nitrogen and then charged with potassium tert-butoxide (18.9 g 2.0 equiv.) and tetrahydrofuran (149 mL). The resulting solution was cooled at 10 °C and diethyl benzylphosphonate (28.8 g, 1.5 equiv.) was added dropwise. The crude mass was allowed to stir for 10 minutes before 4-isopropyl-3,5- dimethoxybenzaldehyde (compound of formula (III)) (17.5 g, 1.0 equiv.) in tetrahydrofuran (61 mL) was added dropwise keeping temperature at 10 °C. The crude mass was heated at 50 °C and was allowed to stir for 2 hours. Then, the resulting crude mass was cooled at room temperature and water (88 mL) was slowly added. The biphasic system obtained was allowed to settle, the aqueous phase was disposed of, and then additional water (16 mL) was added. The tetrahydrofuran was distilled, and isopropanol (37 mL) was charged. The resulting suspension was heated at 60 °C until observing total dissolution. Then, the resulting solution was cooled to 44 °C and was seeded with TPN-4. Solids rapidly appeared and the resulting suspension was cooled to 5 °C. Then, the solids were filtered and washed with a cold mixture of isopropanol / water 7:3 (35 mL). The isolated solid was then dried under vacuum at 40 °C for 16 hours to provide (E)-2-isopropyl-1 ,3-dimethoxy-5-styrylbenzene (compound of formula (IV)) as a white powder solid (22.3 g, 94%).

[0205] 1 H-NMR (400 MHz, MeOD) 5 7.55 (m, 2H), 7.34 (m, 2H), 7.24 (m, 1 H), 7.13 (d, J= 1.1 HZ, 2H), 6.79 (s, 2H), 3.85 (s, 6H), 3.61 (hept, J= 7.0 Hz, 1 H), 1.27 (d, J= 7.1 Hz, 6H).

[0206] 13C-NMR (100 MHz, MeOD) 5 158.6, 137.5, 136.2, 128.7, 128.3, 127.6, 127.1 , 126.1 , 123.7, 102.6, 54.8, 23.9, 19.8.

[0207] DSC (onset, °C): 67.0

[0208] HPLC purity (%area): 99.4 (route a), 99.9 (route b)

[0209] Comparative Example 1 : Synthesis of 4-isopropyl-3,5-dimethoxybenzaldehyde (compound of formula (III))

[0210] Following the procedure reported by Albright and Goldman in JACS 1965, 87, 4214, a round-bottom flask of 10 mL was purged with nitrogen and then charged with 4-isopropyl-3,5-dimethoxybenzyl alcohol (1 g, 4.76 mmol), DMSO (3.77 mL) and acetic anhydride (2.35 mL). The mixture was stirred at room temperature for 3 hours. Water (5 mL) and ethyl acetate (3 mL) were then charged, and the resulting crude mass was stirred for 20 minutes. The resulting organic phase was separated, and the aqueous phase was washed with ethyl acetate (3 mL). The aqueous phases were merged and were washed with ethyl acetate (3 mL). The organic phases were merged and were evaporated to dryness. The resulting solid was dried under vacuum for 16 hours and analyzed by HPLC. The solid obtained is made of 65.8% of 4-isopropyl-3,5-dimethoxybenzyl alcohol (starting material), 17.9% of 4-isopropyl-3,5- dimethoxybenzaldehyde (product) and 11 .0% of impurity 2-isopropy I- 1 ,3-dimethoxy-5-methylbenzene.

Claims

Claims1. A process for the preparation of a compound of formula (III),comprising the following steps: a) reacting a compound of formula (II)with oxalyl chloride and an alkyl methyl sulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III) or a solvate thereof, and b) optionally isolating the obtained compound of formula (III).

2. The process according to claim 1, wherein the alkyl methyl sulfoxide is dimethyl sulfoxide.

3. The process according to any of the claims 1 to 2, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylpyrrolidine and N-ethylpyperidine.

4. The process according to any of the clauses 1 to 3, wherein a compound of formula (III) is converted by reacting with a bisulfite compound to compound of formula (lll-BA- M)wherein M is Na, K or Cs.

5. A process for the preparation of a compound of formula (IV),(IV) comprising the following steps: c) reacting a compound of formula (lll-BA- M)wherein M is Na, K or Cs, with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV), or d) slurrying the compound of formula (lll-BA- M) in water and aqueous hydrochloric acid, filtering the solid and drying the compound of formula (III)and e) reacting a compound of formula (III) with a phosphorous-based reagent in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

6. The process according to claim 5, wherein the phosphorous-based reagent is diethyl benzylphosphonate.

7. The process according to any of the claims 5 to 6, wherein the base is selected from the group consisting of potassium tert-butoxide, sodium methoxide, sodium hydride, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), butyllithium (BuLi), lithium bis(trimethylsilyl)amide (LHMDS) and isopropylmagnesium bromide (IPrMgBr).

8. The process according to any of the claims 1 to 7, for the preparation of a compound of formula (IV),comprising the following steps:a) reacting a compound of formula (II)with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III),solution (III) i) adding water and treatment with an acid; ii) extracting the organic phase with water; iii) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and vi) optionally isolating and drying the compound of formula (lll-BA- Na) thus obtained(lll-BA Na) and c) subsequently reacting a compound of formula (lll-BA' Na) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

9. The process according to any of the claims 1 to 8, for the preparation of a compound of formula (IV),comprising the following steps:a) reacting a compound of formula (II)with oxalyl chloride and dimethylsulfoxide in the presence of a base and a first organic solvent to give a compound of formula (III),solution (III)I) adding water and treatment with an acid;II) extracting the organic phase with water; ill) treating the organic phase with aqueous sodium metabisulfite; iv) removing the first organic solvent by distillation, adding a second organic solvent and stirring the crude; v) heating the mixture obtained in step iv) to a temperature of between 30 °C to the boiling point of the second organic solvent, and allowing the mixture to cool to room temperature and d) slurrying the wet material in water and aqueous hydrochloric acid and allowing the mixture to stir at room temperature, filtering the solid and drying the compound of formula (III)and e) subsequently reacting a compound of formula (III) with diethyl benzylphosphonate in the presence of a base and a suitable organic solvent to give a compound of formula (IV).

10. The process according to any of the claims 1 to 9, wherein the process further comprises several steps to obtain tapinarof.

11. A compound of formula (lll-BA M),(lll-BA M) wherein M is Na, K or Cs or any hydrate.

12. The compound of formula (lll-BA M) of claim 11 wherein M is Na, namely compound of formula (lll-BA-Na)(lll-BA-Na)13. The compound of formula (lll-BA-Na) according to claim 12 characterized by a water content stoichiometry between 1 and 4.

14. The compound of formula (lll-BA-Na) according to claims 12 to 13 characterized by a powder X-Ray diffraction (PXRD) pattern comprising the following peaks: 4.5, 12.2, 14.6, 15.5, 17.8 and 27.0 ± 0.2 degrees 2e.

15. Use of the compound of formula (lll-BA M) as defined in any one of claims 11 to 14 as an intermediate for the preparation of the compound of formula (I), tapinarof.

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