Methods of preparing tapinarof and related compounds

Abstract

The present disclosure provides a process for the preparation of 3,5-Dihydroxy-4-isopropyl-trans-stilbene [Tapinarof] and related compounds.

Description

Methods of Preparing Tapinarof and Related CompoundsFIELD OF THE INVENTION

[0001] The present disclosure relates to processes for the synthesis of Tapinarof and related compounds.BACKGROUND

[0002] Aryl hydrocarbon receptor (AHR) agonists are a novel class of drugs for topical treatment of plaque psoriasis in adults. AHR agonists are believed to function by binding to and activating aryl hydrocarbon receptors on the skin cells and immune cells that cause inflammation in plaque psoriasis, thereby inhibiting the release of proinflammatory proteins (cytokines) by immune cells and downregulating inflammation. 3, 5-Dihydroxy-4-isopropyl- trans-stilbene, also known as (E)-2-isopropyl-5-styrylbenzene-l,3-diol or tapinarof is a naturally occurring compound found in bacterial symbionts of nematodes with antibacterial, antioxidant and anti-cancer properties. Tapinarof is the first drug to be approved in the class of AHR for topical application on the affected areas of the skin.

[0003] Current approaches for the synthesis of tapinarof and its intermediates include several challenging steps performed in the presence of various chemical compounds that may interfere with the purity of the final product. Multiple steps and reagents add complexities to the synthesis process, which may decrease yield, decrease quantity, decrease quality and cause issues related to reproducibility and robustness. For example, US 2021 / 0163388 Al, utilizes various malonate derivatives in a complex synthesis scheme to produce (E)-2-chloro-2- isopropyl-5-styrylcy cl ohexane- 1,3-dione, which is aromatized to form tapinarof. US 10,647,649 utilizes a cinnamaldehyde precursor combined with a methyl isobutyl ketone in multi-step process to arrive at tapinarof. The increased complexity of planning, organization and production can also increase the burden for manufacture compliance and experimental costs, and increase time and other resources, thereby resulting in lower efficiency’.SUMMARY OF THE INVENTION

[0004] Tapinarof is a topical aryl hydrocarbon receptor (AHR) agonist indicated for adults with plaque psoriasis. In some embodiments, the disclosure provides a process for the preparation of a compound of formula (II), or a salt or solvate thereofcomprising reacting a compound of formula (I)wi th styrene in the presence of a base, a solvent and a palladium catalyst to form a compound of Formula (II)and cleaving Ri and / or R2 of the compound of Formula II to form the tapinarof, wherein R1and R2are independently an alkyl or hydrogen, and wherein X is a halogen.

[0005] In some embodiments, at least one of Ri and R2 is alkyl, wherein the method further comprises cleaving Ri and / or R2 of the compound of Formula (II) to form a compound for Formula (III) [Tapinarof]Formula (III).

[0006] In some embodiments. Ri is alkyl and R2 is alkyl. In some embodiments. Ri is alkyl and R2 is hydrogen, or Ri is hydrogen and R2is alkyl. In some embodiments, both Ri and R2 are hydrogen.

[0007] In some embodiments, the disclosure provides a process for the preparation of a compound of formula (III) [Tapinarof] and related compounds, or a salt or solvate thereofcomprising reacting a compound of formula (I)with styrene in the presence of a base, a solvent and a palladium catalyst to form a compound of Formula (II)and cleaving Ri and / or R2 of the compound of Formula II to form the tapinarof, wherein R1and R2are alkyl, and wherein X is a halogen.

[0008] In some embodiments, the alkyl is a methyl, ethyl, propyl, isopropyl, or butyl.

[0009] In some embodiments, Ri is methyl. In some embodiments, both Ri and R2 are methyl.

[0010] In some embodiments, X is chlorine.

[0011] In some embodiments, the reacting is performed in an organic solvent.

[0012] In some embodiments, the organic solvent is an aromatic, non-aromatic. or mixture thereof. In some embodiments, the organic solvent is a mixture of heptane and toluene.

[0013] In some embodiments, the palladium catalyst is selected from palladium acetate, chloro(crotyl)(2-dicyclohyxylphosphino-2', 6'-dimethoxy- 1 , l'-biphenyl)palladium II, trans dichloro bis(triphenylphosphine)palladium, X-Phos aminobiphenyl palladium chloride precatalyst, and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium II ([ P(tBu)s] Palladacycle). In some embodiments, the palladium catalyst is ([P(tBu)s] Palladacycle).

[0014] In some embodiments, the reacting in is performed at a temperature greater than 70°C. In some embodiments, wherein the reacting in is performed at a temperature of about 70°C to about 110° C.

[0015] In some embodiments, the cleaving is performed in anhydrous conditions.

[0016] In some embodiments, the cleaving in (ii) is performed in an organic solvent or in a mixture of at least two organic solvents.

[0017] In some embodiments, the organic solvent is a mixture of aromatic and non- aromatic solvents.

[0018] In some embodiments, the disclosure provides a compound of Formula (III) or a salt thereofFormula (III), wherein the compound of Formula (III) is characterized by a purity of at least 98%.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows an exemplary process for the preparation of Tapinarof [Formula (III)] as described in embodiments herein.DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure relates to methods for the preparation of Tapinarof, and possible intermediates of Tapinarof, e.g., the compounds of Formula (II). The methods provided herein advantageously yield products of Tapinarof with high purity and simplify the complex preparation process by reducing or eliminating reaction steps that require inert conditions, extensive purification and / or costly reagents. The present disclosure provides a convenient, efficient and effective approach for the synthesis of Tapinarof utilizing sequential and straight-forward cross-coupling and cleavage reactions. In some embodiments, the preparation methods disclosed herein reduce both reaction time and reagent usage, by removing the need for isolation and / or purification steps and in the final product.

[0021] As used herein, “a” or "an ’ may mean one or more. As used herein, when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one. As used herein, “another” or “a further” may mean at least a second or more.

[0022] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the method / device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term “about” is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%. 14%. 15%, 16%, 17%, 18%, 19% or 20% or higher variability, depending on the situation. In some embodiments, one of skill in the art will understand the level of variability indicated by the term “about,” due to the context in which it is used herein. It should also be understood that use of the term “about” also includes the specifically recited value.

[0023] The use of the term “or” in the claims is used to mean “and / or,” unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0024] As used herein, the terms “comprising” (and any variant or form of comprising, such as “comprise” and “comprises”), “having” (and any variant or form of having, such as“have” and “has”), “including” (and any variant or form of including, such as “includes” and “include”) or “containing” (and any variant or form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any composition (e.g., formulation) or method of the present disclosure. Furthermore, compositions (e.g., formulations) of the present disclosure can be used to achieve methods of the present disclosure.

[0025] The use of the term ‘Tor example” and its corresponding abbreviation “e.g.” (whether italicized or not) means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

[0026] As used herein, “between” is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y.

[0027] The present disclosure provides a process for the preparation of a compound of Formula (II) or a salt thereof, the method comprising reacting a compound of formula (I)with styrene in the presence of a base and a palladium catalyst to form a compound of Formulawherein R1and R2are independently an alkyl or hydrogen, and wherein X is a halogen. The compound of Formula (II) when Ri and R2 are hydrogen forms the compound for Formula (III) [Tapinarof]. The compound of Formula (II) when Ri and R2 are alkyl can be useful, e.g., as an intermediate in synthesis of Tapinarof . In some embodiments, when at least one of Ri and R2 is alkyl, wherein the method further comprises cleaving Ri and / or R2 of the compound of Formula (II) to form a compound for Formula (III)Formul (III).

[0028] Ri and R2 can be independently alkyl or hydrogen. In some embodiments, Ri is alkyl and R2 is alkyl. In some embodiments, Ri is alkyl and R2 is hydrogen, or Ri is hydrogen and R2is alkyl. In some embodiments, both Ri and R2 are hydrogen.

[0029] The present disclosure also provides a process for the preparation of a compound of Formula (III) [Tapinarof]. or a salt thereofcomprising reacting a compound of formula (I)with styrene in the presence of a base and a palladium catalyst to form a compound of Formulaand cleaving Ri and / or R2 of the compound of Formula II to form the Tapinarof, wherein R1and R2are alkyl, and wherein X is a halogen.

[0030] The present disclosure provides a compound of Formula (III) or a salt thereofFormula (III), wherein the compound of Formula (III) is characterized by a purity of at least 98%, prepared by a process comprising the steps of reacting a compound of Formula (I)Formula (I) with styrene in the presence of a base, a solvent and a palladium catalyst to fonn a compound of Formula IIFormula (II) and cleaving R1 and / or R2 of the compound of Formula (II) to form the Tapinarof, wherein R1 and R2 are alky l, and wherein X is a halogen.

[0031] The methods described herein yield tapinarof compounds that are characterized by a purity7of at least 98%. In some embodiments, a compound of Formula (III) or a salt or thereof as prepared by any process described herein, has a purity' of at least 98%. In some embodiments, a compound of Formula (III) or a salt thereof as prepared by any process described herein, has a purity of at least 99%. For example, the compound of Formula (III) or salt thereof as prepared by any process described herein, has a purity' of 98%, 98.1 %, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%.

[0032] The disclosed process for the preparation of Tapinarof is characterized by the formation of a carbon-carbon bond following the chemical reaction of halogen the compound of Formula (I) with an activated styrene in the presence of a base, solvent and catalytic amounts of a palladium compound. While not being bound by a specific mechanism, in some embodiments the reduction of Pd(II) intermediates to Pd(O) in the chemical reaction enables the coupling Formula (I) with the styrene. In some embodiments, the efficiency of the disclosed process is due to the functional characteristics of the recited palladium catalysts, which has an ability to assemble C-C bonds between appropriately functionalized substrates.

[0033] References herein to compounds of specified Formulae, e.g.. Formula (I), Formula (II) or Formula (III) can include salts thereof, solvates thereof, as well as free bases, for example as pharmaceutically acceptable salts or solvates thereof. The compound of Formula (III) is Tapinarof. In some embodiments, the compound of Formula (III) is a salt of Tapinarof. For a review of suitable pharmaceutically acceptable salts see Berge et al., J. Pharm. Sci., 66: 1-19 (1977). In some embodiments, the compound of Formula (III) is a solvate ofTapinarof. In some embodiments the compound of Formula (III) is in a crystal form or an amorphous form. In some embodiments the compound of Formula (III) is anhydrous.

[0034] In some embodiments, Ri and R2 is an alkyl group having 1 to 10 carbons. In some embodiments, the term “alkyd,” when used alone or in combination with other groups or atoms, refers to a saturated linear or branched chain including 1 to about 10 hydrogensubstituted carbon atoms. Alkyd groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, 1 -methylpropyl, isobutyl, t-butyl, 2,2-dimethylbut 1, n-pentyl, 2 -methylpentyl, 3- methylpentyl, 4-methylpentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0035] In some embodiments, Ri and R2are the same alkyl group. In some embodiments, Ri and R2are different and independently selected from an alky l group. In some embodiments, the alk d group is a methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, Ri is methyl. In some embodiments. R2 is methyl. In some embodiments, both Ri and R2 are methyl.

[0036] The substituent X of Formula (I) is a halogen. In some embodiments, the halogen is fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In some embodiments, X is fluorine (F), chlorine (Cl), or bromine (Br). In some embodiments, X is fluorine (F), or chlorine (Cl). In some embodiments, X is chlorine (Cl).

[0037] The present disclosure provides a synthesis reaction in which the compound of Formula (I) and an activated styrene are joined together to afford the single product of the compound of Formula (II). In some embodiments, the compounds of formula (I) and the styrene are present in a molar ratio of about 1: 10 to about 10: 1, about 1:5 to about 5: 1, about 1:2 to about 2: 1, about 1: 1.5 to about 1.5:1, or about 1 :1. In some embodiments, the compounds of formula (I) and the st rene are independently present in an amount of about 0.01 to about 1 mol / L (solvent), about 0.05 to about 0.5 mol / L (solvent), or about 0.1 to about 0.4 mol / L (solvent).

[0038] The reaction of Formula I with styrene is performed in the presence of a catalyst. In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst comprises a ligand, e.g., a phosphine ligand, a carbon ligand, or a nitrogen ligand. In some embodiments, the ligand is PPI13, PCys, P(o-tolyl)s, P(i-Pr)3, P(O-Pr-i)3, n-BuP(l-Ad)2, P(t-Bu)2(p-NMe2-Ph), a dialkylbiaryl ligand (e.g., as described in Martin et al., Acc Chem Res 41 : 1461 (2008)). a bidentate phosphine ligand such as DPPF, DPPE or DPPP, a carbene-type ligand (e.g., as described in Kuwano et al., OrgLett 7:945 (2005)), an olefin-type ligand (e.g.,as described in Tao el al., J Org Chem 69:4330 (2004)), an amine, or imine (e.g.. as described in Tao el al., J Org Chem 69:4330 (2004)). In some embodiments, the ligand and catalyst are a preformed complex. For example, Pd(PPhtyi includes both a palladium catalyst and phosphine ligand.

[0039] In some embodiments, the palladium catalyst is selected from the group comprising palladium acetate, chloro(crotyl)(2-dicyclohyxylphosphino-2', 6'-dimethoxy-l, T- biphenyl)palladium II, trans dichloro bis(triphenylphosphine)palladium, X-Phos aminobiphenyl palladium chloride precatalyst, and chloro[(tri-tert-butylphosphine)-2-(2- aminobipheny 1)] palladium II ([P(tBu)3] Palladacycle). In some embodiments, the palladium catalyst is Pd(PPh3)2C12 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4'.6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l.T- biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II)]; CATACXIUM® A Pd G3 (mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,T- biphenyl)]palladium(II) or [(di(l-adamantyl)-butylphosphine)-2-(2'-amino-l,T- bi phenyl)] palladium(II) methanesulfonate); APhos Pd G3 (palladium G3-(4-(N,N- dimethylamino)phenyl)di-tert-butylphosphine] or [4-(di-tert-butylphosphino)-N,N- dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy3) Pd-G3 (palladium G3-tricyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'- aminobiphenyl)]palladium(II) methanesulfonate); Allylpalladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)C12 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)]. In some embodiments, the palladium catalyst is [P(tBu)3] Palladacycle.

[0040] In some embodiments, the palladium catalyst comprises 1 to 6 atoms of the metal. In some embodiments, the catalyst comprises 2 to 5 atoms of palladium. In some embodiments, the catalyst comprises 2 to 4 atoms of palladium. In some embodiments, the catalyst comprises 1, 2, 3, 4, 5, or 6 atoms of palladium. In some embodiments, the catalyst is present at about 0.001 to about 1 molar equivalents relative to the compounds of formula (I), preferably about 0.002 to about 0.5 molar equivalents relative to the compounds of formula (I), more preferably about 0.003 to about 0. 1 molar equivalents relative to the compounds of formula (I) and styrene. Palladium-catalyzed coupling reactions are further described, e.g., in R. F. Heck, “VinylSubstitutions with Organopalladium Intermediates” in Comprehensive Organic Syntheses, Vol. 4, Pergamon Press, Oxford, 1991, p. 833.

[0041] In some embodiments, the reaction of Formula I with styrene in the presence of a palladium catalyst is performed at a temperature greater than 70°C. e.g., 70°C to 140°C, 70°C to 130°C, 70°C to 120°C. In some embodiments, the reaction is performed at about 70°C to about 110°C, about 70°C to about 90°C, about 80°C to about 100°C, about 80°C to about 110°C, or about 90°C to about 110 °C.

[0042] In some embodiments, the reacting of compound of Formula 1 with styrene and a palladium catalyst is performed in a solvent suitable for solubilizing Formula I. In some embodiments, the organic solvent is non-aromatic. In some embodiments, the organic solvent is aromatic. In some embodiments, the organic solvent is a mixture of aromatic and non- aromatic. As a solvent for the reaction, any inert organic solvent can be used, examples of such solvents being organic solvents, e.g., hydrocarbons such as toluene and heptane, ethers such as dioxan, nitriles such as acetonitrile, ketones such as acetone, and amides such as dimethylformamide or N-methylpyrrolidone. In some embodiments, the organic solvent is heptane. In some embodiments, the organic solvent is toluene. In some embodiments, the organic solvent is a mixture of heptane and toluene. In some embodiments, the reacting of the compound of Formula (I) with styrene is not performed in the presence of water. In some embodiments, the cleaving in (ii) is performed in an organic solvent or in a mixture of at least two organic solvents. In some embodiments, the organic solvent is a mixture of aromatic and non-aromatic solvents

[0043] In some embodiments, the organic solvent is a mixture of an aromatic and non- aromatic solvent in a ratio of about 10: 1 to 1 : 10, 5: 1 to 1 :5, 2: 1 to 1:2 or about 1 : 1. In some embodiments, the organic solvent two different aromatic solvent in a ratio of about 10: 1 to 1 : 10, 5: 1 to 1 :5, 2: 1 to 1 :2 or about 1 : 1 . In some embodiments, the organic solvent two different non-aromatic solvent in a ratio of about 10: 1 to 1: 10, 5: 1 to 1:5, 2: 1 to 1 :2 or about 1 :1. In some embodiments, the organic solvent is a mixture of heptane and toluene in a ratio of about 10: 1 to 1: 10, 5: 1 to 1:5, 2: 1 to 1:2 or about 1: 1. The reaction is suitably carried out in the presence of a base which may be an inorganic base, e.g., a carbonate or hydrogencarbonate such as sodium carbonate or hydrogen-carbonate, tert phosphates such as K3PO4, or an organic base, e.g., an amine such as triethyl amine or diisopropyl ethylamine; or an alkali acetate such as sodium acetate. In some embodiments, the base is potassium carbonate (K2CO3), potassiumacetate (CH3CO2K), potassium phosphate (K3PO4), potassium tert-butoxide (KOtBu), sodium carbonate (ISteCCh), sodium bicarbonate (NaHCCh), sodium methoxide (NaOMe), calcium carbonate (CaCCh), lithium carbonate (Li2COa), cesium carbonate (CS2CO3), silver phosphate (AgsPCh), silver oxide (Ag2O), thallium carbonate (TI2CO3), thallium ethoxide (TIOEt), thallium hydroxide (T10H), tert-butylamine (t-BuNEh). potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH). barium hydroxide (Ba(OH)2>, or any mixture thereof. In some embodiments, the inorganic base is selected from potassium phosphate tribasic, potassium carbonate and sodium carbonate

[0044] In some embodiments, the reaction is suitably carried out in the presence of an organic base. In some embodiments, the base is an organic base selected from diisopropylethylamine, triethylamine, N,N-Dicylohexylmethylamine, 1,8- Diazabicyclo[5.4.0]undec-7-ene and 1,4-Diazabicyclo[2.2.2]octane. In some embodiments, the base is N,N-Dicylohexylmethyamine.In some embodiments, the base is present at about 0.1 to about 10 molar equivalents relative to the compounds of Formula (I) and styrene, preferably about 1 to about 6 molar equivalents relative to the compounds of Formula (I) and styrene, more preferably about 2 to about 4 molar equivalents relative to the compounds of Formula (I) and styrene. In some embodiments, the reaction can be carried out at normal or elevated pressure, e.g.. at the appropriate pressure of the solvent used and in an inert atmosphere, e g., under argon.

[0045] The compound of Formula (II) obtained in the reaction can be converted into 3, 5- Dihydroxy-4-isopropyl-trans-stilbene [Tapinarof] or a salt or solvate thereof by a cleavage reaction, in which Formula (II) gains one or more hydrogen ions. In some embodiments, cleavage is performed in anhydrous conditions. In some embodiments, cleavage is performed in an organic solvent in anhydrous conditions, i.e., in the substantial absence of water in order to avoid the use or creation of water or other unnecessary molecules. Examples of solvents that can be used for cleavage reactions include but are not limited to organic solvents such as Dimethylacetamide (DMA) dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof.

[0046] In some embodiments, the compound of Formula (II) is present in the cleavage reaction at about 0.1 to about 1 mol / L (solvent), about 0.2 to about 0.8 mol / L (solvent), or about 0.3 to about 0.5 mol / L (solvent). In some embodiments, the compound of Formula (II) ispresent in the cleavage reaction at about 0.1, about 0.2. about 0.3, about 0.4. about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1 mol / L (solvent). In some embodiments, the cleavage is performed at a pH of about 4 to about 6.5, about 4.2 to about 6.2 about 4.5 to about 6, about 4.7 to about 5.7, or about 5 to about 5.5. In some embodiments, the cleavage reaction is performed at pH about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3. about 5.4, about 5.5. about 5.6, about 5.7. about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0047] In some embodiments the process for preparing Tapinarof further comprises purifying the obtained compound of Formula (III) or a salt or solvate thereof. In some embodiments the purifying comprises crystallization of the compound of Formula (III) or a salt or solvate thereof. In some embodiments the compound of Formula (III) is a crystal form.

[0048] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (III), a salt or salt thereof prepared by the process disclosed herein and a pharmaceutically acceptable excipient. As used herein a “pharmaceutically acceptable excipient” refers to one or more pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula (III) a salt or salt thereof when administered to a patient.

[0049] In some embodiments, the compound of Formula (III) a salt or salt thereof is present in a therapeutically effective amount. A “therapeutically effective amount” of a compound, pharmaceutically acceptable salt or solvate thereof or pharmaceutical composition according to any embodiment described herein, is an amount sufficient to produce a selected effect on at least one symptom or parameter of a specific disease or disorder. A therapeutically effective amount of a compound, according to any embodiment described herein, is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0050] All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.EXAMPLESExample 1. Synthesis of 3. 5-Dihydroxy-4-isopropyl-trans-stilbene [Tapinarofl Formula II]Formula II

[0051] 3,5- Dimethoxy-4-isopropyl-trans-stilbene was prepared according to the following procedure. 10.8 g (0.044_mol) of 3,5- Dimethoxy-4-isopropyl-benzoyl chloride was added into a mixture contained 4.2 g (0.040_mol) of styrene (CsHs). 17.3 ml of N,N- Dicyclohexylmethylamine and 517 mg ( 0.001 mol) of tBu3P-Coordinated 2-phenylaniline- based palladacycle complex chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium II ([P(tBu)3] Palladacycle) in 54 ml of heptane and 60 ml of toluene under inert atmosphere. The reaction medium was heated to 95-100°C and stirred for 6 hours. The reaction was subsequently cooled to room temperature and filtered. The filtrate was filtered through silica gel column, column was washed with heptane. The fractions were collected and then concentrated in vacuum till dryness. 3,5- Dimethoxy-4-isopropyl-trans-stilbene was obtained; 65% yield; HPLC purity 80%.B. Conversion of 3,5- Dimethoxy-4-isopropyl-trans-stilbene [Formula II] to 3, 5-Dihydroxy- 4-isopropyl-trans-stilbene [Tapinarof] [Formula III]Formula III

[0052] 3.5- Dimethoxy-4-isopropyl-trans-stilbene [Formula II] was dissolved in Toluene(78mL) in anhydrous conditions, to the resulted solution 10.5 ml (0.08 mol) of N,N- Dimethylaniline were added at room temperature. The mixture was cooled to less than 15°C, and to this 11 gr (0.08 mol) of anhydrous aluminum chloride were added. The reaction medium was than heated and stirred under reflux for 1 hour. The mixture was cooled to room temperature, acidified with diluted hydrochloric acid, extracted with ethyl acetate. The organic fractions were washed with diluted hydrochloric acid and then with water till neutral pH. The solvent was removed in vacuum. The residue was suspended in mixture of Heptane and Toluene. The precipitate was filtered off to afford crude 3, 5-Dihydroxy-4-isopropyl-trans- stilbene [Tapinarof] [Formula III].-The solid was crystallized in the mixture of Toluene Heptane. 3, 5-Dihydroxy-4-isopropyl-trans-stilbene [Tapinarof] [Formula III] was obtained; 60% Yield; HPLC purity 99.9%.

Claims

WHAT IS CLAIMED IS:

1. A method for the preparation of a compound of Formula II or salt or solvate thereof, the method comprising reacting a compound of Formula (I)Formula (I) with styrene in the presence of a base, a solvent and a palladium catalyst to form a compound of Formula II;Formula (II) wherein Ri and R2 are independently an alkyl or hydrogen, and wherein X is a halogen.

2. The method of claim 1, wherein at least one of Ri and R2 is alkyl, wherein the method further comprises cleaving Ri and / or R2 of the compound of Formula (II) to form a compound for Formula (III)Formula (III).

3. The method of claim 1 or 2, wherein Ri is alkyl and R2 is alkyl.

4. The method of claim 1 or 2, wherein Ri is alkyd and R2 is hydrogen, or Ri is hydrogen and R2 is alkyl.

5. The method of claim 1 or 2, wherein both Ri and R2 are hydrogen.

6. The method of any one of claims 1 to 4, wherein the alkyl is a methyl, ethyl, propyl, isopropyl, or butyl,7. The method of any one of claims 1 to 4, wherein Ri is methyl.

8. The method of any one of claims 1 to 3, wherein both Ri and R2 are methyl.

9. The method of any one of claims 1 to 8, wherein X is a chloro compound.

10. The method of any one of claims 1 to 9, wherein the reacting in (i) is performed in an organic solvent.

11. The method of claim 10. wherein the organic solvent is an aromatic, non-aromatic or mixture thereof.

12. The method of claim 10 or 11, wherein the organic solvent is a mixture of heptane and toluene.

13. The method of any one of claims 1 to 12, wherein the palladium catalyst is selected from palladium acetate, chloro(crotyl)(2-dicyclohyxylphosphino-2', 6'-dimethoxy-l, T- biphenyl)palladium II, trans dichloro bis(triphenylphosphine)palladium, X-Phos aminobiphenyl palladium chloride precatalyst, and chloro[(tri-tert-butylphosphine)-2-(2- aminobiphenyl)]palladium II ([ P(tBu)s] Palladacycle).

14. The method of claim 13, wherein the palladium catalyst is ([P(tBu)3] Palladacycle).

15. The method of any one of claims 1 to 14, wherein the base is an organic base selected from diisopropylethylamine, triethylamine, N,N-Dicylohexylmethylamine, 1,8- Diazabicyclo[5.4.0]undec-7-ene and 1,4-Diazabicyclo[2.2.2]octane, or non-organic base selected from potassium phosphate tnbasic, potassium carbonate and sodium carbonate.

16. The method of claim 15, wherein the base is N,N-Dicylohexylmethyamine.

17. The method of any one of claims 1 to 16, wherein the reacting in (i) is performed at a temperature greater than 70°C.

18. The method of any one of claims 1 to 17, wherein the reacting in (i) is performed at a temperature of about 70°C to about 110°C.

19. The method of any one of claims 1 to 18, wherein the cleaving in (ii) is performed in anhydrous conditions.

20. The method of any one of claims 1 to 19, wherein the cleaving in (ii) is performed in an organic solvent or in a mixture of at least two organic solvents.

21. The method of claim 20, wherein the organic solvent is a mixture of aromatic and nonaromatic solvents.

22. A method for the preparation of a Tapinarof (Formula III) or salt of solvate thereofFormula (III) the method comprising; i. reacting a compound of Formula (I)Formula (I) with styrene in the presence of a base, a solvent and a palladium catalyst to form a compound of Formula II;Formula (II) ii. cleaving Ri and / or R2 of the compound of Formula (II) to form the Tapinarof; wherein Ri and R2 are alky l, and wherein X is a halogen.

23. A compound of Formula (III) or a salt thereof:Formula (III), wherein the compound of Formula (III) is characterized by a purity of at least 98%, prepared by a process comprising the steps of i. reacting a compound of Formula (1)Formula (I) with styrene in the presence of a base, a solvent and a palladium catalyst to form a compound of Formula II; andFormula (II) ii. cleaving Ri and / or R2 of the compound of Formula (II) to form the Tapinarof, wherein Rl and R2 are alkyl, and wherein X is a halogen.

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