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WO2025133100A1 - Procédé de préparation d'intermédiaires utiles pour la préparation de tapinarof - Google Patents

Procédé de préparation d'intermédiaires utiles pour la préparation de tapinarof Download PDF

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Publication number
WO2025133100A1
WO2025133100A1 PCT/EP2024/087871 EP2024087871W WO2025133100A1 WO 2025133100 A1 WO2025133100 A1 WO 2025133100A1 EP 2024087871 W EP2024087871 W EP 2024087871W WO 2025133100 A1 WO2025133100 A1 WO 2025133100A1
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Prior art keywords
compound
formula
lll
iii
organic solvent
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English (en)
Inventor
Francisco De Asís MARQUILLAS OLONDRIZ
Thierry LEÓN SERRANO
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Interquim SA
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Interquim SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/24—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation

Definitions

  • 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.
  • Tapinarof also known as benvitimod, is 3,5-dihydroxy-4-isopropylstilbene and it has the following chemical structure of formula (I):
  • Tapinarof market as Vtama®, is a therapeutic aryl hydrocarbon receptor (AhR) modulating agent (TAMA) and has been developed for the treatment of psoriasis and atopic dermatitis.
  • AhR aryl hydrocarbon receptor
  • 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.
  • 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.
  • EP1248774B1 discloses an oxidation reaction for preparing the aldehyde intermediate (III) using pyridinium chlorochromate (PCC).
  • PCC pyridinium chlorochromate
  • 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.
  • DMSO dimethylsulfoxide
  • acetic anhydride as oxidative agent
  • 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.
  • 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.
  • 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).
  • 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.
  • the adduct used is the compound of formula (lll-BA- M):
  • 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)
  • a third aspect of the invention relates to a compound of formula (I ll-BA- M),
  • 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.
  • Figure 1 FTIR of compound of formula (lll-BA Na) prepared in Example 1.
  • 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.
  • 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.
  • any ranges given include both the lower and the upper endpoints of the range.
  • room temperature is 20-25 °C.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • 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 alkyl group of the alkyl methyl sulfoxide comprises a carbon chain length from 1 to 16 carbon.
  • 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.
  • the alkyl methyl sulfoxide is dimethyl sulfoxide.
  • 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.
  • the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylpyrrolidine and N- ethylpyperidine.
  • 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.
  • the first organic solvent is selected from the group consisting of toluene, chlorobenzene, xylene, anisole, tetrahydrofuran, acetonitrile, dichloromethane, and mixtures thereof.
  • the first solvent is dichloromethane.
  • 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.
  • the reaction is carried out at a temperature below -50 °C, particularly at a temperature comprised from -60 to -80 °C.
  • a compound of formula (III) is converted by reacting with a bisulfite compound to compound of formula (lll-BA-M)
  • 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.
  • the step a) further comprises:
  • 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.
  • the bisulfite compound in combination with any of the embodiments of the invention, 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.
  • bisulfite compound refers to a mixture of salts that dissolve in water to give solutions composed of a metal (M) and bisulfite ions.
  • step iv) is performed before step ill).
  • the steps I) to ill) are carried out at a temperature comprised from 20 to 25 °C.
  • 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).
  • the step vi) comprises evaporating part of the solvent and further crystallization or precipitation.
  • 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)
  • 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 further comprises several steps to obtain tapinarof.
  • 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)
  • 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).
  • the phosphorous-based reagent is selected from the group consisting of phosphonium halide, phosphonate or phosphine oxide, particularly phosphonate .
  • the phosphorous- based reagent is selected from the group consisting of benzytriphenyphosphonium chloride, benzytriphenyphosphonium bromide, dimethyl benzylphosphonate, diethyl benzylphosphonate or benzyldiphenylphosphine oxide.
  • the phosphorous-based reagent is diethyl benzylphosphonate.
  • 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.
  • 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).
  • the base is potassium tert-butoxide.
  • 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.
  • 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).
  • the suitable organic solvent is tetrahydrofuran.
  • the reaction in combination with any of the embodiments of the invention, 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.
  • the process 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)
  • step 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
  • the process 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
  • the process further comprises several steps to obtain tapinarof.
  • a third aspect of the invention relates to a compound of formula (lll-BA M), i OMe
  • 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.
  • 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.
  • DSC Differential Scanning Calorimetry
  • 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 cm 1 .
  • FTIR refers to Fourier-Transform Infra-Red spectroscopy.
  • 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.
  • 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.
  • 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.
  • PXRD Powder X-Ray Diffraction
  • 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).
  • 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
  • step i) is hydrochloric acid (HCI), hydrobromic acid (HBr), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), particularly hydrochloric acid.
  • HCI hydrochloric acid
  • HBr hydrobromic acid
  • H2SO4 sulfuric acid
  • HNO3 nitric acid
  • H3PO4 phosphoric acid
  • the bisulfite compound is selected from the group consisting of sodium metabisulfite, sodium bisulfite, potassium metabisulfite, potassium bisulfite, caesium metabisulfite and caesium bisulfite.
  • step iv) is performed before step ill).
  • steps I) to ill) are independently carried out at a temperature comprised from 20 to 25 °C.
  • 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).
  • step vi) comprises evaporating part of the solvent and further crystallization or precipitation.
  • 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)
  • 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).
  • the phosphorous-based reagent is selected from the group consisting of phosphonium halide, phosphonate, or phosphine oxide, particularly phosphonate.
  • the phosphorous-based reagent is selected from the group consisting of benzytriphenyphosphonium chloride, benzytriphenyphosphonium bromide, dimethyl benzylphosphonate, diethyl benzylphosphonate or benzyldiphenylphosphine oxide.
  • 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).
  • 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).
  • 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.
  • the chromatograph is programmed as follows:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de produits de synthèse intermédiaires utiles pour la préparation de tapinarof, et les nouveaux intermédiaires ainsi obtenus.
PCT/EP2024/087871 2023-12-22 2024-12-20 Procédé de préparation d'intermédiaires utiles pour la préparation de tapinarof Pending WO2025133100A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23383371 2023-12-22
EP23383371.4 2023-12-22

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WO2025133100A1 true WO2025133100A1 (fr) 2025-06-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1248774B1 (fr) 1999-12-06 2009-10-07 Welichem Biotech Inc. Traitement anti-inflammatoire et psoriasique et inhibition de la proteine kinase par des hydroxylstilbenes et de nouveaux derives de stilbene ou analogues
CN101830764A (zh) 2010-05-05 2010-09-15 河北科技大学 利用Pfitzner-moffatt氧化反应合成茋类化合物的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1248774B1 (fr) 1999-12-06 2009-10-07 Welichem Biotech Inc. Traitement anti-inflammatoire et psoriasique et inhibition de la proteine kinase par des hydroxylstilbenes et de nouveaux derives de stilbene ou analogues
CN101830764A (zh) 2010-05-05 2010-09-15 河北科技大学 利用Pfitzner-moffatt氧化反应合成茋类化合物的方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Intermediates for the preparation of (E)-2-isopropyl-5styrylbenzene-1,3-diol An IP.com Prior Art Database Technical Disclosure", 2 August 2022 (2022-08-02), XP093165263, Retrieved from the Internet <URL:https://priorart.ip.com/IPCOM/000270726> *
I P ANONYMOUS: "Intermediate for the preparation of (E)-2-isopropyl-5styrylbenzene-1,3-diol An IP.com Prior Art Database Technical Disclosure", 25 July 2023 (2023-07-25), XP093165261, Retrieved from the Internet <URL:https://priorart.ip.com/IPCOM/000272729> *
JUN GANG GAO ET AL: "Synthesis of Novel Drug Benvitimod", vol. 236-238, no. Part. 3, 1 May 2011 (2011-05-01), pages 2378 - 2382, XP009554230, ISSN: 1662-8985, Retrieved from the Internet <URL:https://doi.org/10.4028/www.scientific.net/AMR.236-238.2378?locatt=mode:legacy> DOI: 10.4028/WWW.SCIENTIFIC.NET/AMR.236-238.2378 *
SHAUKAT AWAIS ET AL: "Benzimidazole derivatives: synthesis, leishmanicidal effectiveness, and molecular docking studies", vol. 22, no. 8, 28 November 2012 (2012-11-28), US, pages 3606 - 3620, XP093165313, ISSN: 1054-2523, Retrieved from the Internet <URL:http://link.springer.com/article/10.1007/s00044-012-0375-5/fulltext.html> DOI: 10.1007/s00044-012-0375-5 *
ZHANG YUE ET AL: "Synthesis of a Benvitimod Impurity: (Z)-3,5-Dihydroxy-4-Isopropylstilbene", JOURNAL OF CHEMICAL RESEARCH, vol. 39, no. 3, 1 April 2015 (2015-04-01), GB, pages 154 - 158, XP093119154, ISSN: 1747-5198, DOI: 10.3184/174751915X14241928341993 *

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