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WO2025099634A1 - Procédé de préparation de la forme polymorphe iii de tapinarof - Google Patents

Procédé de préparation de la forme polymorphe iii de tapinarof Download PDF

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WO2025099634A1
WO2025099634A1 PCT/IB2024/061047 IB2024061047W WO2025099634A1 WO 2025099634 A1 WO2025099634 A1 WO 2025099634A1 IB 2024061047 W IB2024061047 W IB 2024061047W WO 2025099634 A1 WO2025099634 A1 WO 2025099634A1
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compound
tapinarof
solvent
temperature
group
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Stefano Gobbato
Matteo BAUDINO
Giovanni BISBANO
Lorenzo LOMBARDI
Lorenzo MAGGI
Matteo MOSSOTTI
Jacopo Roletto
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Procos SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • 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
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • 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
    • C07C45/298—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 with manganese derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Definitions

  • the present invention concerns a process for preparing tapinarof and its polymorphic form III.
  • Tapinarof is an active ingredient approved by the Food and Drug Administration (FDA) and it is an aryl hydrocarbon receptor-modulating agent (TAMA) used for the treatment of psoriasis and atopic dermatitis thanks to its immunomodulatory effect. By binding directly to the receptor, it induces a downregulation of inflammatory cytokines, regulates the expression of proteins involved in the skin barrier formation, and also acts as an antioxidant.
  • FDA Food and Drug Administration
  • TAMA aryl hydrocarbon receptor-modulating agent
  • WO2019094934 describes a process for the synthesis of tapinarof and the process for obtaining the polymorphic form I.
  • CN101648851 describes a route for the synthesis of tapinarof through the Homer- Wadsworth-Emmons reaction.
  • WO2021236709 describes nine different solvated forms of tapinarof and the processes for obtaining them.
  • the polymorphic form III of tapinarof is described in the International Patent Application WO2019/063002, and is characterized by an X-ray diffraction spectrum having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.4°, 23.7°, 24.4°, 28.3°, 30.6°, 40.8°, 42.4°( ⁇ 0.2° 20).
  • the processes known in the art, for obtaining both tapinarof and its polymorphic form III have critical issues especially related to the applicability on an industrial scale.
  • some of the processes known for obtaining tapinarof such as those described in WO2001042231 , CN101830764, CN101838173, CN101531571 , and CN104003848 proceed through a reaction intermediate corresponding to Compound 5.
  • the synthesis of Compound 5 may involve the use of MnO2, which is suspended in the mixture comprising the reagents. The mixture thus obtained is then filtered. The filtration step is very slow and difficult; this has a significant impact on the efficiency of the process and on the costs, especially when it involves industrial scale production.
  • the object of the present invention is therefore to provide an efficient process for the synthesis of tapinarof, and its polymorphic form III, that overcomes the drawbacks of the prior art while being at the same time advantageous from an industrial point of view.
  • the above-mentioned object has been achieved by means of a process that allows to obtain Compound 5, avoiding the slow and difficult filtration step, and using reproducible and scalable isolation techniques to obtain tapinarof and its polymorphic form III.
  • the present invention relates to a process for preparing the compound tapinarof, (E)-3,5-dihydroxy-4-isopropylstilbene, comprising the steps of: i) reacting Compound 1 with a methylating agent and an organic or inorganic base, in an appropriate solvent, to obtain Compound 2; ii) reacting Compound 2 with an isopropylating agent in the presence of a Lewis acid, and subsequently methylating it with a methylating agent in the presence of a base to obtain Compound 3; iii) reacting Compound 3 with a reducing reagent to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing MnCX, while maintaining a solution temperature in
  • the process of the invention which provides for the synthesis of Compound 5 using the column containing solid Mn02 through which the solution of Compound 4 is eluted, allows to significantly reduce times and costs with respect to the processes described in the prior art, such as CN104003848.
  • the column can be easily disposed of, thus avoiding the step of removing the solid from the reaction environment through a difficult filtration.
  • the present invention relates to a process for obtaining the polymorphic form III of tapinarof characterized by an X-ray spectrum having peak s at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4° ⁇ 0.2° 20, comprising the steps of: a) adding a solvent selected from the group consisting of toluene, DMSO, n- heptane, chlorobenzene, to the compound tapinarof, crude or amorphous, or in any other crystalline form; b) heating the solution to a temperature in the range from 30°C to 100°C, preferably from 40°C to 100°C, more preferably from 80°C to 100°C; c) optionally adding a second solvent and cooling the solution to a temperature in the range from 20°
  • the tapinarof obtained by crystallization from various appropriate solvents completely converts into the polymorphic form III, when subjected to heating at a temperature in the range from 70°C to 90°C.
  • the object of the present invention is therefore to provide an efficient process for the synthesis of tapinarof and its polymorphic form III that overcomes the drawbacks of the prior art, while being at the same time advantageous from an industrial point of view.
  • Figure 1 shows the XRPD diffractogram of the polymorph form III of the compound tapinarof, having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4° ⁇ 0.2° 28.
  • Figure 2 shows the DSC thermogram of the polymorphic form III of the compound tapinarof.
  • Figure 3 shows the thermogravimetric curve of the polymorphic form III of the compound tapinarof
  • solvate is intended to mean a crystalline form that incorporates a solvent into the crystalline structure.
  • the solvent is water, it may be referred to as a “hydrate”.
  • the solvent in a solvate may be either stoichiometric or non-stoichiometric.
  • isolated with reference to the polymorphic crystalline form of tapinarof, in the following invention, refers to a polymorphic crystalline form of tapinarof that is physically separated from the reaction mixture in which it is formed.
  • reduced pressure is intended to mean a pressure lower than the atmospheric pressure, usually a pressure between 500 and 2000 Pa.
  • any other crystalline form of tapinarof is intended to mean any other polymorphic form of tapinarof other than form III, such as the known forms I, II, IV, and all solvated forms;
  • the present invention relates to an efficient process for the synthesis of the compound tapinarof and its polymorphic form III.
  • the present invention relates to a process for preparing the compound tapinarof, comprising the steps of: i) reacting Compound 1 with a methylating agent and an organic or inorganic base in an appropriate solvent to obtain Compound 2; ii) reacting Compound 2 with an isopropylating agent in the presence of a Lewis acid, and subsequently methylating it with a methylating agent in the presence of a base to obtain Compound 3; iii) reacting Compound 3 with a reducing reagent to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing MnO2, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from 60°C to 80°C, to obtain Com
  • the methylating agent of step i) is selected from the group consisting of dimethyl sulfate, methyl iodide, and dimethyl carbonate.
  • the methylating agent of step i) is dimethyl sulfate.
  • the organic or inorganic base of step i) is selected from the group consisting of potassium carbonate, sodium hydride, and potassium tert-butoxide.
  • the inorganic base of step i) is potassium carbonate.
  • the isopropylating agent of step ii) is selected from the group consisting of isopropyl bromide, isopropyl chloride, isopropyl methanesulfonate, isopropyl trifluoromethanesulfonate, isopropyl tosylate, and isopropanol.
  • the isopropylating agent of step ii) is isopropyl bromide.
  • the Lewis acid of step ii) is selected from the group consisting of aluminum trichloride, boron tribromide, aluminum tribromide, boron trichloride, boron trifluoride, tin tetrachloride.
  • the methylating agent of step ii) is selected from the group consisting of dimethyl sulfate, methyl iodide, and dimethyl carbonate.
  • the methylating agent of step ii) is dimethyl sulfate.
  • the organic or inorganic base of step ii) is selected from the group consisting of potassium carbonate, sodium hydride, and potassium tert-butoxide.
  • the inorganic base of step ii) is potassium carbonate.
  • the reducing agent of step iii) is selected from the group consisting of sodium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane, and di-iso-butyl aluminum hydride.
  • the reducing agent of step iii) is sodium borohydride.
  • the base of step vi) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, and potassium hydride.
  • the base of step vi) is sodium tert-butoxide.
  • the tertiary amine of step vii) is selected from the group consisting of DIPEA, TEA, N,N-dimethylaniline.
  • the tertiary amine of step vii) is TEA.
  • step v) the flow is adjusted to ensure a residence time comprised between 5 and 60 minutes, preferably between 10 and 30 minutes, even more preferably between 10 and 20 minutes.
  • the process of the invention that involves the synthesis of Compound 5 using the column containing solid Mn02 through which the solution of Compound 4 is eluted, allows to significantly reduce times and costs with respect to the processes described in the prior art.
  • the column can be easily disposed of, thus avoiding the step of removing the solid from the reaction environment by filtration.
  • the process for preparing tapinarof comprises the steps of: i) reacting Compound 1 with dimethyl sulfate and potassium carbonate in acetone to obtain Compound 2; ii) reacting Compound 2 with isopropyl bromide in the presence of a Lewis acid, and subsequently methylating it with dimethyl sulfate and potassium carbonate in acetone to obtain Compound 3; iii) reacting Compound 3 with sodium borohydride in the presence of MeOH or BF3 to obtain Compound 4; iv) adding Compound 4 to toluene, and heating the resulting mixture to a temperature in the range from 60°C to 95°C, preferably from 80°C to 90°C, thus obtaining a clear solution; v) eluting the solution obtained from step iv) through the column containing Mn02, while maintaining a solution temperature in the range from 40°C to 100°C, preferably from 60°C to 80°C, to obtain
  • the polymorphic form III of tapinarof characterized by an X-ray spectrum having peaks at 5.6°, 11.3°, 12.3°, 13.9°, 15.8°, 16.7°, 17.1 °, 18.9°, 20.4°, 20.6°, 22.1 °, 22.8°, 23.7°, 28.3°, 30.6°, 40.8°, 42.4° ⁇ 0.2° 20 may be obtained by a process comprising the steps of: a) adding a solvent selected from the group consisting of toluene, DMSO, n- heptane, chlorobenzene, to the compound tapinarof, crude or amorphous, or in any other crystalline form; b) heating the solution to a temperature in the range from 30°C to 100°C, preferably from 40°C to 100°C, more preferably from 80°C to100 °C; c) optionally adding a second solvent and cooling the solution to a temperature in the range from 20°C to 45°C, preferably from 35
  • the tapinarof of step a) is obtained according to steps i)-vii).
  • the solvent of step c) is selected from the group consisting of n-heptane and water.
  • the solvent of step a) is toluene
  • the solvent of step c) is n-heptane
  • the solution in step b) is heated to a temperature in the range from 80°C to 100°C.
  • the solvent of step a) is DMSO and the solvent of step c) is water.
  • the solution in step b) is heated to a temperature in the range from 40°C to 60°C.
  • the solvent of step a) is n- heptane.
  • the solution in step b) is heated to a temperature in the range from 80°C to 100°C.
  • the tapinarof obtained by crystallization from different appropriate solvents completely converts into the polymorphic form III once subjected to heating at a temperature comprised in the range from 70°C to 90°C.
  • DIPEA N,N-Diisopropylethylamine
  • AlCh aluminum trichloride
  • Thermogravimetric analysis was performed with a Perkin Elmer Pyris 1 TGA by heating a 6 mg sample from 30°C to 200°C in an open ceramic crucible. The sample compartment was conditioned with nitrogen.
  • the reaction mixture was added to an aqueous solution of 2 M HCI and ice at 0°C; the layers were separated, and the organic layer was washed with saturated Rochelle salt solution, then with a saturated sodium bicarbonate solution, followed by water and brine. The solvent was removed under reduced pressure. If necessary, the residue obtained can be methylated according to the procedure described for Compound 2 to increase the yield of Compound 3.
  • Compound 4 was obtained by suspending methyl 4-isopropyl-3,5- dimethoxybenzoate (Compound 3, 100.0 g, 419.7 mmol) and sodium borohydride (17.5 g, 461.6 mmol) in THF (420 mL). BF 3 THF (60.1 mL, 545.6 mmol) was slowly added dropwise into the reaction mixture, heating at reflux. A solution of MeOH in THF, an aqueous solution of NaHCOs, and toluene were added in succession. The two layers formed were separated, and the organic layer was washed with an aqueous solution of NaCI. Compound 4 was isolated by evaporating the solvent.
  • Example 4 Preparation of Compound 5 (4-lsopropyl-3,5-dimethoxyphenyl)methanol (Compound 4, 90 g, 428.02 mmol) was solubilized in toluene. The solution was heated to 80°C and eluted on a column previously packed with MnO2, for a residence time of 15 min. The toluene solution containing Compound 5 was then concentrated to dryness, and the product crystallized from an EtOH/water mixture.
  • Compound 5 (4-lsopropyl-3,5-dimethoxyphenyl)methanol
  • Example 7 Preparation of the Polymorphic Form III of Tapinarof by Crystallization from Toluene/n-Heptane
  • Toluene (10 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 80-100°C with stirring for 20-30 minutes, until completely dissolved.
  • Heptane (20 mL) was added over 15-30 minutes, and then the mixture was cooled down to room temperature to obtain crystallization. The mixture was left at 0°C for 1 -3 hours, and the crystal obtained was recovered by filtration and washed with heptane.
  • the white solid obtained was placed in an oven at reduced pressure at 80°C, overnight, to obtain the polymorphic form III.
  • the product taken from the oven was subjected to XRPD, TGA, and DSC analysis.
  • Example s Preparation of Tapinarof Polymorph III by Crystallization from DMSO/Water DMSO (10 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 40-60°C with stirring for 20-30 minutes, until completely dissolved. Water (20 mL) was then added over 15-30 minutes, and the mixture was cooled down to room temperature to achieve crystallization. The mixture was left at 4°C for 1 -3 hours, and the crystal was recovered by filtration and washed with water. The resulting white solid was placed in a vacuum oven at 80°C, overnight, to obtain polymorph III. To demonstrate that form III was obtained, the product taken from the oven was subjected to XRPD, TGA, and DSC analysis. The same graphs as in Figures 1 , 2 and 3 of Example 7, which confirmed that the polymorphic form III had been formed, were obtained.
  • Example 9 Preparation of Polymorphic Form III of Tapinarof by Crystallization from n- Heptane n-Heptane (400 mL) was added to tapinarof (5 g) as obtained in Example 6, and the mixture was heated to 80-100°C with stirring for 20-30 minutes, until completely dissolved. The mixture was cooled down to room temperature to achieve crystallization. The mixture was then left at 0°C for 1 -3 hours, and the crystal was recovered by filtration and washed with n-heptane. The resulting white solid was placed in a vacuum oven at 80°C, overnight, to obtain the polymorphic form III.

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

Abstract

La présente invention concerne un procédé de préparation de tapinarof et sa forme polymorphe III, qui permet d'obtenir du tapinarof par l'intermédiaire d'un processus optimisé, le tapinarof étant ensuite chauffé pour obtenir la forme polymorphe III. Le procédé selon la présente invention est donc très simple, efficace et peut être utilisé à l'échelle industrielle.
PCT/IB2024/061047 2023-11-08 2024-11-07 Procédé de préparation de la forme polymorphe iii de tapinarof Pending WO2025099634A1 (fr)

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IT102023000023508A IT202300023508A1 (it) 2023-11-08 2023-11-08 Processo per la preparazione della forma polimorfa iii di tapinarof
IT102023000023508 2023-11-08

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004031117A1 (fr) * 2000-10-06 2004-04-15 Welichem Biotech Inc. Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques
WO2019063002A1 (fr) * 2017-09-30 2019-04-04 北京文丰天济医药科技有限公司 Forme cristalline de benvitimod, son utilisation et son procédé de préparation
WO2021236709A1 (fr) * 2020-05-19 2021-11-25 Teva Pharmaceuticals International Gmbh Formes à l'état solide de tapinarof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1319959C (zh) 1999-12-06 2007-06-06 天济药业（深圳）有限公司 抗发炎、治疗牛皮癣和抑制蛋白质致活酶的羟基芪、芪衍生物及其类似物
CN101531571B (zh) 2009-04-17 2013-03-20 河北科技大学 六次甲基四胺氧化合成二苯乙烯类化合物的方法
CN101648851B (zh) 2009-09-03 2012-10-10 河北科技大学 (e)-3,5-二羟基-4-异丙基二苯乙烯的清洁制备方法
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
CN101838173A (zh) 2010-05-07 2010-09-22 河北科技大学 利用Kornblum氧化反应合成茋类化合物的方法
CN104003848B (zh) 2013-02-25 2016-02-10 武汉诺安药业有限公司 （e）-3,5-二羟基-4-异丙基二苯乙烯制备方法
EP3706725A4 (fr) 2017-11-10 2021-08-25 Dermavant Sciences GmbH Processus pour la préparation de tapinarof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004031117A1 (fr) * 2000-10-06 2004-04-15 Welichem Biotech Inc. Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques
WO2019063002A1 (fr) * 2017-09-30 2019-04-04 北京文丰天济医药科技有限公司 Forme cristalline de benvitimod, son utilisation et son procédé de préparation
WO2021236709A1 (fr) * 2020-05-19 2021-11-25 Teva Pharmaceuticals International Gmbh Formes à l'état solide de tapinarof

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