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US 11,597,692 B2Granted
Process for preparing tapinarof
AssigneeDermavant Sciences GmbH
InventorsIan Paul Andrews, Nicholas Calandra, Tyler Andrew Davis, Ravinder Reddy Sudini
Life of this patent
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Abstract
The present invention provides processes for the preparation of 3, 5-Dihydroxy-4-isopropyl-trans-stilbene or a salt or solvate thereof and novel intermediates used therein. In some embodiments the 3, 5-Dihydroxy-4-isopropyl-trans-stilbene is prepared from (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione. Also disclosed are crystal forms of 3, 5-Dihydroxy-4-isopropyl-trans-stilbene or a salt or solvate thereof and pharmaceutical compositions comprising same.
Claims12
A pharmaceutical composition comprising:
- a compound consisting of
- at least 99% by weight of a compound of Formula (I)
- wherein the compound is at least 95% form 1, characterized by an X-ray powder diffraction pattern having peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees2θ (±0.1° 2θ);
- and
- less than or equal to 1% impurities;
- wherein the impurities include at least a compound of the Formula
- and
- a pharmaceutically acceptable excipient.
5 more elements
A compound of Formula (I)
- or a salt or solvate thereof;
- wherein the compound or a salt or solvate thereof, is at least 99% pure by weight and wherein the compound is at least 95% form 1 characterized by an X-ray powder diffraction pattern having peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees2θ (±0.1° 2θ);
- prepared by a process comprising:
- a) decarboxylating a compound of Formula (VI)
- in the presence of a base selected from trimethylamine, imidazole, pyridine, and lutidine (2,6-dimethylpyridine) to form a compound of Formula (V) or a salt thereof
- b) esterifying the compound of Formula (V) or a salt thereof with methanol and aqueous hydrochloric acid to form a compound of Formula (IVa)
- c) cyclizing the compound of Formula (IVa) with potassium tert-butoxide to form a compound of Formula (III)
- d) halogenating the compound of Formula (III) with a halogenating agent selected from 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, and trichloroisocyanuric acid, to form a compound of Formula (IIa)
- and
- e) aromatizing the compound of Formula (IIa) in the presence of an additive reagent selected from tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, to form the compound of Formula (I) or a salt or solvate thereof.
7 more elements
Dependencies are inferred from the claim text.