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US 10,647,649 B2Granted
Process for preparing tapinarof
AssigneeDermavant Sciences GmbH
InventorsIan Paul Andrews, Nicholas Calandra, Tyler Andrew Davis, Ravinder Reddy Sudini
Life of this patent
Estimating the term…
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.
Claims66
A process for preparing a compound of Formula (I) or a salt or solvate thereof
- comprising:
- a) decarboxylating a compound of Formula (VI) or a salt thereof
- to form a compound of Formula (V) or a salt thereof
- b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof
- wherein R is C1-4 alkyl;
- c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof
- d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof
- wherein X is selected from Br, Cl and I;
- and
- e) aromatizing the compound of Formula (II) or a salt thereof to form the compound of Formula (I) or a salt or solvate thereof.
7 more elements
A process for preparing a compound of Formula (I) or a salt or solvate thereof
- comprising:
- a) heating a compound of Formula (VI)
- with catalytic triethylamine to form a compound of Formula (V)
- b) heating the compound of Formula (V) with methanol and aqueous hydrochloric acid to form a compound of Formula (IVa)
- c) treating a cooled solution of the compound of Formula (IVa) with potassium tert-butoxide to form a compound of Formula (III)
- d) heating the compound of Formula (III) with 1, 3-dichloro-5,5-dimethylhydantoin to form a compound of Formula (IIa)
- and
- e) heating the compound of Formula (IIa) with tetraethylammonium chloride to form the compound of Formula (I).
5 more elements
A process for preparing a compound of Formula (VI) or a salt thereof
- comprising:
- a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- b) adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof
- and
- c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof.
2 more elements
A process for preparing a compound of Formula (V) or a salt thereof
- comprising decarboxylating a compound of Formula (VI) or a salt thereof
- in the presence of a base, to form the compound of Formula (V) or a salt thereof.
A process for preparing a compound of Formula (IVa) or a salt thereof,
- comprising esterifying a compound of Formula (V) or a salt thereof,
- to form the compound of Formula (IVa) or a salt thereof.
A process for preparing a compound of Formula (IIa) or a salt thereof,
- comprising halogenating a compound of Formula (III) or a salt thereof,
- to form the compound of Formula (IIa) or a salt thereof.
A compound of Formula (I) or a salt or solvate thereof
- wherein the compound or a salt or solvate thereof is about 98% 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 degrees 2θ (±0.1° 2θ);
- prepared by a process comprising:
- a) decarboxylating a compound of Formula (VI) or a salt thereof
- to form a compound of Formula (V) or a salt thereof
- b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof
- wherein R is C1-4 alkyl;
- c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof
- d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof
- wherein X is selected from Br, Cl and I;
- and
- e) aromatizing the compound of Formula (II) or a salt thereof to form the compound of Formula (I) or a salt or solvate thereof.
8 more elements
A compound of Formula (VI) or a salt thereof
- prepared by a process comprising:
- a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- b) adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof
- and
- c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof.
2 more elements
A compound of Formula (V) or a salt thereof
- prepared by a process comprising:
- a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- b) adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof
- c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof
- and
- d) decarboxylating the compound of Formula (VI) or a salt thereof, in the presence of a base, to form the compound of Formula (V) or a salt thereof.
3 more elements
A compound of Formula (IVa) or a salt thereof
- prepared by a process comprising:
- a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- b) adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof
- c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof
- d) decarboxylating the compound of Formula (VI) or a salt thereof, in the presence of a base, to form the compound of Formula (V) or a salt thereof
- and
- e) esterifying a compound of Formula (V) or a salt thereof to form the compound of Formula (IVa) or a salt thereof.
4 more elements
A compound of Formula (IIa) or a salt thereof
- prepared by a process comprising:
- a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- b) adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof
- c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof
- d) decarboxylating the compound of Formula (VI) or a salt thereof, in the presence of a base, to form the compound of Formula (V) or a salt thereof
- e) esterifying a compound of Formula (V) or a salt thereof to form the compound of Formula (IVa) or a salt thereof
- f) cyclizing a compound of Formula (IVa) or a salt thereof to form the compound of Formula (III) or a salt thereof
- and
- g) halogenating a compound of Formula (III) or a salt thereof to form the compound of Formula (IIa) or a salt thereof.
6 more elements
A compound of Formula (I)
- in the form of an acetic acid solvate thereof.
A compound of Formula (I)
- wherein the compound is about 98% 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 degrees 2θ (±0.1° 2θ).
A compound of Formula (IIa) or a salt thereof
A compound of Formula (IVa) or a salt thereof
A compound of Formula (V) or a salt thereof
A compound of Formula (VI) or a salt thereof
A pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I)
- wherein the compound is about 98% 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 degrees 2θ (±0.1° 2θ);
- and a pharmaceutically acceptable excipient.
A pharmaceutical composition comprising a therapeutically effective amount of an acetic acid solvate of the compound of Formula (I)
- and a pharmaceutically acceptable excipient.
A compound of Formula (I) or a salt or solvate thereof
- wherein the compound or a salt or solvate thereof is about 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 degrees 2θ (±0.1° 2θ);
- prepared by a process comprising:
- a) decarboxylating a compound of Formula (VI) or a salt thereof
- to form a compound of Formula (V) or a salt thereof
- b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof
- wherein R is C1-4 alkyl;
- c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof
- d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof
- wherein X is selected from Br, Cl and I;
- and
- e) aromatizing the compound of Formula (II) or a salt thereof to form the compound of Formula (I) or a salt or solvate thereof.
8 more elements
A compound of Formula (I)
- wherein the compound is about 99% pure by weight and wherein the compound is at least 95% form 1, characterised 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 degrees 2θ (±0.1° 2θ).
A pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I)
- wherein the compound is about 99% pure by weight, and wherein the compound is at least 95% form 1, characterised 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 degrees 2θ (±0.1° 2θ);
- and a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.