Process for preparing tapinarof
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.
1. A process for the preparation of a compound of Formula (I) or a salt or solvate thereof
comprising one or more of the process steps (a), (b) and (c) wherein:
(a) comprises (i) reaction of a compound of Formula (III) or a salt thereof
to form a compound of Formula (II) or a salt thereof
wherein X is Cl, Br, or I, and thereafter (ii) conversion of the compound of Formula (II) or a salt thereof into the compound of Formula (I) or a salt or solvate thereof;
(b) comprises conversion of a compound of Formula (VI) or a salt thereof
into a compound of Formula (III) or a salt thereof
and thereafter conversion of the compound of Formula (III) or a salt thereof into a compound of Formula (I) or a salt or solvate thereof; and
(c) comprises conversion of a compound of Formula (IX) or a salt thereof
into a compound of Formula (VI) or a salt thereof
and thereafter conversion of the compound of Formula (VI) or a salt thereof into a compound of Formula (I) or a salt or solvate thereof.
2. The process according to claim 1 in which X is Cl and the process step (a) (i) is carried out using a chlorination reagent selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide and trichloroisocyanuric acid.
3. The process according to claim 1 wherein the conversion step (a) (ii) is carried out in the presence of an additive reagent which is a quaternary ammonium salt.
4. The process according to claim 3 wherein the additive reagent is a quaternary ammonium chloride salt.
5. The process according to claim 4 wherein the quaternary ammonium chloride salt is selected from the group consisting of benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride.
6. The process according to claim 3 wherein the conversion is carried out in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone.
7. The process according to claim 1 in which process step (b) comprises a decarboxylation of the compound of Formula (VI) or a salt thereof to form the compound of Formula (V) or a salt thereof
followed by esterification of the compound of Formula (V) or salt thereof to form the compound of Formula (IV) or a salt thereof
wherein R is C 1-4 alkyl; and thereafter cyclization of the compound of Formula (IV) or a salt thereof to form the compound of Formula (III) or a salt thereof.
8. The process according to claim 7 which comprises a decarboxylation in the presence of a base.
9. The process according to claim 8 wherein the base is triethylamine.
10. The process according to claim 7 wherein esterification is performed using methanol and hydrochloric acid.
11. The process according to claim 7 wherein cyclization is performed using potassium tert-butoxide.
12. The process according to claim 7 wherein the compound of Formula (III) or a salt thereof is acidified and isolated by precipitation with methylcyclohexane.
13. The process according to claim 1 in which process step (c) comprises the condensation of the compound of Formula (IX) or a salt thereof to form the compound of Formula (VIII) or a salt thereof
followed by addition of a malonic ester (R 1 O(O)C—CH 2 —C(O)OR 2 ) to form a compound of Formula (VII) or a salt thereof
wherein R 1 and R 2 are independently C 1-4 alkyl;
and thereafter hydrolysation of the compound of Formula (VII) or a salt thereof to form the compound of Formula (VI) or a salt thereof.
14. The process according to claim 13 wherein the condensation is performed using potassium or sodium hydroxide in methanol.
15. The process according to claim 13 wherein the malonic ester is diethyl malonate.
16. The process according to claim 1 in which step (a) (ii) further comprises the formation of an acetic acid solvate of the compound of Formula (I).
17. The process according to claim 1 wherein the process further comprises a step of recrystallization of the compound of Formula (I) or a salt thereof.
18. The process according to claim 17 wherein the recrystallization is carried out using methanol and water.