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 preparing a compound of Formula (I) or a salt or solvate thereof
comprising aromatizing a compound of Formula (II)
wherein X is Cl, Br, or I
to obtain the compound of Formula (I).
2. The process of claim 1 wherein X is Cl.
3. The process of claim 1 wherein the aromatizing comprises contacting the compound of Formula (II) with quaternary ammonium salt in a solvent.
4. The process of claim 3 , wherein the quaternary ammonium salt is tetraethylammonium chloride.
5. The process of claim 1 , further comprising halogenating a compound of Formula (III),
with a halogenating agent to obtain the compound of Formula (II).
6. The process of claim 5 wherein the halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin; N-chlorosuccinimide; and trichloroisocyanuric acid.
7. The process of claim 5 , wherein the halogenating is carried out in methanol and the halogenating agent is 1,3-dichloro-5,5-dimethylhydantoin.
8. The process of claim 5 , further comprising cyclizing a compound of Formula (IV),
wherein R is C 1-4 alkyl, to obtain the compound of Formula (III).
9. The process of claim 8 , wherein R is selected from the group consisting of methyl, ethyl, propyl, or butyl.
10. The process of claim 8 , wherein R is methyl or t-butyl.
11. The process of claim 8 , wherein the cyclizing comprises contacting the compound of Formula (IV) with potassium tert-butoxide in 2-methyltetrahydrofuran.
12. The process of claim 8 , further comprising esterifying a compound of Formula (V) or a salt thereof
to obtain the compound of Formula (IV).
13. The process of claim 12 , wherein the esterifying comprises heating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
14. The process of claim 12 , further comprising decarboxylating a compound of Formula (VI)
in the presence of a base, to obtain the compound of Formula (V) or a salt thereof.
15. The process of claim 14 , wherein the decarboxylating comprises heating the compound of Formula (VI) in the presence of triethylamine.
16. The process of claim 14 , further comprising hydrolyzing a compound of Formula (VII)
wherein each of R 1 and R 2 is independently C 1-4 alkyl; to obtain the compound of Formula (VI).
17. The process of claim 16 , wherein each of R 1 and R 2 is ethyl.
18. The process of claim 16 , wherein the hydrolyzing comprises treating the compound of Formula (VII) with sodium hydroxide in ethanol.
19. The process of claim 16 , further comprising adding a dialkyl malonic ester to a compound of Formula (VIII)
to obtain the compound of Formula (VII).
20. The process of claim 19 wherein the dialkyl malonic ester is di-tert-butylmalonate or diethyl malonate.
21. The process of claim 19 , wherein the adding comprises contacting the dialkyl malonic ester with the compound of Formula (VIII) in the presence of lithium bromide/triethylamine.
22. The process of claim 19 , further comprising condensing trans-cinnamaldehyde (IX)
with methyl isobutyl ketone to form the compound of Formula (VIII).
23. The process of claim 22 , wherein the condensing comprises treating the methyl isobutyl ketone with the trans-cinnamaldehyde in the presence of sodium hydroxide in methanol.