Claims for Patent: 10,647,649

Summary for Patent: 10,647,649

Title:	Process for preparing tapinarof
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.
Inventor(s):	Andrews; Ian Paul (King of Prussia, PA), Calandra; Nicholas (Cambridge, MA), Davis; Tyler Andrew (Research Triangle Park, NC), Sudini; Ravinder Reddy (King of Prussia, PA)
Assignee:	DERMAVANT SCIENCES GMBH (Basel, CH)
Application Number:	16/189,268
Patent Claims:	1. A process for preparing a compound of Formula (I) or a salt or solvate thereof ##STR00163## comprising: a) decarboxylating a compound of Formula (VI) or a salt thereof ##STR00164## to form a compound of Formula (V) or a salt thereof ##STR00165## b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof ##STR00166## wherein R is C.sub.1-4 alkyl; c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof ##STR00167## d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof ##STR00168## 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. 2. The process of claim 1, further comprising f) purifying the compound of Formula (I) obtained from step e) by crystallization. 3. The process of claim 1 wherein R in step (b) is methyl and X in step (d) is chloro. 4. The process of claim 1, wherein the compound of Formula (VI) or a salt thereof is prepared by a process comprising: i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof ##STR00169## ii. adding a dialkyl malonic ester of the Formula R.sub.1(O)C--CH.sub.2--C(O)OR.sub.2, wherein each of R.sub.1 and R.sub.2 is independently C.sub.1-4 alkyl, to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VII) or a salt thereof ##STR00170## wherein each of R.sub.1 and R.sub.2 is as defined for the dialkyl malonic ester; iii. hydrolyzing the compound of Formula (VII) or a salt thereof to form the compound of Formula (VI) or a salt thereof. 5. The process of claim 4, wherein each of R.sub.1 and R.sub.2 is independently ethyl. 6. A process for preparing a compound of Formula (I) or a salt or solvate thereof ##STR00171## comprising: a) heating a compound of Formula (VI) ##STR00172## with catalytic triethylamine to form a compound of Formula (V) ##STR00173## b) heating the compound of Formula (V) with methanol and aqueous hydrochloric acid to form a compound of Formula (IVa) ##STR00174## c) treating a cooled solution of the compound of Formula (IVa) with potassium tert-butoxide to form a compound of Formula (III) ##STR00175## d) heating the compound of Formula (III) with 1, 3-dichloro-5,5-dimethylhydantoin to form a compound of Formula (IIa) ##STR00176## and e) heating the compound of Formula (IIa) with tetraethylammonium chloride to form the compound of Formula (I). 7. The process of claim 6, further comprising f) purifying the compound of Formula (I) from step e) by crystallization. 8. The process of claim 6, wherein the compound of Formula (VI) is prepared by a process comprising: i. treating methyl isobutyl ketone with trans-cinnamaldehyde in the presence of methanolic sodium hydroxide to form a compound of Formula (VIII) ##STR00177## ii. treating the compound of Formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of Formula (VIIa) ##STR00178## iii. hydrolyzing the compound of Formula (VIIa) with sodium hydroxide and ethanol to obtain the compound of Formula (VI). 9. A process for preparing a compound of Formula (VI) or a salt thereof ##STR00179## comprising: a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof ##STR00180## 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 ##STR00181## and c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof. 10. A process for preparing a compound of Formula (V) or a salt thereof ##STR00182## comprising decarboxylating a compound of Formula (VI) or a salt thereof ##STR00183## in the presence of a base, to form the compound of Formula (V) or a salt thereof. 11. The process of claim 10, wherein the compound of Formula (VI) or a salt thereof is prepared by a process comprising: i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof ##STR00184## ii. adding diethyl malonate to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VIIa) or a salt thereof ##STR00185## and iii. hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof. 12. A process for preparing a compound of Formula (IVa) or a salt thereof, ##STR00186## comprising esterifying a compound of Formula (V) or a salt thereof, ##STR00187## to form the compound of Formula (IVa) or a salt thereof. 13. The process of claim 12 wherein the compound of Formula (V) or a salt thereof, is prepared by a process comprising decarboxylating a compound of Formula (VI), or a salt thereof, ##STR00188## in the presence of a base, to form the compound of Formula (V) or a salt thereof. 14. The process of claim 13, wherein the compound of Formula (VI) or a salt thereof, is prepared by a process comprising: i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof, ##STR00189## ii. adding diethyl malonate to the compound of Formula (VIII) or a salt thereof, to form a compound of Formula (VIIa) or a salt thereof, ##STR00190## and iii. hydrolyzing the compound of Formula (VIIa) or a salt thereof, to form the compound of Formula (VI) or a salt thereof. 15. A process for preparing a compound of Formula (IIa) or a salt thereof, ##STR00191## comprising halogenating a compound of Formula (III) or a salt thereof, ##STR00192## to form the compound of Formula (IIa) or a salt thereof. 16. The process of claim 15 wherein the compound of Formula (III) or a salt thereof, is prepared by a process comprising cyclizing a compound of Formula (IVa) or a salt thereof, ##STR00193## to form the compound of Formula (III) or a salt thereof. 17. The process of claim 16, wherein the compound of Formula (IVa) or a salt thereof, is prepared by a process comprising esterifying a compound of Formula (V) or a salt thereof, ##STR00194## to form the compound of Formula (IVa) or a salt thereof. 18. The process of claim 17, wherein the compound of Formula (V) or a salt thereof, is prepared by a process comprising decarboxylating a compound of Formula (VI) or a salt thereof ##STR00195## in the presence of a base, to form the compound of Formula (V) or a salt thereof. 19. The process of claim 18, wherein the compound of Formula (VI) or a salt thereof, is prepared by a process comprising i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof, ##STR00196## ii. adding diethyl malonate to the compound of Formula (VIII) or a salt thereof, to form a compound of Formula (VIIa) or a salt thereof, ##STR00197## and iii. hydrolyzing the compound of Formula (VIIa) or a salt thereof, to form the compound of Formula (VI) or a salt thereof. 20. A compound of Formula (I) or a salt or solvate thereof ##STR00198## 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 2.theta. (.+-.0.1.degree. 2.theta.); prepared by a process comprising: a) decarboxylating a compound of Formula (VI) or a salt thereof ##STR00199## to form a compound of Formula (V) or a salt thereof ##STR00200## b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof ##STR00201## wherein R is C.sub.1-4 alkyl; c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof ##STR00202## d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof ##STR00203## 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. 21. A compound of Formula (VI) or a salt thereof ##STR00204## 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 ##STR00205## 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 ##STR00206## and c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof. 22. A compound of Formula (V) or a salt thereof ##STR00207## 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 ##STR00208## 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 ##STR00209## c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof ##STR00210## 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. 23. A compound of Formula (IVa) or a salt thereof ##STR00211## 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 ##STR00212## 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 ##STR00213## c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof ##STR00214## 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 ##STR00215## and e) esterifying a compound of Formula (V) or a salt thereof to form the compound of Formula (IVa) or a salt thereof. 24. A compound of Formula (IIa) or a salt thereof ##STR00216## 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 ##STR00217## 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 ##STR00218## c) hydrolyzing the compound of Formula (VIIa) or a salt thereof to form the compound of Formula (VI) or a salt thereof ##STR00219## 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 ##STR00220## e) esterifying a compound of Formula (V) or a salt thereof to form the compound of Formula (IVa) or a salt thereof ##STR00221## f) cyclizing a compound of Formula (IVa) or a salt thereof to form the compound of Formula (III) or a salt thereof ##STR00222## and g) halogenating a compound of Formula (III) or a salt thereof to form the compound of Formula (IIa) or a salt thereof. 25. A compound of Formula (I) ##STR00223## in the form of an acetic acid solvate thereof. 26. The compound of claim 25, characterized by an X-ray powder diffraction pattern having peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2.theta. (.+-.0.1.degree. 2.theta.). 27. A compound of Formula (I) ##STR00224## 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 2.theta. (.+-.0.1.degree. 2.theta.). 28. A compound of Formula (IIa) or a salt thereof ##STR00225## 29. A compound of Formula (IVa) or a salt thereof ##STR00226## 30. A compound of Formula (V) or a salt thereof ##STR00227## 31. A compound of Formula (VI) or a salt thereof ##STR00228## 32. A pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I) ##STR00229## 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 2.theta. (.+-.0.1.degree. 2.theta.); and a pharmaceutically acceptable excipient. 33. A pharmaceutical composition comprising a therapeutically effective amount of an acetic acid solvate of the compound of Formula (I) ##STR00230## and a pharmaceutically acceptable excipient. 34. A compound of Formula (I) or a salt or solvate thereof ##STR00231## 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 2.theta. (.+-.0.1.degree. 2.theta.); prepared by a process comprising: a) decarboxylating a compound of Formula (VI) or a salt thereof ##STR00232## to form a compound of Formula (V) or a salt thereof ##STR00233## b) esterifying the compound of Formula (V) or a salt thereof to form a compound of Formula (IV) or a salt thereof ##STR00234## wherein R is C.sub.1-4 alkyl; c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof ##STR00235## d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof ##STR00236## 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. 35. The compound of claim 20, wherein the compound is about 96% form 1. 36. The compound of claim 20, wherein the compound is about 97% form 1. 37. The compound of claim 20, wherein the compound is about 98% form 1. 38. The compound of claim 20, wherein the compound is about 99% form 1. 39. The compound of claim 20, wherein the compound is at least 99% form 1. 40. The compound of claim 34, wherein the compound is about 96% form 1. 41. The compound of claim 34, wherein the compound is about 97% form 1. 42. The compound of claim 34, wherein the compound is about 98% form 1. 43. The compound of claim 34, wherein the compound is about 99% form 1. 44. The compound of claim 34, wherein the compound is at least 99% form 1. 45. A compound of Formula (I) ##STR00237## 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 2.theta. (.+-.0.1.degree. 2.theta.). 46. The compound of claim 27, wherein the compound is about 96% form 1. 47. The compound of claim 27, wherein the compound is about 97% form 1. 48. The compound of claim 27, wherein the compound is about 98% form 1. 49. The compound of claim 27, wherein the compound is about 99% form 1. 50. The compound of claim 27, wherein the compound is at least 99% form 1. 51. The compound of claim 45, wherein the compound is about 96% form 1. 52. The compound of claim 45, wherein the compound is about 97% form 1. 53. The compound of claim 45, wherein the compound is about 98% form 1. 54. The compound of claim 45, wherein the compound is about 99% form 1. 55. The compound of claim 45, wherein the compound is at least 99% form 1. 56. A pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I) ##STR00238## 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 2.theta. (.+-.0.1.degree. 2.theta.); and a pharmaceutically acceptable excipient. 57. The pharmaceutical composition of claim 32, wherein the compound is about 96% form 1. 58. The pharmaceutical composition of claim 32, wherein the compound is about 97% form 1. 59. The pharmaceutical composition of claim 32, wherein the compound is about 98% form 1. 60. The pharmaceutical composition of claim 32, wherein the compound is about 99% form 1. 61. The compound of claim 32, wherein the compound is at least 99% form 1. 62. The pharmaceutical composition of claim 56, wherein the compound is about 96% form 1. 63. The pharmaceutical composition of claim 56, wherein the compound is about 97% form 1. 64. The pharmaceutical composition of claim 56, wherein the compound is about 98% form 1. 65. The pharmaceutical composition of claim 56, wherein the compound is about 99% form 1. 66. The compound of claim 56, wherein the compound is at least 99% form 1.