Process for preparing tapinarof

1. 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 C 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

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.

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

ii. adding a dialkyl malonic ester of the Formula R 1 (O)C—CH 2 —C(O)OR 2 , wherein each of R 1 and R 2 is independently C 1-4 alkyl, to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VII) or a salt thereof

wherein each of R 1 and R 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 1 and R 2 is independently ethyl.

6. 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).

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)

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)

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

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.

10. 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.

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

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

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,

comprising esterifying a compound of Formula (V) or a salt thereof,

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,

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,

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,

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,

comprising halogenating a compound of Formula (III) or a salt thereof,

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,

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,

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

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,

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,

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

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 C 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

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.

21. 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.

22. 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.

23. 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.

24. 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.

25. A compound of Formula (I)

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 2θ (±0.1° 2θ).

27. 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).

28. A compound of Formula (IIa) or a salt thereof

29. A compound of Formula (IVa) or a salt thereof

30. A compound of Formula (V) or a salt thereof

31. A compound of Formula (VI) or a salt thereof

32. 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.

33. A pharmaceutical composition comprising a therapeutically effective amount of an acetic acid solvate of the compound of Formula (I)

and a pharmaceutically acceptable excipient.

34. 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 C 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

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.

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)

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).

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)

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.

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.