PREPARATION OF PSILOCYBIN, DIFFERENT POLYMORPHIC FORMS, INTERMEDIATES, FORMULATIONS AND THEIR USE
This invention relates to the large-scale production of psilocybin for use in medicine. More particularly, it relates to a method of obtaining high purity crystalline psilocybin, particularly, in the form of Polymorph A. It further relates to a method for the manufacture of psilocybin and intermediates in the production thereof and formulations containing psilocybin.
1 - 28 . (canceled)
29 . A compound having the following structure:
30 . A pharmaceutical composition comprising a compound of claim 29 .
31 . Crystalline psilocybin having no single impurity greater than 1% prepared by recrystallization of psilocybin from water at a temperature not greater than about 80° C.
32 . The crystalline psilocybin of claim 31 , having less than 1% psilocin.
33 . The crystalline psilocybin of claim 31 , having less than 0.5% psilocin.
34 . The crystalline psilocybin of claim 31 , characterized by X-ray powder diffraction (XRPD) peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1 and 19.7±0.1 020.
35 . The crystalline psilocybin of claim 33 , further characterized by XRPD peaks at least one of 2θ4±0.1, 22.2±0.1, 24.3±0.1, or 25.7±0.1° 2θ.
36 . The crystalline psilocybin of claim 31 , wherein the crystalline psilocybin has a chemical purity of greater than 97%.
37 . The crystalline psilocybin of claim 31 , wherein the crystalline psilocybin has a chemical purity of greater than 98%.
38 . The crystalline psilocybin of claim 31 , wherein the crystalline psilocybin has a chemical purity of greater than 99%.
39 . The crystalline psilocybin of claim 31 , wherein the crystalline psilocybin has a melting point of about 2θ5° C. to about 220° C.
40 . A method for manufacturing crystalline psilocybin, the method comprising:
i) reacting psilocin with tetrabenzylpyrophosphate to form benzyl 3-[2-(benzyldimethylazaniumyl)ethyl]-1H-indol-4-yl phosphate;
ii) reacting the benzyl 3-[2-(benzyldimethylazaniumyl)ethyl]-1H-indol-4-yl phosphate with hydrogen in the presence of a catalyst to form psilocybin; and
iii) crystallizing the psilocybin from water at a temperature not greater than about 80° C. to obtain the crystalline psilocybin.
41 . The method of claim 31 , wherein crystalline psilocybin is characterized by X-ray powder diffraction (XRPD) peaks at 11.5±0.1, 12.0±0 0.1, 14.5±0.1, 17.5±0.1 and 19.7±0.1 020.
42 . The method of claim 41 , wherein the crystalline psilocybin is further characterized by XRPD peaks at least one of 20.4±0.1, 22.2±0.1, 24.3±0.1, or 25.7±0.1 020.
43 . The method of claim 41 , wherein the crystalline psilocybin has no single impurity greater than 1%.
44 . The method of claim 43 , wherein the crystalline psilocybin has less than 1% psilocin.
45 . The method of claim 43 , wherein the crystalline psilocybin has less than 0.5% psilocin.
46 . The method of claim 41 , wherein the crystalline psilocybin has a chemical purity of greater than 97%.
47 . The method of claim 41 , wherein the crystalline psilocybin has a chemical purity of greater than 98%.
48 . The method of claim 41 , wherein the crystalline psilocybin has a chemical purity of greater than 99%.
49 . The method of claim 41 , wherein the psilocin is prepared by a method comprising:
i) reacting 1H-indol-4-yl acetate with oxalyl chloride and dimethylamine to form 3-([(dimethylcarbamoyl)carbonyl])-1H-indol-4-yl acetate; and
ii) reacting the 3-([(dimethylcarbamoyl)carbonyl)-1H-indol-4-yl acetate with lithium aluminium hydride to form psilocin.