Methods of preparing synthetic cannabinol and homologs thereof
The present disclosure relates to the preparation of synthetic cannabinol and homologs thereof having the structure of Formula (I), wherein, n is 1, 2, 3 or 4. The methods described herein provide for high yields and purity in a one-pot synthesis or high yields and purity without the need for lengthy column chromatography. The present disclosure also relates to solid forms of cannabinol.
1. A method of preparing a compound of Formula I,
wherein, n is 1, 2, 3 or 4;
comprising,
contacting a compound of Formula II,
wherein,
n is 1, 2, 3 or 4; and
R 1 is an alkyl or aryl;
one of is a double bond, the other is a single bond;
with an oxidant, optionally in the presence of a first solvent, to prepare a compound of Formula III,
wherein,
n is 1, 2, 3 or 4; and
R 1 is an alkyl or aryl;
and,
contacting the compound of Formula III with a base in the presence of a second solvent to prepare a composition comprising a compound of Formula I.
2. The method of claim 1 , wherein n is 2 or 4.
3. The method of claim 2 , wherein n is 4.
4. The method of claim 1 , wherein R 1 is an optionally substituted straight or branched C 1-6 alkyl selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, neopentyl, or hexyl or an optionally substituted C 6-10 aryl selected from the group consisting of phenyl, indenyl, and napthalenyl.
5. The method of claim 4 , wherein said C 6-10 aryl is naphthalenyl.
6. The method of claim 1 , wherein said oxidant is present in an amount of about 1 equivalent to about 10 equivalents.
7. The method of claim 1 , wherein the method does not comprise separating a compound of Formula I by column chromatography.
8. The method of claim 7 , further comprising crystallizing a compound of Formula III, said crystallizing comprising, contacting the compound of Formula III with at least two crystallizing solvents to prepare a purified compound of Formula III.
9. The method of claim 8 , wherein said purified compound of Formula III has a purity (AUC) of at least 80%.
10. The method of claim 8 , wherein said at least two crystallizing solvents are selected from the group consisting of methanol, ethanol, isopropanol, acetone.
11. The method of claim 10 , wherein said solvents are acetone and methanol.
12. The method of claim 10 , wherein said solvents are in a ratio of about 1:1.
13. The method of claim 8 , wherein:
n is 4;
R 1 is
wherein
is the point of attachment to the carbonyl;
said first solvent is present and is toluene;
said contacting a compound of Formula II is at reflux;
said method further comprising:
filtering said compound of Formula III to prepare a first solid;
contacting said first solid with acetone (about 1 volume) and heating to about 55° C. to form a first solution;
contacting said first solution with MeOH (about 2 volumes), and heating to about 58° C. to form a second solution;
allowing said second solution to cool to about 20° C. to prepare a second solid;
filtering said second solid to prepare a filtered second solid and a filtrate;
preparing a third solid from said filtrate and re-crystallizing from acetone/methanol (about 1:1) to prepare a fourth solid;
combining said filtered second solid and said fourth solid and re-crystallizing from acetone/methanol (about 2:1) to prepare a purified compound of Formula III from said combined solids.
14. The method of 13 , where said contacting the compound of Formula III with a base, comprises:
contacting the purified compound of Formula III with LiOH to prepare a compound of Formula I, having the structure:
15. The method of claim 1 , wherein said method is a one-pot preparation of a compound of Formula I.
16. The method of claim 15 , further comprising a fractional distillation of said composition comprising a compound of Formula I to prepare a purified compound of Formula I.
17. The method of claim 16 , wherein said compound of Formula I has a purity (AUC) of at least 99%.