PROCESS FOR THE PRODUCTION OF CANNABIDIOL AND DELTA-9-TETRAHYDROCANNABINOL
The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivatives thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivatives thereof.
1 . A process for the preparation of a compound of formula (I)
wherein
a is an integer from 0 to 3;
R 1 and R 2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl or heterocycle;
wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl;
wherein the aryl or heteroaryl, whether alone or as part of a sub stituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl;
R 3 is selected from the group consisting of H, alkyl, acyl, —SO 2 -alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR E R F , —S— alkyl, —SO-alkyl, —SO 2 -alkyl, aryl and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR G R H , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R G and R H are each independently selected from hydrogen and C 1-4 alkyl;
each represents a single or double bond; provided that both groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment;
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (II), wherein each X is independently selected from the group consisting of Br, F and Cl, with a compound of formula (III) wherein R 0 is H or OH, in the presence of a protic or first Lewis acid catalyst to form a compound of formula (IV);
then either (i) cyclizing the compound of formula (IV) by reacting the compound of formula (IV) with a second Lewis acid catalyst to form a compound of formula (V); and then
reacting the compound of formula (V) with a reducing agent to form the compound of formula (I)
or
(ii) reacting the compound of formula (IV) with a reducing agent to form a compound of formula (VI); and then
cyclizing the compound of formula (VI) by reacting the compound of formula (VI) with a second Lewis acid catalyst to form the compound of formula (I).
2 . The process of claim 1 wherein the process comprises cyclizing the compound of formula (IV) by reacting the compound of formula (IV) with a second Lewis acid catalyst to form a compound of formula (V); and then
reacting the compound of formula (V) with a reducing agent to form the compound of formula (I)
3 . The process of claim 1 wherein the process comprises reacting the compound of formula (IV) with a reducing agent to form a compound of formula (VI); and then
cyclizing the compound of formula (VI) by reacting the compound of formula (VI) with a second Lewis acid catalyst to form the compound of formula (I)
4 . The process of claim 1 for the preparation of a compound of formula (XI)
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (XII), wherein each X is independently selected from Br, F or Cl, with a compound of formula (XIII) in the presence of a protic or first Lewis acid catalyst to form a compound of formula (XIV);
cyclizing the compound of formula (XIV) by reacting the compound of formula (XIV) with a second Lewis acid catalyst to form a compound of formula (XV); and then
reacting the compound of formula (XV) with a reducing agent to form the compound of formula (XI)
5 . The process of claim 1 for the preparation of a compound of formula (XI)
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (XII), wherein each X is independently selected from Br, F or Cl, with a compound of formula (XIII) in the presence of a protic or first Lewis acid catalyst to for a compound of formula (XIV)
reacting the compound of formula (XIV) with a reducing agent to for a compound of formula (XVI); and then
cyclizing the compound of formula (XVI) by reacting the compound of formula (XVI) with a second Lewis acid catalyst to form the compound of formula (XI)
6 . The process of claim 1 wherein the compound of formula (I) is selected from the group consisting of ethyl cannabidiolate, delta-9-tetrahydrocannabidiol and delta-8-tetrahydrocannabidiol.
7 . The process of claim 1 wherein the protic or first Lewis acid catalyst is selected from the group consisting of p-toluene sulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, sulfuric acid, iron(II) chloride, scandium(III) triflate, zinc chloride, aluminum chloride and combinations thereof.
8 . The process of claim 1 wherein the second Lewis acid catalyst is selected from the group consisting of p-toluene sulfonic acid, BF 3 , diethyl etherate, BF 3 *AcOH, tri-isobutyl aluminum, and combinations thereof.
9 . The process of claim 1 wherein the reducing agent is a sulfur-containing compound.
10 . The process of claim 1 wherein the reduction occurs in a polar solvent.
11 . The process of claim 1 wherein the reduction occurs in the presence of an organic or weak inorganic base.
12 . A process for the preparation of a compound of formula (VI)
wherein
a is an integer from 0 to 3;
le and R 2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl or heterocycle;
wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl;
wherein the aryl or heteroaryl, whether alone or as part of a sub stituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl;
R 3 is selected from the group consisting of H, alkyl, acyl, —SO 2 -alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR E R F , —S—alkyl, —SO-alkyl, —SO 2 -alkyl, aryl and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR G R H , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R G and R H are each independently selected from hydrogen and C 1-4 alkyl;
each represents a single or double bond; provided that both groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment;
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (II), wherein each X is independently selected from the group consisting of Br, F and Cl, with a compound of formula (III) wherein R 0 is H or OH, in the presence of a protic or first Lewis acid catalyst to form a compound of formula (IV);
reacting the compound of formula (IV) with a reducing agent to form the compound of formula (VI); and
13 . The process of claim 12 for the preparation of a compound of formula (XVI)
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (XII), wherein each X is independently selected from Br, F or Cl, with a compound of formula (XIII) in the presence of a protic or first Lewis acid catalyst to form a compound of formula (XIV); and
reacting the compound of formula (XIV) with a reducing agent to form the compound of formula (XVI)
14 . The process of claim 12 for the preparation of a compound of formula (XX)
or a pharmaceutically acceptable salt or ester thereof;
the process comprises reacting a compound of formula (XXI), wherein each X is independently selected from Br, F or Cl, with a compound of formula (XIII) in the presence of a protic or first Lewis acid catalyst to form a compound of formula (XXII); and
reacting the compound of formula (XXII) with a reducing agent to form the compound of formula (XX)
15 . The process of claim 12 wherein the compound of formula (VI) is selected from the group consisting of cannibidiol, cannabidivarin or
16 . The process of claim 12 wherein the protic or first Lewis acid catalyst is selected from the group consisting of p-toluene sulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, sulfuric acid, iron(II) chloride, scandium(III) triflate, zinc chloride, aluminum chloride and combinations thereof.
17 . The process of claim 12 wherein the second Lewis acid catalyst is selected from the group consisting of p-toluene sulfonic acid, BF 3 , diethyl etherate, BF 3 *AcOH, tri-isobutyl aluminum, and combinations thereof.
18 . The process of claim 12 wherein the reducing agent is a sulfur-containing compound.
19 . The process of claim 12 wherein the reduction occurs in a polar solvent.
20 . The process of claim 12 wherein the reduction occurs in the presence of an organic or weak inorganic base.