Analogs of Cannabichromene and Cannabichromenic Acid and Process of Preparing

A single enantiomer compound of structure (S)-7 or (R)-7 or a scalemic mixture thereof:

• wherein:
• RA is H;
• RB is selected from the group consisting of H, methyl, ethyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups;
• n-propyl or n-hexyl substituted by one or two hydroxyl groups or substituted by one or more fluoro-groups;
• branched C3 to C10 alkyl optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups or double branched C4 to C10 alkyl substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups;
• (CH2)o—C3 to C6 cycloalkyl, (CH2)p—ORF, and C3 to C6 cycloalkyl, optionally substituted by a C1 to C8 alkyl;
• o is selected from 0, 1, 2, 3, 4, 5 and 6;
• p is selected from 1, 2, 3, 4, 5 and 6;
• RF is C1 to C6 alkyl or (CH2)r—C3 to C6 cycloalkyl;
• r is selected from 0, 1, 2, 3, 4, 5 and 6;
• or
• RA is selected from the group consisting of CO2H and its pharmaceutically acceptable salts or co-crystals, CO2RC, CONHRD, and CONRDRE;
• RB is selected from the group consisting of H, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups;
• branched C3 to C10 alkyl or double branched C4 to C10 alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups;
• (CH2)o—C3 to C6 cycloalkyl, (CH2)p—ORF, and C3 to C6 cycloalkyl, optionally substituted by a C1 to C8 alkyl;
• o is selected from 0, 1, 2, 3, 4, 5 and 6;
• p is selected from 1, 2, 3, 4, 5 and 6;
• RC is selected from the group consisting of C1 to C6 alkyl, (CH2)q—C3 to C6 cycloalkyl, allyl, optionally substituted benzyl and optionally substituted 2-phenylethyl;
• q is selected from 0, 1, 2, 3, 4, 5 and 6;
• RD is selected from the group consisting of C1 to C6 alkyl, (CH2)r—C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, optionally substituted 2-phenylethyl;
• and RE is selected from the group consisting of C1 to C6 alkyl, (CH2)r—C3 to C6 cycloalkyl, allyl, optionally substituted benzyl and optionally substituted 2-phenylethyl;
• or NRDRE is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl, each optionally substituted by one or two hydroxyl groups or one hydroxymethyl group, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine;
• RF is C1 to C6 alkyl or (CH2)r—C3 to C6 cycloalkyl;
• and
• r is selected from 0, 1, 2, 3, 4, 5 and 6,
• with the proviso that each hydroxyl group in RB cannot be on the carbon bearing a fluoro group or a second hydroxyl group.

An intermediate compound of structure 9:

• wherein:
• RB is selected from the group consisting of H, protected hydroxymethyl, linear C2 to C10 alkyl optionally substituted by one or two protected hydroxyl groups or optionally substituted by one or more fluoro-groups, branched C3 to C10 alkyl optionally substituted by one or two protected hydroxyl groups or optionally substituted by one or more fluoro-groups, double branched C4 to C10 alkyl optionally substituted by one or two protected hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH2)o—C3 to C6 cycloalkyl, (CH2)p—ORF, and C3 to C6 cycloalkyl optionally substituted by a C1 to C8 alkyl;
• o is selected from 0, 1, 2, 3, 4, 5 and 6;
• p is selected from 1, 2, 3, 4, 5 and 6;
• RF is C1 to C6 alkyl or (CH2)r—C3 to C6 cycloalkyl;
• Rα is C1 to C6 alkyl or optionally substituted aryl;
• and
• Rβ is C1 to C6 alkyl or optionally substituted aryl;
• with the proviso that each protected hydroxyl group in RB cannot be on the carbon bearing a fluoro group or a second protected hydroxyl group.