US 12,264,143 B2
Synthesis of cannabinoids and cannabinoid precursors, and related compounds, formulations, and methods of use
Glenn M. Sammis, Vancouver (CA); and Markus Roggen, Vancouver (CA)
Assigned to Nalu Bio, Inc., San Francisco, CA (US)
Filed by Nalu Bio, Inc., San Francisco, CA (US)
Filed on Jun. 21, 2024, as Appl. No. 18/750,852.
Application 18/750,852 is a continuation of application No. 18/212,061, filed on Jun. 20, 2023.
Application 18/212,061 is a continuation in part of application No. PCT/US2021/064243, filed on Dec. 17, 2021.
Claims priority of provisional application 63/126,923, filed on Dec. 17, 2020.
Prior Publication US 2024/0368108 A1, Nov. 7, 2024
Int. Cl. C07D 311/80 (2006.01); A61K 31/00 (2006.01); C07C 39/23 (2006.01); C07C 215/50 (2006.01); C07D 311/78 (2006.01)
CPC C07D 311/80 (2013.01) [A61K 31/658 (2023.05); C07C 39/23 (2013.01); C07C 215/50 (2013.01); C07D 311/78 (2013.01)] 12 Claims
 
1. A method for synthesizing a cannabinoid, wherein the method comprises:
(a) reacting an optionally substituted phloroglucinol reactant having the structure

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with an electron-withdrawing hydroxyl-protecting reagent under conditions effective to provide a first intermediate comprising a hydroxyl-protected compound having the structure

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wherein n is zero, 1 or 2; R2 is selected from C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkoxyalkyl, C1-C12 alkylsulfanyl, C2-C12 acyl, C2-C12 acyloxy, C2-C12 alkoxycarbonyl, C6-C18 aryloxycarbonyl, carboxyl, and halo; and PR is a hydroxyl-protecting group;
(b) effecting a cross-coupling reaction between the first intermediate and a reactant R1-M in a solvent in the presence of a cross-coupling catalyst, wherein:
R1 is selected from C1-C12 alkyl; (C1-C8 alkoxy)-substituted C1-C12 alkyl; C1-C12 alkyl substituted with N (C1-C8 alkyl)2; C1-C12 alkyl substituted with C1-C8 alkylsulfonyl (—SO2-alkyl); and C1-C12 alkyl substituted with oxanyl, morpholino, or diazinanyl, and
M is selected from —Zn—X, —B(OH)2, —B(OR)2, —MgX and —CuLi in which X is halo and R is alkyl, thereby providing a second intermediate in which a protected hydroxyl group has been replaced with R1, the second intermediate having the structure

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(c) hydrolyzing the second intermediate to remove the hydroxyl-protecting groups, thereby providing an R1-substituted deprotected compound as a third intermediate having the

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(d) contacting the R1-substituted deprotected compound with a substituted cyclohexene reactant having the structure

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wherein R5 is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo; R8 is methyl, hydroxymethyl, or halomethyl; and L is a leaving group, in the presence of a Lewis acid catalyst under reaction conditions effective to result in coupling of the R1-substituted deprotected intermediate and the substituted cyclohexene reactant to provide a reaction product composition comprising a cannabinoid having the structure

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