US 12,084,417 B2
Synthesis of N,N-dimethyltryptamine-type compounds, methods, and uses
Peter Rands, London (GB); George Knight, London (GB); Richard Chubb, London (GB); Derek Londesbrough, London (GB); Tiffanie Benway, London (GB); and Zelah Joel, London (GB)
Assigned to CYBIN UK LTD, London (GB)
Filed by CYBIN UK LTD, London (GB)
Filed on Mar. 31, 2023, as Appl. No. 18/193,866.
Application 18/193,866 is a continuation of application No. 17/412,828, filed on Aug. 26, 2021, granted, now 11,643,390.
Application 17/412,828 is a continuation of application No. PCT/EP2020/081503, filed on Nov. 9, 2020.
Claims priority of application No. 1916210 (GB), filed on Nov. 7, 2019; application No. 1917320 (GB), filed on Nov. 28, 2019; and application No. 2008303 (GB), filed on Jun. 2, 2020.
Prior Publication US 2023/0250059 A1, Aug. 10, 2023
Int. Cl. C07D 209/16 (2006.01); C07D 209/20 (2006.01)
CPC C07D 209/16 (2013.01) [C07D 209/20 (2013.01); C07B 2200/05 (2013.01)] 19 Claims
 
1. A method of synthesising a compound of formula III, or a pharmaceutically acceptable salt thereof,

OG Complex Work Unit Chemistry
wherein each xH is independently selected from protium and deuterium, and at least one xH is deuterium,
n is selected from 0, 1, 2, 3 or 4,
R1 is independently selected from —R3, —OR3, —O(CO)R3, —F, —Cl, —Br or —I, and
R2 and R3 are independently selected from C1-C4alkyl,
the method comprising:
reacting a compound of formula I

OG Complex Work Unit Chemistry
with two or more coupling agents to produce an activated compound, the two or more coupling agents comprising:
a carbodiimide selected from the group consisting of diisopropylcarbodiimide (DIC), (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) and 1-cyclohexyl-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate (CMCT), and
an additive coupling agent selected from the group consisting of 1-hydroxybenzotriazole, hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide, 1-hydroxy-7-aza-1H-benzotriazole, ethyl 2-cyano-2-(hydroximino)acetate and 4-(N,N-Dimethylamino)pyridine;
reacting the activated compound with an amine having the formula (R2)2NH to produce a compound of formula II;

OG Complex Work Unit Chemistry
reacting the compound of formula II with about 1.8 equivalents of solid LiAlD4 or LiAlH4/LiAlD4 mixture to produce a compound of Formula III; and
optionally reacting the compound of Formula III with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of Formula III.