US 12,006,275 B2
Process for making levoamphetamine
Harold Meckler, Delmar, NY (US); Praveen Suryadevara, Raleigh, NC (US); Marcus Brackeen, Raleigh, NC (US); and Darryl Cleary, Raleigh, NC (US)
Assigned to Pharmapotheca A, Inc., Wilmington, DE (US)
Appl. No. 17/435,881
Filed by CHEMAPOTHECA, LLC, Delmar, NY (US)
PCT Filed Mar. 2, 2020, PCT No. PCT/US2020/020713
§ 371(c)(1), (2) Date Sep. 2, 2021,
PCT Pub. No. WO2020/180825, PCT Pub. Date Sep. 10, 2020.
Claims priority of provisional application 62/813,033, filed on Mar. 2, 2019.
Prior Publication US 2022/0162153 A1, May 26, 2022
Int. Cl. C07C 209/62 (2006.01); C07C 209/86 (2006.01); C07F 9/22 (2006.01); C07F 9/564 (2006.01); G01N 33/94 (2006.01)
CPC C07C 209/62 (2013.01) [C07C 209/86 (2013.01); C07F 9/222 (2013.01); C07F 9/564 (2013.01); G01N 33/946 (2013.01)] 20 Claims
 
1. A process of making levoamphetamine sulfate, said process comprising:
preparing an in situ phenyl magnesium bromide from a reaction of bromobenzene with magnesium in the presence of catalytic diisobutyl aluminum hydride (DIBAL) in tetrahydrofuran (THF) refluxing at a temperature of 60 deg Celsius;
reacting a compound of Formula 4

OG Complex Work Unit Chemistry
with the in situ phenyl magnesium bromide and a copper catalyst under solvent and temperature conditions effective to produce a compound of Formula 5 having a regioisomeric purity >99%:

OG Complex Work Unit Chemistry
wherein R is alkyl or aryl; and
deprotecting the compound of Formula 5 at a temperature of 80 deg Celsius and under acidic conditions effective to produce levoamphetamine free base

OG Complex Work Unit Chemistry
and then levoamphetamine sulfate of Formula I:

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wherein the solvent conditions for preparing the compound of Formula 5 comprise a crystallization step requiring a mixture of two or more solvents, wherein one of the two or more solvents is residue THF.