US 11,717,498 B2
Methods of treatment using amphetamine controlled release, prodrug, and abuse deterrent dosage forms
Karl Popp, Schodack Landing, NY (US); and Harold Meckler, Delmar, NY (US)
Assigned to Pharmapotheca A, Inc., Delmar, NY (US); and Chemapotheca, LLC, Delmar, NY (US)
Filed by CHEMAPOTHECA, LLC, Delmar, NY (US)
Filed on Oct. 9, 2020, as Appl. No. 17/66,488.
Application 15/062,872 is a division of application No. 14/189,630, filed on Feb. 25, 2014, granted, now 9,278,904, issued on Mar. 8, 2016.
Application 17/066,488 is a continuation of application No. 16/941,534, filed on Jul. 29, 2020, abandoned.
Application 16/941,534 is a continuation of application No. PCT/US2017/019285, filed on Feb. 24, 2017.
Application PCT/US2017/019285 is a continuation of application No. 15/441,424, filed on Feb. 24, 2017, granted, now 11,123,310.
Application 15/441,424 is a continuation in part of application No. 15/062,872, filed on Mar. 7, 2016, granted, now 9,657,041, issued on May 23, 2017.
Claims priority of provisional application 62/299,108, filed on Feb. 24, 2016.
Claims priority of provisional application 61/922,729, filed on Dec. 31, 2013.
Prior Publication US 2021/0030699 A1, Feb. 4, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/137 (2006.01); A61K 47/64 (2017.01); A61K 9/50 (2006.01); A61K 47/54 (2017.01); A61K 9/20 (2006.01); A61K 9/28 (2006.01)
CPC A61K 31/137 (2013.01) [A61K 9/2031 (2013.01); A61K 9/2866 (2013.01); A61K 9/5026 (2013.01); A61K 9/5047 (2013.01); A61K 47/542 (2017.08); A61K 47/64 (2017.08)] 32 Claims
 
1. A process for preparing a drug substance comprising the steps of:
(i) providing a substituted amphetamine or a pharmaceutically acceptable salt, solvate, or mixture of two or more thereof, as an active pharmaceutical ingredient, wherein the substituted amphetamine comprises not more than 0.1% by weight of amphetamine-process related impurity,
wherein the substituted amphetamine is produced by a process that comprises the steps of performing a stereospecific cuprate addition reaction upon an aziridine phosphoramidate compound to obtain a aryl or aryl-alkyl phosphoramidate amphetamine precursor, and deprotecting the aryl or aryl-alkyl phosphoramidate amphetamine precursor under acidic conditions effective to produce a substituted amphetamine,
wherein the substituted amphetamine is selected from the group consisting of: dex-amphetamine, dex-N-methylamphetamine, and dex-N-ethylamphetamine, and a racemic mixture of amphetamine isomers, wherein the dex-amphetamine, dex-N-methylamphetamine, dex-N-ethylamphetamine, and racemic mixture of amphetamine isomers is made according to the process comprising the steps 1a and 2a:
(1a) providing a compound of Formula 5:

OG Complex Work Unit Chemistry
wherein R is alkyl or aryl; and
(2a) deprotecting the compound of Formula 5 under acidic conditions effective to produce (2S)-1-phenylpropan-2-amine of Formula I:

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and wherein the racemic mixture of amphetamine isomers is made according to the process comprising the steps 1b and 2b:
(1b) providing a compound of Formula 6:

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wherein R is alkyl or aryl; and
(2b) deprotecting the compound of Formula 6 under acidic conditions effective to produce a racemic mixture of amphetamine isomers of Formula 7:

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further comprising the step of formulating the drug substance with one or more excipients to produce a pharmaceutical composition
wherein the regioisomeric purity of Formula 5 is >99% and the regioisomer is <0.1%.