Process for the preparation of lisdexamfetamine and related derivatives
Inventors
Goudriaan, Pietertje Elisabeth • Kaiser, Jasper • Ibrahim, Hemen • Verspui, Govert Arie • Cox, Douglas Phillip
Assignees
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Publication Number
US-10544434-B2
Publication Date
2020-01-28
Expiration Date
Abstract
The present invention is directed to processes for the preparation of lisdexamfetamine and related derivatives, wherein the processes comprise coupling to racemic or enantiomerically enriched amphetamine and wherein the resulting product is advantageously enantiomerically or diastereomerically enriched in the desired stereoisomer.
Core Innovation
The invention relates to processes for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, including lisdexamfetamine and salts such as dimesylate, by reacting protected precursors with racemic compounds and then de-protecting. The process uses enzyme catalysis to obtain enantiomeric excess in the intermediate and diastereomeric excess in the product.
In one aspect, a compound of formula (V), wherein the protecting groups include tert-butoxycarbonyl (BOC), is reacted with a racemic compound of formula (VI) to yield a compound of formula (VII), followed by de-protecting to yield the corresponding compound of formula (I). The enzyme catalyst is an immobilized S-selective protease enzyme derived from Bacillus lichenformis, and the reaction is carried out neat or in a solvent or in a mixture of solvents, including acetonitrile.
The document additionally includes processes for preparing diastereomerically enriched compounds of formula (XX) or pharmaceutically acceptable salts thereof, including compounds where R4 is an amino acid radical and the amino acid is lysine. These processes use an immobilized R-selective protease enzyme derived from Bacillus lichenformis to react intermediates of formula (XXIa) or formula (XXIb) with racemic compound of formula (XII), followed by de-protecting to yield the corresponding compound of formula (XX).
Claims Coverage
The consolidated content includes four independent claims. The inventive scope centers on immobilized Bacillus lichenformis-derived protease enzymes in S-selective or R-selective form, racemic partner compounds, de-protection, and stereochemical enrichment expressed as enantiomeric excess and/or diastereomeric excess.
S-selective immobilized protease enzyme coupling to form formula (I)
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, reacting a BOC-protected compound of formula (V) with a racemic compound of formula (VI) in the presence of an S-selective enzyme catalyst that is an immobilized S-selective protease enzyme derived from Bacillus lichenformis, to yield formula (VII), then de-protecting to yield formula (I), wherein formula (VII) is present in an enantiomeric excess and formula (I) is present in a diastereomeric excess.
Dimesylate salt formation with immobilized S-selective protease
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, including reacting a compound of formula (V) with a racemic compound of formula (VI) in acetonitrile in the presence of an S-selective immobilized S-selective protease enzyme derived from Bacillus lichenformis, to yield formula (VII), de-protecting to yield formula (I), and reacting formula (I) with methanesulfonic acid to yield a dimesylate salt, wherein the dimesylate salt is present in a diastereomeric excess.
R-selective immobilized protease enzyme coupling to form formula (XX)
A process for preparing a diastereomerically enriched compound of formula (XX) or a pharmaceutically acceptable salt thereof, reacting a compound of formula (XXIa) with a racemic compound of formula (XII) in the presence of an R-selective enzyme catalyst that is an immobilized R-selective protease enzyme derived from Bacillus lichenformis, to yield the corresponding compound of formula (XX), wherein formula (XX) is present in an enantiomeric excess.
BOC-protected lysine precursor with R-selective immobilized protease and de-protection to formula (XX)
A process for preparing a diastereomerically enriched compound of formula (XX) or a pharmaceutically acceptable salt thereof, reacting a compound of formula (XXIb) wherein the amino acid is lysine and the nitrogen protecting group is tert-butoxycarbonyl (BOC), with a racemic compound of formula (XII) in the presence of an R-selective enzyme catalyst that is an immobilized R-selective protease enzyme derived from Bacillus lichenformis, to yield formula (XXIII) present in an enantiomeric excess, and then de-protecting formula (XXIII) to yield formula (XX) present in an enantiomeric excess.
The claims cover enzyme-catalyzed processes using racemic precursors and immobilized Bacillus lichenformis-derived proteases with specified S-selective or R-selective enzyme action. The claims further require intermediate enantiomeric enrichment and subsequent de-protection to give the final products with the stated stereochemical enrichment.
Stated Advantages
Provides a rationale for cost/handling advantages versus prior art.
Improved impurity profile with reduced N-hydroxysuccinimide impurity and reduced peptide coupling byproducts.
Documented Applications
Medicinal use indications are described, including attention deficit hyperactivity disorder (ADHD), major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness, and binge eating disorder.
Treatment and prevention concepts are discussed in the document.
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