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US 10,544,434 B2Granted
Process for the preparation of lisdexamfetamine and related derivatives
AssigneeNoramco, Inc.
InventorsPietertje Elisabeth Goudriaan, Jasper Kaiser, Hemen Ibrahim, Govert Arie Verspui, Douglas Phillip Cox
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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.
Claims29
A process for the preparation of a compound of formula (I)
- or a pharmaceutically acceptable salt thereof;
- comprising the steps of
- reacting a compound of formula (V), wherein
- PG1 and PG2 are each tert-butoxycarbonyl (BOC), wherein A1 is selected from the group consisting of C1-12 alkyl, with a compound of formula (VI);
- wherein the compound of formula (VI) is racemic;
- in the presence of an S-selective enzyme catalyst;
- wherein the S-selective enzyme catalyst is an immobilized S-selective protease enzyme derived from Bacillus lichenformis;
- neat or in a solvent or in a mixture of solvents;
- to yield the corresponding compound of formula (VII);
- wherein the compound of formula (VII) is present in an enantiomeric excess;
- de-protecting the compound of formula (VII), to yield the corresponding compound of formula (I);
- wherein the compound of form6ula (I) is present in a diastereomeric excess.
9 more elements
A process for the preparation of a compound of formula (I)
- or a pharmaceutically acceptable salt thereof;
- comprising the steps of
- reacting a compound of formula (V), wherein PG1 is a first nitrogen protecting group, wherein PG2 is a second nitrogen protecting group, wherein PG1 and PG2 are the same, wherein PG1 and PG2 are each Boc, and wherein A1 is methyl;
- with a compound of formula (VI);
- wherein the compound of formula (VI) is racemic;
- and wherein the compound of formula (VI) is present in an amount of about 5 molar equivalents;
- in the presence of a S-selective enzyme catalyst;
- wherein the S-selective enzyme catalyst is an immobilized S-selective protease enzyme catalyst derived from Bacillus lichenformis;
- and wherein the S-selective enzyme catalyst is present in an amount in the range of from about 50 wt % to about 200 wt %, relative to the amount of the compound of formula (V);
- in an organic solvent;
- wherein the organic solvent is acetonitrile;
- and wherein the acetonitrile is present in an amount in the range of from about 2:1 vol:vol to about 15:1 vol:vol ratio, relative to the amount of the compound of formula (VI);
- at a temperature in the range of from about 30° C. to about 45° C.;
- to yield the corresponding compound of formula (VII);
- wherein the compound of formula (VII) is present in a diastereomeric excess;
- de-protecting the compound of formula (VII), to yield the corresponding compound of formula (I);
- wherein the compound of formula (I) is present in a diastereomeric excess;
- reacting the compound of formula (I) with methanesulfonic acid;
- to yield the corresponding dimesylate salt;
- wherein the dimesylate salt of the compound of formula (I) is present in a diastereomeric excess.
17 more elements
A process for the preparation of a diastereomerically enriched compound of formula (XX)
- wherein
- R1 is benzyl;
- R2 methyl;
- R3 hydrogen;
- R4 is an amino acid radical, wherein the amino acid is lysine;
- or a pharmaceutically acceptable salt thereof;
- comprising
- reacting a compound of formula (XXIa), wherein
- R5 is selected from the group consisting of C1-12 alkyl, with a compound of formula (XII);
- wherein the compound of formula (XII) is racemic;
- in the presence of an R-selective enzyme catalyst;
- wherein the R-selective enzyme catalyst is an immobilized R-selective protease enzyme derived from Bacillus Lichenformis;
- neat or in a solvent;
- to yield the corresponding compound of formula (XX);
- wherein the compound of formula (XX) is present in an enantiomeric excess.
12 more elements
A process for the preparation of a diastereomerically enriched compound of formula (XX)
- wherein
- R1 is benzyl;
- R2 is methyl;
- R3 is hydrogen;
- R4 is an amino acid radical, wherein the amino acid is lysine;
- or a pharmaceutically acceptable salt thereof;
- comprising
- reacting a compound of formula (XXIb), wherein
- R4A is a nitrogen-protected amino acid radical, wherein the amino acid is lysine and the nitrogen protecting group is tert-butoxycarbonyl (BOC), and wherein R5 is selected from the group consisting of C1-12 alkyl, with a compound of formula (XII);
- wherein the compound of formula (XII) is racemic;
- in the presence of a R-selective enzyme catalyst;
- wherein the R-selective enzyme catalyst is an immobilized R-selective protease enzyme derived from Bacillus Lichenformis;
- neat or in a solvent;
- to yield the corresponding compound of formula (XXIII);
- wherein the compound of formula (XIII) is present in an enantiomeric excess;
- de-protecting the compound of formula (XXIII);
- to yield the corresponding compound of formula (XX);
- wherein the compound of formula (XX) is present in an enantiomeric excess.
15 more elements
Dependencies are inferred from the claim text.