US 11,767,317 B1
Methods of synthesizing enantiopure deuterium-enriched pioglitazone
Laure Françoise Valérie Navarre, Lyons (FR); Vincent Jacques, Somerville, MA (US); and Sébastien Bolze, Massieux (FR)
Assigned to Poxel SA, Lyons (FR)
Filed by Poxel SA, Lyons (FR)
Filed on Jun. 28, 2021, as Appl. No. 17/360,315.
Claims priority of provisional application 63/081,732, filed on Sep. 22, 2020.
Claims priority of provisional application 63/046,336, filed on Jun. 30, 2020.
Int. Cl. C07D 417/12 (2006.01); C07B 59/00 (2006.01)
CPC C07D 417/12 (2013.01) [C07B 59/002 (2013.01); C07B 2200/05 (2013.01)] 20 Claims
 
1. A method of producing compound (IV) or salt thereof, the method comprising the steps:
a) reacting compound (I) or salt thereof with D2O and DCl at a temperature from about 80° C. to about 100° C. to produce compound (II) or salt thereof

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b) reacting compound (II) or salt thereof with L-dibenzoyl tartaric acid in a first solvent comprising at least 90% by volume of MeOD and/or MeOH, or at least 90% by volume of a mixture of MeOD and/or MeOH, and D2O to produce compound (III)

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c) recrystallizing compound (III) one or more times in a second solvent comprising at least 90% by volume of a mixture of D2O, DCl and/or HCl, and MeOH and/or MeOD to produce recrystallized compound (III′)

OG Complex Work Unit Chemistry
and
d) reacting recrystallized compound (III′) with DCl and/or HCl, in a third solvent which comprises deuterated and/or non-deuterated solvent, to produce compound (IV), or salt thereof, which is obtained by crystallization

OG Complex Work Unit Chemistry