US 7,569,598 B2
Process for the preparation of the R,R (or S,S) configured glycopyrronium stereoisomer
Christian Noe, Vienna (Austria); and Martin Walter, Kriftel (Germany)
Assigned to Meda Pharma GmbH & Co. KG, Bad Homburg (Germany)
Appl. No. 10/540,187
PCT Filed Dec. 18, 2003, PCT No. PCT/EP03/14432
§ 371(c)(1), (2), (4) Date Feb. 13, 2006,
PCT Pub. No. WO2004/054971, PCT Pub. Date Jul. 01, 2004.
Claims priority of application No. A 1896/2002 (AT), filed on Dec. 18, 2002.
Prior Publication US 2006/0167275 A1, Jul. 27, 2006
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 207/12 (2006.01); C07D 207/14 (2006.01); A61K 31/40 (2006.01); A61K 31/4025 (2006.01)
U.S. Cl. 514—424  [548/527; 548/551] 16 Claims
 
1. A process for the isolation
a) of the 3R,2′R stereoisomer of glycopyrronium bromide or iodide (formula II: A=Br or I),

OG Complex Work Unit Drawing
 or
b) of the 3S,2′S stereoisomer (formula IV: A=Br or I),

OG Complex Work Unit Drawing
 or
c) of the 3R,2′S stereoisomer of the thienyl analog of glycopyrronium (formula VI: A=Br or I),

OG Complex Work Unit Drawing
 or
d) of the 3S,2′R stereoisomer (formula VIII: A=Br or I),

OG Complex Work Unit Drawing
 where
a) for the isolation of the 3R,2′R stereoisomer of glycopyrronium bromide or iodide (formula II: A=Br or I),

OG Complex Work Unit Drawing
 the diastereomer mixture consisting essentially of the 3R,2′R isomer and 3R,2′S isomer (formula III)

OG Complex Work Unit Drawing
 or the diastereomer mixture consisting essentially of the 3R,2′R isomer and 3S,2′R isomer (formula IIIb)

OG Complex Work Unit Drawing
 or
b) for the isolation of the 3S,2′S isomer (formula IV: A=Br or I),

OG Complex Work Unit Drawing
 the diastereomer mixture consisting essentially of the 3S,2′R isomer and 3S,2′S isomer (formula V)

OG Complex Work Unit Drawing
 or the diastereomer mixture consisting essentially of the 3R,2′S isomer and 3S,2′S isomer (formula Vb)

OG Complex Work Unit Drawing
 or
c) for the isolation of the 3R,2′S stereoisomer of the thienyl analog of glycopyrronium (formula VI: A=Br or I),

OG Complex Work Unit Drawing
 the diastereomer mixture consisting essentially of the 3R,2′S isomer and 3R,2′R isomer (formula VII)

OG Complex Work Unit Drawing
 or the diastereomer mixture consisting essentially of the 3R,2′S isomer and 3S,2′S isomer (formula VIIb)

OG Complex Work Unit Drawing
 or
d) for the isolation of the 3S,2′R isomer (formula VIII: A=Br or I),

OG Complex Work Unit Drawing
 the diastereomer mixture consisting essentially of the 3S,2′S isomer and 3S,2′R isomer (formula IX)

OG Complex Work Unit Drawing
 or the diastereomer mixture consisting essentially of the 3S,2′R isomer and 3R,2′R isomer (formula IXb)

OG Complex Work Unit Drawing
 is combined for re-crystallizing and the stereoisomer to be isolated in each case is precipitated and obtained in enriched form, wherein for the preparation of those tertiary, basic diastereomer mixtures employed in the quaternization which lead to the abovementioned quaternary diastereomer mixtures a solvent is selected from the group consisting of branched and unbranched alcohols having one to four carbon atoms, acetone, butanone and acetonitrile in which the diastereomer mixture dissolves readily in said solvent, and said solvent consisting of branched and unbranched alcohols having one to four carbon atoms is preferably methanol, ethanol, or combinations thereof, and the stereoisomer to be isolated in each case is precipitated to be obtained in enriched form, using a second solvent preferably selected from ethyl acetate and/or tert-butyl methyl ether causing crystallization.