I 1111111111111111 11111 1111111111 111111111111111 1111111111111111 IIII IIII IIII  US0084613 3 8B2  c12)  United States Patent  Arad et al.  (54)  (lR, l’R)-ATRACURIUM SALTS SEPARATION  PROCESS  (IO)  Patent No.:  US 8,461,338 B2  (45)  Date of Patent:  *Jun. 11, 2013  (75)  Inventors:  Oded Arad,  Rehovot (IL);  Elena  Ostrovsky,  Rishon Le-Zion (IL)  (73)  Assignee:  Chemagis Ltd.,  Bnei Brak (IL)  (21)  Appl. No.:  12/529,269  (22)  PCT Filed:  Mar. 5, 2008  (86)  PCT No.:  PCT /IL2008/000289  § 371 (c)(l),  (2), ( 4) Date:  Dec.16, 2009  ( *)  Notice:  Subject to any disclaimer, the term ofthis  patent is extended or adjusted under 35  U.S.C. 154(b) by 560 days.  This patent is subject to a terminal dis› claimer.  (87)  PCT Pub. No.:  WO2008/107887  PCT Pub. Date:  Sep. 12, 2008  (65)  Prior Publication Data  US 2010/0099878 Al  Apr. 22, 2010  Related U.S. Application Data  (60)  Provisional application No. 60/893,749, filed on Mar.  8, 2007.  (51)  Int. Cl.  C07D 401112  (2006.01)  (52)  U.S. Cl.  USPC ..........................................................  546/140  ( 58)  Field of Classification Search  USPC .......................................................... 546/140  See application file for complete search history.  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Stereochemical Studies on Atracurium and Related Polyalkylene  Diesters," European Journal of Medicinal Chemistry, Editions  Scientifique Elsevier, Paris, FR, vol. 19, No. 5, pp. 441-450 (Jan. 1,  1984).  Stenlake et al., "Neuromuscular Block Agents: Some approaches to  short acting compounds," European Journal of Medicinal Chemistry,  vol. 27, No. 5, pp. 463-477 (1992).  (Continued)  Primary Examiner  - Yong Chu  (74)  Attorney, Agent, or Firm  - Leydig, Voit & Mayer, Ltd.  (57)  ABSTRACT  The present invention provides an improved method of chro› matographically separating the isomers of (lR,rR)-atracu› rium salts by high-performance liquid chromatography  (HPLC), in the absence of a strong acid. The separation is  preferably performed on a silica gel HPLC column using an  eluent containing an organic solvent, a polar aprotic co-sol› vent and a weak organic acid.  21 Claims, 3 Drawing Sheets 