(10)  Patent No.:  US 8,357,805 B2  (45)  Date of Patent:  *Jan. 22, 2013  c12)  United States Patent  Arad et al.  (54)  (lR,l’R)-ATRACURIUM SALTS SEPARATION  PROCESS  (75)  Inventors:  Oded Arad,  Rehovot (IL);  Elena  Ostrovsky,  Rishon Le-Zion (IL)  (73)  Assignee:  CHEMAGIS Ltd.,  Bnei Brak (IL)  ( *)  Notice:  Subject to any disclaimer, the term ofthis  patent is extended or adjusted under 35  U.S.C. 154(b) by 460 days.  This patent is subject to a terminal dis› claimer.  (21)  Appl. No.:  12/601,734  (22)  PCT Filed:  Mar. 5, 2008  (86)  PCT No.:  PCT /IL2008/000290  § 371 (c)(l),  (2), ( 4) Date:  Nov. 24, 2009  (87)  PCT Pub. No.:  WO2008/155752  (60)  Provisional application No. 60/944,597, filed on Jun.  18, 2007.  (51)  Int. Cl.  A61K 3114725  (2006.01)  C07D 401112  (2006.01)  (52)  U.S. Cl.  ........................................  546/140;  514/308  (58)  Field of Classification Search  .................. 514/308;  546/140  See application file for complete search history.  FOREIGN PATENT DOCUMENTS  OTHER PUBLICATIONS  (57)  ABSTRACT  12 Claims, No Drawings  (56)  References Cited  U.S. PATENT DOCUMENTS  Related U.S. Application Data  (65)  Prior Publication Data  4,179,507 A  4,491,665 A  4,701,460 A  4,761,418 A  4,851,537 A  4,988,815 A  5,240,939 A  5,453,510 A  5,556,978 A  5,684,154 A  6,015,903 A  6,177,445 Bl  6,187,789 Bl  6,830,933 B2  7,265,099 Bl  2006/0009485 Al  2008/0139482 Al  2009/0156562 Al  2010/0016596 Al  2010/0087650 Al  2010/0099878 Al  2010/0168431 Al  12/1979 Stenlake et al.  1/1985 El-Sayad et al.  10/1987 El-Sayad et al.  8/ 1988 Swaringen, Jr. et al.  7/1989 Noyori et al.  l/ 1991 Andre et al.  8/1993 Demko  9/1995 Hill et al.  9/ 1996 Hill et al.  1111997 Chamberlin et al.  1/2000 Viergutz et al.  1/2001 Bigham et al.  2/2001 Bigham et al.  12/2004 Lennnens et al.  9/2007 Born et al.  1/2006 Friedman et al.  6/2008 Savarese  6/2009 Winch  1/2010 Pozzoli et al.  4/2010 Ostrovsky et al.  4/2010 Arad et al.  7/2010 Naddakaetal.  2010/0184988 Al  2010/0234602 Al  2010/0256381 Al  2010/0298570 Al  2011/0185796 Al  7/2010 Naddaka et al.  9/2010 Arad et al.  10/2010 Arad et al.  11/2010 Segnalini et al.  8/2011 Arad et al.  CN  CN  CN  CN  CN  EP  EP  WO  WO  WO  WO  WO  WO  WO  WO  WO  WO  WO  WO  WO  WO  101084896 A  101337935 A  101337936 A  101475530 A  101845017 A  0 219 616  0219616  WO 92/00965 Al  WO 9200965 Al  *  WO 98/42675 Al  WO2007/091753 Al  WO 2008/107887 A2  WO 2008/117271 Al  WO 2008/132746 Al  WO 2008/132748 Al  WO 2009/007946 Al  WO 2009/057086 Al  WO 2009/106547 Al  WO 2009/133556 A2  WO 2010/128518 A2  WO 2010/128519 Al  12/2007  1/2009  1/2009  7/2009  9/2010  4/1987  4/1987  1/1992  1/1992  10/1998  8/2007  9/2008  10/2008  11/2008  11/2008  1/2009  5/2009  9/2009  11/2009  11/2010  11/2010  PCT Pub. Date:  Dec. 24, 2008  US 2010/0174082Al  Jul. 8, 2010  The present invention provides an improved method for  obtaining cisatracurium besylate, which preferably chro› matographically separating cisatracurium besylate from a  mixture of (1 R, 1 ’R)-atracurium isomers via flash chromatog› raphy.  Primary Examiner  - Joseph Kosack  Assistant Examiner  - Matthew Coughlin  (74)  Attorney, Agent, or Firm  - Leydig, Voit & Mayer, Ltd.  (Continued)  ICH Guideline, International Conference on Harmonization of Tech› nical Requirements of Registration of Pharmaceuticals for Human  Use (ICH), ICH Q3CR4 residual solvents MEDIA5254 (Feb. 2009).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000291 (Jul. 4, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000290 (Jul. 7, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000289 (Sep. 5, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000586 (Aug. 27, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000589 (Aug. 21, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/000590 (Aug. 29, 2008).  European Patent Office, International Search Report in International  Patent Application No. PCT/IL2008/001329 (Feb. 4, 2009).  U.S. Patent & Trademark Office, International Search Report in  International Patent Application No. PCT/IL2009/000452 (Aug. 12,  2009).  Lindon et al. "Directly coupled HPLC-NMR and HPLC-NMR-MS in  pharmaceutical research and development," Journal of Chromatog› raphy B : Biomedical Applications, Elsevier Science Publishers, NL,  vol. 748, No. 1, pp. 233-258 (Oct. 1, 2000).  Liu et al. "High-performance liquid chromatography of atracurium  besylate," Yao Hsueh Hsueh Pao-Acta Pharmaceutica Sinica,  Beijing, CN, vol. 29, No. 1, pp. 68-73 (Jan. 1, 1994).  US008357805B2 