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## (lR, l’R)-ATRACURIUM SALTS SEPARATION PROCESS 

The present invention relates to chromatography and more particularly to an improved method of separating the (IR, 1 ’R)-atracurium salt isomers by means ofhigh pressure liquid chromatography (HPLC). 

Cisatracurium besy late has the chemical name ( 1 R, 1 ’R,2R, 2’R)-2,2’-[ 1,5-pentanediylbis[ oxy(3-oxo-3, 1-propanediyl) ]] bis[l-[ (3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6, 7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate and is represented by the structural formula (I) below: 

## BACKGROUND OF THE INVENTION 

## TECHNICAL FIELD 

Cisatracurium besylate possesses an activity that is superior to atracurium besylate, with significantly less side effects. 

Cisatracurium besylate is marketed in the United States and Europe by Glaxo Wellcome and Abbott Laboratories under the trade name Nimbexfi, which is a sterile, non› pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzenesulfonic acid. The drug is provided in 2.5 ml, 5 ml and 10 ml ampules having a strength of 2 mg/ml cisatra› curium besylate. In addition, a 30 ml vial containing 5 mg/ml cisatracurium besylate is also available. 

Cisatracurium besylate slowly loses potency with time at a rate ofapproximately 5% peryearunder refrigeration (5° C.). Nimbex should be refrigerated at 2° to 8° C. (36° to 46° F.) in the carton to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C. (77° F.). 

Atracurium besylate is disclosed in U.S. Pat. No. 4,179, 507 (hereinafter U.S. ’507), which describes a series of bis 

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Cisatracurium besylate is the dibenzenesulfonate salt of lR-cis,1 ’R-cis isomer of atracurium (i.e., two molecules of benzenesulfonate per one diammonium molecule of cisatra› curium). Cisatracurium besylate is one of the 10 possible isomers of atracurium besylate and constitutes approximately 15% of that mixture ( atracurium has four chiral centers, two on each half of the molecule, one at each of the nitrogen atoms and the other at position 1 in each of the tetrahydroisoquino› linium rings so theoretically there are expected 16 possible isomers; however, due to the symmetry of the molecule, the number of atracurium isomers is reduced to 10). 

Cisatracurium besylate is a nondepolarizing neuromuscu› lar blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intuba› tion, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU). 

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veratryl isoquinolinium quaternary ammonium salts, includ› ing atracurium besylate. The synthesis of atracurium besy› late, as taught in U.S. ’507, involves the coupling of(–)› tetrahydropapaverine base, compound (II), with 1,5- pentamethylene diacrylate, compound Treatment of the resulting tertiary amine base with oxalic acid results in the isolation of N,N’-4, 1 0-dioxa-3, 11-dioxotridecylene-l, 13- bis-tetrahydropapaverine dioxalate, compound (IV). The dioxalate salt ( compound (IV) is converted to the free base, compound (V), with sodium bicarbonate solution and extracted into toluene. After evaporation of the toluene, the residue is dissolved in acetonitrile and treated with methyl benzenesulfonate. The addition of diethyl ether results in the precipitation of atracurium besylate, compound (VI), which is subsequently filtered and dried. Scheme 1 below illustrates the chemical pathway described above. 

