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

[0001] The present invention relates to chromatography and more particularly to an improved method of separating the (lR,1 ’R)-atracurium salts isomers by means of high pres› sure liquid chromatography (HPLC). 

[0002] Neuromuscular blocking agents (e.g., atracurium besylate, pancuronium bromide, rocuronium bromide, vecu› ronium bromide) are known to have muscle paralyzing activ› ity that is similar to the alkaloid curare or d-tubocurarine. Neuromuscular blocking agents interrupt transmission of nerve impulses at the skeletal neuromuscular junction and are typically divided into two types: competitive, stabilizing blockers (non-depolarizing neuromuscular agents) and non› competitive, depolarizing agents ( depolarizing neuromuscu› lar agents). Both types prevent acetylcholine from triggering the muscle contraction and are typically used as anesthesia adjuvants in the operating theatre for aiding intubation i.e. relaxation of vocal cords, trachea, jaw muscles etc and also for surgery i.e. providing generalized muscle relaxation, as relaxants during electroshock, in convulsive states, etc. Typi› cally, therapy is performed by i.v. administration of a suitable dosage form. 

[0003] Atracurium besylate [2,2’-[1,5-pentanediylbis[ oxy (3-oxo-3, 1-propanediyl) ]]bis[ 1-[ (3,4-dimethoxyphenyl)me› thyl]-1,2,3,4-tetrahydro-6, 7-dimethoxy-2-methyl-isoquino› linium dibenzenesulfonate] was first approved for human medical use in 1982. The isomer lR-cis-l’R-cis-2,2’2,2’-[1, 5-pentanediylbis[ oxy(3-oxo-3, 1-propanediyl) ]]bis[ 1-[ (3,4- dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6, 7- dimethoxy-2-methy 1-isoquinolinium dibenzenesulfonate is named cisatracurium besylate and it is 3-4 times more potent than atracurium besylate itself. The product was launched by GSK and Abbott Laboratories in 1996 under the trade name NIMBEXfi. NIMBEXfi is a sterile, non-pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzene› sulfonic acid. The drug is provided in 2.5 ml, 5 ml and 10 ml ampules having a strength of2 mg/ml cisatracurium besylate. In addition, a 30 ml vial containing 5 mg/ml cisatracurium besylate is also available. 

[0004] Cisatracurium besylate has the structural formula below. 

## BACKGROUND OF THE INVENTION 

## TECHNICAL FIELD 

[0005] Because the atracurium compound has 4 chiral cen› ters, there are theoretically 16 possible isomers. Due to sym› metry of the molecule, the number ofisomers is reduced to 10 (optical and geometrical isomers). This is discussed in detail by J. B. Stenlake et al. in "Biodegradable neuromuscular blocking agents," Eur. J. Med. Chem.-Chem. Ther., 19, No. 5, pages 441-450 (1984 ). 

[0006] The preparation of cisatracurium besylate is described in U.S. Pat. Nos. 5,453,510, and 5,556,987 and is depicted in Scheme 1 below. The process involves reacting 1,5-pentanediol with 3-bromopropionic acid in toluene with a trace of p-toluenesulfonic acid to afford 1,5-pentamethylene diacrylate. (–)-terahydropapaverine hydrochloride 1s resolved with N-acetyl-L-leucine to obtain (R)-terahydropa› paverine N-acetyl-L-leucinate, which is converted to the free base and reacted with the 1,5-pentamethylene diacrylate in hot glacial acetic acid, purified by colunm chromatography, and treated with oxalic acid to afford (lR,l’R)-2,2’-(3,11- dioxo-4, 10-dioxatridecylene )-bis-(1,2,3,4-tetrahydro-6, 7- dimethoxy-2-methy 1-1-veratryliso-quinolinium dioxalate (II), which is treated with methyl benzenesulfonate to obtain the (lR,l’R)-atracurium besylate isomer mixture, i.e., (lR› cis-l’R-cis), (lR-cis-1 ’R-trans) and (lR-trans-1 ’R-trans) iso› mers in a ratio of 58:34:6 respectively. The mixture is sepa› rated by means of liquid chromatography, using either irregular or spherical silica colunm in a mixture of dichlo› romethane and a strong acid, e.g., methanesulfonic acid, or in a mixture of dichloromethane, methanol and a strong acid, e.g., benzenesulfonic acid. 

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