Atracurium besylate

Chemical Name N,N -4,10-dioxa-3,11 -dioxotridecylene-1,13-bis-tetrahydropapaverine di-benzenesulfonate 

Chemical Abstracts Registry No. 6422B.81-5 Trade Name Manufacturer 

Burroughs Wellcome Burroughs Wellcome Burroughs Wellcome 

Acryloyl chloride (0.2 mol) in dry benzene (60 ml) was added over 0.5 hour with mechanical stirring to pentane-1,5-diol (0.1 mol), triethylamine (0.2 mol) and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (ca 100 ml) was added followed by triethylamine (10 ml), and the mixture stirred at 50°C for 0.5 hour. The triethylamine hydrochloride was fii-tered off and the solvent removed In vacuo to leave a yellow oil which was distilled in the presence of a trace of p-methoxyphenol, excluding light, to give 1,5-pen tarn ethylene diacrylate (12.9g 61% BP90°to95°C/0,01 mm Hg), 

A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 4B hours excluding light. The solvent was removed in vacuo and the residual pale red oil dissolved in chloroform (10 ml). Addition of ether (ca 400 ml), followed by saturated ethereal oxalic acid solution (ca 500 ml) gave a floc-culent white precipitate, which was filtered off, washed with ether and dried. Crystallization (twice) from ethanol gave N,N -4,10 )ioxa-3,11 )ioxotridecvlene-1,13-bis-tetrahydropapa-verlne dioxalate as a white powder (3.5 g 51% MP 117°to 121°C). 

Trade Name Manufacturer Country Year Introduced 

The free base, N,N -4,10-dioxa-3,11-dioxotridecylene-l, 13-bis-tetrahydropapaverine, was obtained by basifying an aqueous solution of the dioxalate with sodium bicarbonate solution, followed by extraction with toluene and evaporation of the solvent, to give a colorless viscous oil. 

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Online detection using 4H nuclear magnetic resonance (NMR) is a detection mode that has become increasingly practical. In a recent application, cell culture supernatant was monitored on-line with 1-dimensional NMR for trehalose, P-D-pyranose, P-D-furanose, succinate, acetate and uridine.33 In stopped-flow mode, column fractions can also be analyzed by 2-D NMR. Reaction products of the preparation of the neuromuscular blocking compound atracurium besylate were separated on chiral HPLC and detected by 4H NMR.34 Ten isomeric peaks were separated on a cellulose-based phase and identified by online NMR in stopped-flow mode. 

Mistry, N., Roberts, A.D., Tranter, G.E., Francis, P., Barylski, I., Ismail, I.M., Nicholson, J.K., and Lindon, J.C., Directly coupled chiral HPLC-NMR and HPLC-CP spectroscopy as complementary methods for structural and enantiomeric isomer identification application to atracurium besylate, Anal. Chem., 71, 2838, 1999. 

Atracurium besylate (Tracrium) is a benzylisoquinolin-ium compound like d-tubocurarine. Its actions are similar to those of d-tubocurarine, but its duration of action is shorter (45 minutes) because of spontaneous degradation of the molecule (Hofmann elimination). Because of this, atracurium is useful in patients with low or atypical plasma cholinesterase and in patients with renal or hepatic impairment. 

Figure 3.3 Expansions of the 750 MHz 1 H NMR spectra for key peaks in the chiral HPLC-NMR spectra for the different isomers of atracurium besylate...

Papaver somnifemm (opium poppy) (Papaveraceae) [opium exudate] metabolite of synthetic NM relaxant atracurium besylate... 

Basta SJ, Ali HH, Savarese JJ, Sunder N, Gionfriddo M, Cloutier G, Lineberry C, Cato AE. Clinical pharmacology of atracurium besylate (BW 33A) a new non-depolarizing muscle relaxant. Anesth Analg 1982 61(9) 723-9. 

Lavery GG, Mirakhur RK. Atracurium besylate in paediatric anaesthesia. Anaesthesia 1984 39(12) 1243-6. 

The drug PO incorporates aspects of the first three items in the preceding shopping list with some success. Acetate hydrolysis, as the metabolic inactivation route, however, fails to meet the requirements of item 4. The introduced atracurium besylate (Tracrium, Fig. 8-15), however, does meet the requirements. The following discussion then will pertain to the chemical logic that went into the design of atracurium. 

Figure 8-15. Synthesis of atracurium besylate (benzene sulfonate salt). (From Stenlake, 1985.)...

Figure 8-16. Metabolism of atracurium besylate (from Stenlake et al., 1983).

Atracurium Besylate. 2,2 -(l,S-Pentanediylbis-(oxy<3-oxo-3,l-propanediyTy)]bis[I.[(3,4-dimethoxyphenyl)-methyl]-Ti2,3,4-tetra hyd ro-6,7-dimeth oxy-2-methyliso u ino-liniumj dibenzenesulfonate 2 -(2 -vArboxyethy]) 1,2,3,4-tet -rahydro-6,7 -dimethoxy-2-methyl-1 -veratrylisoquinolirtum... 

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