106861-44-3

Off-White Solid

Non-depolarizing neuromuscular blocking agent. Muscle relaxant (skeletal)

Mivacurium chloride,a mixture of three stereoisomers, is an intravenously administered, short-acting skeletal muscle relaxant introduced as an adjunct to general anesthesia. Structurally mivacurium chloride is closely related to doxacurium chloride introduced in 1991 by Wellcome as a muscle relaxant. It is a nondepolarizing neuromuscular blocking agent reportedly with a shorter duration of action and a more rapid rate of spontaneous recovery than other nondepolarizing agents. In extensive clinical trials mivacurium chloride was well tolerated with few side effects.

Wellcome (United Kingdom)

ChEBI: Mivacurium chloride is a member of isoquinolines.

To ()-5'-methoxylaudanosine (46.4 g) in methanol (240 mL) was added (-)- dibenzoyltartaric acid monohydrate (45.2 g). The mixture was heated to boiling, cooled at 5°C for 16 h and the (S)-(-)-5'-methoxylaudanosinium dibenzoyltartrate salt (35.6 g, 80%) was filtered and discarded. The mother liquors were made basic with concentrated aqueous NaOH and evaporated under vacuum. The solid residue was partitioned between H2O and diethyl ether. The ether phase was dried and evaporated to an oil (24.9 g). To the oil in methanol (128 mL) was added (+)-dibenzoyltartaric acid monohydrate (26.6 g). The mixture was heated to boiling and cooled at 5°C for 16 h. Crystals were collected and recrystallized from methanol until a constant specific rotation of [α]D20=+17.7° (1% EtOH) had been achieved. The yield of (R)-(+)-5'-methoxylaudanosinium dibenzoyltartrate as white crystals was 29.4 g (66%). A portion of the salt (15.0 g) in methanol (200 mL) was made basic with concentrated aqueous NaOH. The mixture was evaporated under vacuum and the residue was partitioned between H2O and diethyl ether. The combined ether layers were dried and evaporated under vacuum to yield 7.2 g (92%) of (R)-(-)-5'-methoxylaudanosine as an oil.
(R)-(-)-5'-Methoxylaudanosine (7.2 g), 3-chloropropanol (3.5 g), sodium iodide (5.6 g) and sodium carbonate (0.5 g) were refluxed in 2-butanone (125 mL) for 16 h. The white suspension was filtered hot and solvent removed from the filtrate under vacuum. The residual gum was trituated with hot ethyl acetate to remove excess 3-iodopropanol, dissolved in 200 mL methanol and passed through a column packed with Dowex RTM.1-X8 ion exchange resin (60 g chloride form). The eluant was stripped of solvent under vacuum to give N-3-hydroxypropyl-1-(R)-5'-methoxylaudanosinium chloride (8.4 g) as an amophous solid. The material was assayed by HPLC as a 2.3/1 mixture of the trans/cis diastereomers.
N-3-Hydroxypropyl-1-(R)-5'-methoxylaudanosinium chloride (2.3/1, trans/cis by HPLC, 2.5 g) was dissolved in 60 mL 1,2-dichloroethane at about 70°C. (E)-4-Octene-1,8-dioic acid chloride (0.5 g) (K. Sisido, K. Sei, and H. Nozaki, J. Org. Chem., 1962, 27, 2681) was added and the mixture was stirred at ambient temperature for 19 h. Solvent was removed under vacuum to give an amorphous solid which was dissolved in chloroform (25 mL) and washed with 5% aqueous sodium chloride solution to remove unreacted quaternary salts. The chloroform layer was dried and evaporated under vacuum to give an amorphous solid. The acid ester impurities were substantially removed by washing with hot 2-butanone. Residual solvent was evaporated under vacuum and the resulting amorphous solid was dissolved in methanol, filtered and lyophilized to give 1.9 g of (E)-(1R,1'R)-2,2'-[4-octenedioylbis (oxytrimethylene)]bis[1,2,4,3-tetrahydro-6,7-dimethoxy-2-methyl-1-(3,4,5- trimethoxybenzyl)isoquinolinium] dichloride, which was assayed by HPLC as 44.6% RS-RS (trans-trans) diester, 42.4% RR-RS (cis-trans) diester, 7.5% RRRR(cis-cis) diester, 4.0% RS (trans) acid ester and 1.5% RR (cis) (E)- (1R,1'R)-2,2'-[4-Octenedioylbis(oxytrimethylene)]bis[1,2,3,4-tetrahydro-6,7- dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)isoquinolinium]dichloride acid ester, [α]D20=-62.7° (1.9% in water).

Mivacron (Abbott).

Muscle relaxant

Mivacurium chloride (Mivacron) is a newer agent that is chemically related to atracurium. The primary mechanism of inactivation is hydrolysis by plasma cholinesterase. Although it is useful for patients with renal or hepatic disease, some caution is warranted, since these individuals may have reduced plasma cholinesterase as a result of the disease.Mivacurium has an onset of action (1.8 minutes) and duration of effect (20 minutes) only twice that of succinylcholine, and in this respect, it is the most similar to succinylcholine of all of the nondepolarizing agents.

Mivacurium chloride, 1,2,3,4-tetrahydro-2-(3-hydroxypropyl)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)isoquinolinium chloride, (E)-4-octandioate (Mivacron), is a mixture of three stereoisomers,the trans-trans, cis-trans, and cis-cis diesters, each ofwhich has neuromuscular blocking properties. The cis-cisisomer is about one tenth as potent as the other isomers.Mivacurium chloride is a short-acting nondepolarizing drugused as an adjunct to anesthesia to relax skeletal muscle.The drug is hydrolyzed by plasma esterases, and it is likelythat anticholinesterase agents used as antidotes could prolongrather than reverse the effects of the drug.