Levobupivacaine hydrochloride

Description

Levobupivacaine was first launched in the US for the production of local anesthesia for surgery and obstetrics and for post-operative pain management. It is the (S)-enantiomer of the long acting, highly potent local anesthetic bupivacaine (Marcaine) that can be prepared by a three step sequence from (S)-pipecolic acid or from (S)-lysine by oxidative deamination and stereospecific ring closure to (S)-pipecolamide core structure. Levobupivacaine exhibits its long-acting local anesthetic effect by blocking neuronal sodium channel ion flow in nerve axons. Clinical studies demonstrated an efficacy and a general profile closely resembling those of the racemic bupivacaine currently in use; however, it produced an enhanced safety profile, in particular substantially reduced (about one-third) cardiotoxicity (less effect on myocardial contractility and QT, prolongation) and CNS depressive side effects. Onset and duration of blockade were also equivalent or even better.

Chemical properties

white crystalline powder

Originator

Chiroscience (UK)

The Uses of Levobupivacaine hydrochloride

Levobupivacaine hydrochloride has been used as an analyte in tandem mass spectrometry. It may be used to test its inhibitory effect on phosphorylation of extracellular signal-regulated kinase (ERK) mediated by capsaicin It may also be used as a component of poly(D,L-lactide-co-glycolide) (PLGA) microparticles for testing its sustainable release by electrospraying technique.

Definition

ChEBI: Levobupivacaine hydrochloride (anhydrous) is the monohydrochloride salt of levobupivacaine. It has a role as a local anaesthetic, an adrenergic antagonist, an amphiphile, an EC 3.1.1.8 (cholinesterase) inhibitor and an EC 3.6.3.8 (Ca(2+)-transporting ATPase) inhibitor. It contains a levobupivacaine(1+). It is an enantiomer of a dextrobupivacaine hydrochloride (anhydrous).

Manufacturing Process

Synthesis of L-pipecolic acid 2,6-xylidide (Patent US 4,695,576)
130 g of pipecolic acid and 158.6 g of Laevo (+)-tartaric acid are dissolved under stirring in 2 L 95% ethyl alcohol and 125 ml water at 80°C. The solution is allowed to cool to room temperature and after two days the crystallized D-pipecolic-tartrate is separated. The L-pipecolic-tartrate remains in solution. The filtrate is evaporated and dissolved in 5% acetic acid. Finally the solution is treated with Amberlite IR 45* in an ion exchanger. The eluate thus obtained is evaporated and the resulting crystalline residue is dried with potassium hydroxide in vacuo. The product obtained consists of L-pipecolic acid [α]D24 = -26.2°(C = 5, H2O).
4 g of phosphorus pentachloride was added to a suspension of 4 g of Lpipecolic acid hydrochloride in 40 ml acetylchloride. The initial reaction is effected at a temperature of about 35°C under stirring for 2 hours. The chlorination is completed by adding during a time period of about 10 minutes an additional two grams of phosphorus pentachloride and stirring over a further period of 4 hours while maintaining the suspension at a temperature of about 35°C. The resulting L-pipecolic acid chloride hydrochloride is filtered and washed with toluene and acetone. The crystalline residue is then dried in vacuo, m.p. 155°C.
A mixture of 2.7 ml 2,6-dimethylaniline, 4 ml acetone, and 4 ml Nmethylpyrrolidone is gradually added under stirring for 2 hours at 70°C to a suspension of 4 g of L-pipecolic acid chloride hydrochloride. This yields a crystalline product, which is filtered, washed with acetone and dried. This crystalline product is then dissolved in water and the base is precipitated by the addition of ammonia. The base is then extracted by the use of toluene and is recovered by evaporation. The base is recrystallized from a mixture of hexane and ethanol to yield L-pipecolic acid 2,6-xylidide. The melting point of this compound is 129-130°C.
Preparation of L-N-n-butylpipecilic acid 2,6-xylidide may de carried out by analogy with the preparation of L-N-n-propylpipecolic acid 2,6-xylidide (Patent US 5,777,124).
n-Butylbromide and potassium carbonate are added to a solution of L-pipecolic acid 2,6-xylidide dissolved in isopropyl alcohol. Thereafter, 5 ml of water is added to the mixture and the reaction is carried out for 4 hours at 72°C.
To complete the reaction, a further 0.8 ml n-butylbromide are added under continuous stirring and heating for 4 hours. The residue is treated with a mixture of 250 ml toluene and an equal amount of water at 50°C. The toluene layer is separated and washed three times with 100 ml warm water (40°C). A 175 ml portion of the toluene is removed by evaporation and the remainder is stored at +5°C for 6 hours to achieve crude crystalline L-N-n-butylpipecilic acid 2,6-xylidide. The crystalline product is separated by filtration, washed with some cooled toluene and dried at 70°C. Recrystallization may be carried from toluene. This product is dissolved in 100 ml ethanol and neutralized with concentrated hydrochloric acid. Ethanol is removed by evaporation and the hydrochloride product obtained is vacuum dried. Finally the latter is recrystallized from isopropyl alcohol.

brand name

Chirocaine (Purdue).

Therapeutic Function

Local anesthetic

Biological Functions

Levobupivacaine hydrochloride (Chirocaine) is the S-enantiomer of bupivacaine. It too has long action. Animal studies show that it has less CNS and cardiac toxicity than does bupivacaine. It also is slightly more motor sparing than is bupivacaine.

General Description

Levobupivacaine belongs to the N-alkyl substituted pipecoloxylidide family and comprises amino-amide group.

Biochem/physiol Actions

Levobupivacaine hydrochloride is a sodium channel blocker used as a long-acting local anaesthetic for epidural anesthesia. Levobupivacaine is the (S)-isomer of bupivacaine, with efficacy similar to that of bupivacaine with a reduced risk of cardiotoxicity.

Mode of action

Levobupivacaine Hydrochloride is the hydrochloride salt of levobupivacaine, an amide derivative with anesthetic property. Levobupivacaine reversibly binds voltage-gated sodium channels to modulate ionic flux and prevent the initiation and transmission of nerve impulses (stabilizing neuronal membrane), thereby resulting in analgesia and anesthesia. In comparison with racemic bupivacaine, levobupivacaine is associated with less vasodilation and has a longer duration of action.