2180-92-9

Basic information

• Product Name: Bupivacaine
• Synonyms: MARCAINE;BUPIVACAINE;BUPIVACAINE BASE;(.+/-.)-1-Butyl-2',6'-pipecoloxylidide;1-Butyl-2-(2,6-xylycarbamoyl)piperidine;1-Butyl-2',6'-pipecoloxylidide;1-butyl-2’,6’-pipecoloxylidide;1-butyl-n-(2,6-dimethylphenyl)-2-piperidinecarboxamid
• CAS NO: 2180-92-9
• Molecular Formula: C₁₈H₂₈N₂O
• Molecular Weight: 288.43
• EINECS: 218-553-3
• Product Categories: Active Pharmaceutical Ingredients;research chemical
• Mol File: 2180-92-9.mol

Chemical Properties

• Melting Point: 107.5-108°
• Boiling Point: 430.65°C (rough estimate)
• Flash Point: 140.9oC
• Appearance: /
• Density: 1.0238 (rough estimate)
• Refractive Index: 1.5700 (estimate)
• PKA: 8.09; also reported as 8.17(at 25℃)
• Water Solubility: 101.5mg/L(25 oC)
• CAS DataBase Reference: Bupivacaine(CAS DataBase Reference)
• NIST Chemistry Reference: Bupivacaine(2180-92-9)
• EPA Substance Registry System: Bupivacaine(2180-92-9)

Safety Data

• Hazard Codes: T+
• Statements: 26/27/28-38-41
• Safety Statements: 22-26-36/37/39-45
• RIDADR: 2811
• Hazardous Substances Data: 2180-92-9(Hazardous Substances Data)

Usage

Chemical Description

Bupivacaine is a local anesthetic that is often used in epidural anesthesia.

Uses

Used in Anesthetic Applications:
Bupivacaine is used as a local anesthetic for various medical procedures, including infiltration, spinal, and epidural anesthesia. It is particularly effective in blocking nerve transmission and is known for its long-lasting action.
Used in Surgical Interventions:
In the medical field, bupivacaine is used for surgical interventions in urology and lower thoracic surgery, providing anesthesia for durations ranging from 3 to 5 hours. It is also used in abdominal surgeries lasting approximately 45 to 60 minutes.
Used in Nerve Blockade Procedures:
Bupivacaine is utilized to block the trifacial nerve, the sacral and brachial plexuses, and is applied in resetting dislocations. It is also used in epidural anesthesia and during Cesarean sections to provide pain relief and ensure a smooth surgical process.

Therapeutic Function

Local anesthetic

Mechanism of action

Bupivacaine is a local anaesthetic containing a chiral centre and adopts dextro and laevo forms. The enantiopure l form is less cardio- and neurotoxic and has an equivalent potency to the racemic mixture; therefore levobupivacaine is often preferred to reduce the potential for toxicity. Stereoselectivity describes the differences in response at a given receptor for the different enantiomers (such as the response discussed for S(+) ketamine). The opioid and NMDA receptors also exhibit stereoselectivity.

Pharmacology

Bupivacaine is a chiral compound used clinically for 50 years, with a slower onset, greater potency and longer duration of action than lidocaine. Initial benefits of bupivacaine were sensory–motor separation and minimal tachyphylaxis, unlike repeated doses of lidocaine. However, it has greater potential for cardiac toxicity, related to its avid binding to and slow dissociation from cardiac N a+ channels. Inadvertent intravenous administration may result in systemic toxicity (see later), and it is contraindicated for intravenous regional anaesthesia.Bupivacaine is commonly used for epidural administration in obstetrics and postoperative pain management. A hyperbaric preparation containing 80 mg ml-1 glucose is available for spinal anaesthesia.

Side effects

Common side effects of bupivacaine include:weakness, long-lasting numbness or tingling;feeling restless or drowsy;tremors;headache, blurred vision;fast or slow heartbeats;breathing problems;chills or shivering;back pain; nausea, vomiting.

Synthesis

Bupivacaine, N-2,6-(dimethyl)1-butyl-2-piperidincarboxamide (2.2.7), is chemically similar to mepivacaine and only differs in the replacement of the N-methyl substituent on the piperidine ring with an N-butyl substituent. There are also two suggested methods of synthesis. The first comes from α-picolin-2,6-xylidide (2.2.4). The alkylation of the last with butyl bromide gives the corresponding pyridine salt (2.2.6). Finally, it is reduced by hydrogen using platinum oxide as a catalyst into a piperidine derivative—bupivacaine. The other method results directly from the piperidine-2-carboxylic acid chloride, which is reacted with 2,6-dimethylaniline. The resulting amide (2.2.8) is further alkylated with butyl bromide to bupivacaine [17–19].

InChI:InChI=1/C18H28N2O/c1-4-5-12-20-13-7-6-11-16(20)18(21)19-17-14(2)9-8-10-15(17)3/h8-10,16H,4-7,11-13H2,1-3H3,(H,19,21)

Upstream product

• 109-65-9 1-bromo-butane 
• 14252-80-3 bupivacaine hydrochloride 
• 27262-45-9 (+)-Bupivacaine 
• 856838-98-7 racemic 1-butylpiperidine-2-carboxylic acid 
• 87-62-7 2,6-dimethylaniline 
• 4043-87-2 pipecolic Acid 
• 39627-98-0 2-pyridine-carboxamide-N-(2,6-dimethylphenyl) 
• 123-72-8 butyraldehyde 
• 98-98-6 2-Picolinic acid 

Downstream Products

• 27262-45-9 (+)-Bupivacaine 
• 27262-47-1 levobupivacaine 

Relevant articles and documents

HYDROPHOBIC ACID ADDITION SALTS AND PHARMACEUTICAL FORMULATIONS THEREOF

The invention provides hydrohphobic drug salts and pharmaceutical compositions comprising such salts. The invention fourther provides compositions for delivering poorly soluble drugs, including hydrophobic drug salts.

Preparation method of levobupivacaine hydrochloride

The invention belongs to the technical field of chemical synthesis and particularly relates to a preparation method of levobupivacaine hydrochloride. The preparation method comprises the steps of carrying out catalytic hydrogenation on racemic or S-form 2-piperidinecarboxylicacid as a raw material and n-butanal so as to obtain 1-butylpiperidine-2-carboxylic acid, carrying out condensation reaction on 1-butylpiperidine-2-carboxylic acid and 2,6-dimethylaniline so as to generate bupivacaine or levobupivacaine, and carrying out subsequent treatment, so as to obtain a final product, namely levobupivacaine hydrochloride. Compared with existing synthetic routes, the preparation method has the advantages that the synthetic route is short, the method is simple, convenient in operation, low in cost and easy for industrial production, reaction conditions of each step are relatively mild, the process is stable, a strong-corrosion chlorinated reagent is not used, and the environmental pollution is reduced.

Preparation method of levobupivacaine hydrochloride

The invention belongs to the technical field of chemical synthesis and in particular relates to a preparation method of levobupivacaine hydrochloride. The preparation method takes racemic or S-configuration 2-piperidinecarboxylic acid as a starting raw material and comprises the following steps: taking the starting raw material and n-butylaldehyde to react and carrying out borohydride reduction reaction to obtain 1-butylpiperidine-2-carboxylic acid; taking the 1-butylpiperidine-2-carboxylic acid and 2,6-dimethylaniline to be subjected to condensation reaction, so as to generate bupivacaine or levobupivacaine; carrying out subsequent treatment to obtain a final product levobupivacaine hydrochloride. Compared with an existing synthesis route, the preparation method has the advantages of short synthesis route, simple method, convenience for operation, low cost and easiness for industrial production; reaction conditions of each step are relatively moderate, a process is stable, a strong-corrosion chlorination reagent is not used, the pollution to environment is reduced and the like.

Synthesis of Mepivacaine and Its Analogues by a Continuous-Flow Tandem Hydrogenation/Reductive Amination Strategy

Herein we report a convenient, fast, and high-yielding method for the generation of the racemic amide anaesthetics mepivacaine, ropivacaine, and bupivacaine. Coupling of α-picolinic acid and 2,6-xylidine under sealed-vessel microwave conditions generates the intermediate amide after a reaction time of only 5 min at 150 °C. Subsequent reaction in a continuous-flow high-pressure hydrogenator (H-Cube ProTM) in the presence of the respective aldehyde directly converts the intermediate to the final amide anaesthetics in a continuous, integrated, multi-step ring-hydrogenation/reductive amination protocol. Merits and limitations of the protocol are discussed.

Sustained-release liposomal anesthetic compositions

The invention provides a method for obtaining local anesthetics encapsulated in liposomes, such as multivesicular liposomes, with high encapsulation efficiency and slow release in vivo. When the encapsulated anesthetic is administered as a single intracutaneous dose, the duration of anesthesia and half-life of the drug at the local injection site is increased as compared to injection of unencapsulated anesthetic. The maximum tolerated dose of the encapsulated anesthetic is also markedly increased in the liposomal formulation over injection of unencapsulated anesthetic. These results show that the liposomal formulation of local anesthetic is useful for sustained local infiltration and nerve block anesthesia.

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine - Synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml-1 corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1-9.8 (37°C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (～80%) and an unknown compound X (～20%) was observed. LC-MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37°C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pKa values below approximately 6 and intrinsic solubilities in the low μM range.

PHARMACOLOGICALLY ACTIVE SALTS

Novel salts formed between two active drug substances, wherein the first drug substance is an NSAID drug substance containing a carboxylic acid group and the second drug substance contains an amine group and is a local anaesthetic or selected from the group consisting of non-opioid analgesics, antipsychotics, antidepressants, narcotic antagonists and local anaesthetics. Such salts that are poorly soluble in tissue fluids are feasible for injectable prolonged release formulations where the NSAID additionally to minimize pain and tissue reaction at the site of administration.

Racemisation of R-Bupivacaine: A key factor in the integrated and economic process for the production of levobupivacaine

Two methods for the racemisation of nonracemic bupivacaine and 2′,6′-pipecoloxylidide, a key intermediate in the synthesis of bupivacaine, are described. One uses carboxylic acids at high temperature and the other uses water and a cosolvent. The product obtained from the carboxylic acid racemisation is of suitable quality to generate commercial levobupivacaine hydrochloride (Chirocaine) 1[S], a less cardiotoxic alternative to bupivacaine hydrochloride (Marcaine) 1[R,S].