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Bupivacaine

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Bupivacaine Basic information

Product Name:
Bupivacaine
Synonyms:
  • MARCAINE
  • BUPIVACAINE
  • BUPIVACAINE BASE
  • 2',6'-Pipecoloxylidide, 1-butyl-
  • 6’-pipecoloxylidide,1-butyl-2
  • Anekain
  • Carbostesin
  • DL-Bupivacaine
CAS:
2180-92-9
MF:
C18H28N2O
MW:
288.43
EINECS:
218-553-3
Product Categories:
  • research chemical
  • Active Pharmaceutical Ingredients
Mol File:
2180-92-9.mol
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Bupivacaine Chemical Properties

Melting point:
107.5-108°
Boiling point:
430.65°C (rough estimate)
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
2180-92-9(CAS DataBase Reference)
NIST Chemistry Reference
2-Piperidinecarboxamide, 1-butyl-n-(2,6-dimethylphenyl)-(2180-92-9)
EPA Substance Registry System
2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)- (2180-92-9)
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Safety Information

Hazard Codes 
T+
Risk Statements 
26/27/28-38-41
Safety Statements 
22-26-36/37/39-45
RIDADR 
2811
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Bupivacaine Usage And Synthesis

Originator

Carbostesin,Astra,W. Germany,1967

Uses

Like lidocaine and mepivacaine, bupivacaine is used in infiltration, spinal, and epidural anesthesia in blocking nerve transmission. Its most distinctive property is its long-lasting action. It is used for surgical intervention in urology and in lower thoracic surgery from 3 to 5 h in length, and in abdominal surgery lasting from 45 to 60 min. It is used to block the trifacial nerve, the sacral and brachial plexuses, in resetting dislocations, in epidural anesthesia, and during Cesarian sections.

Uses

Anesthetic (local).

Manufacturing Process

121 parts by weight of 2.6-xylidine are heated with 400 parts of diethylmalonate at 160°C for 1 hour, and the alcohol formed by the reaction is allowed to distill off. Thereafter the reaction mass is cooled to 80°C, and 500 parts of alcohol are added. After cooling the dixylidide is sucked off, and the alcohol solution with malonic ester monoxylidide is poured into 2,000 parts of water. The monoxylidide precipitates, is filtered off and washed with water, and recrystallized in diluted alcohol. Nitrosation thereafter takes place by dissolving the dried monoxylidide in chloroform and by introducing nitrosyl chloride at 0°C until the nitrosation is completed. The isonitrosomalonic ester xylidide is filtered off and dried. Thereafter the reduction takes place with zinc powder and formic acid at 90°-100°C.
The formic acid is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. After 6 hours of boiling, the sodium bromide formed is separated, and the mixture is steamdistilled in order to remove the excess of tetramethylene bromide. The remaining oil, which mainly consists of deltabromobutylaminomalonic ester xylidide is separated from the water and boiled with 3 parts of concentrated hydrochloric acid for 3 hours. Thereafter carbonfiltering and evaporation to dryness under vacuum takes place. The residue is dissolved in water, and the pH adjusted with sodium hydroxide to 5.5. The solution is extracted twice with ether, and the water is made strongly alkaline with sodium hydroxide.
The oil precipitates and is crystallized after a time. The crystals are separated and dried under vacuum. The pipecolyl-2,6-xylidide produced is alkylated by boiling for 10-20 hours with 0.6 part n-butylbromide in an n-butanol solution in the presence of 0.5 part potassium carbonate. The potassium carbonate is filtered off and the butanol is distilled off in vacuum. The residue is dissolved in diluted hydrochloric acid and carbon treated, after which the base is precipitated with sodium hydroxide in the form of white crystals, which are filtered off and washed with water. The base obtained, which consists of N-n-butyl-pipecolyl-2,6-xylidide is sufficiently pure for the production of salts.

brand name

Marcaine (Hospira); Sensorcaine (AstraZeneca).

Therapeutic Function

Local anesthetic

General Description

Bupivacaine was synthesized simultaneously with mepivacainein 1957 but was at first overlooked because of the increasedtoxicity compared with mepivacaine. When themethyl on the cyclic amine of mepivacaine is exchanged fora butyl group the lipophilicity, potency and the duration ofaction all increase. Literature reports of cardiovascular toxicity,including severe hypotension and bradycardia, areabundant in the literature.91 Bupivacaine is highly bound toplasma proteins (95%), and thus the free concentration mayremain low until all of the protein binding sites are occupied.After that point, the plasma levels of bupivacaine rise rapidlyand patients may progress to overt cardiac toxicity withoutever showing signs of CNS toxicity. The cardiotoxicity ofbupivacaine is a result of its affinity to cardiac tissues and itsability to depress electrical conduction and predispose theheart to reentry types of arrhythmias. The cardiotoxicity ofbupivacaine was found to be significantly more prominentwith the “R” isomer, or the racemic mixture, thus the “S”stereoisomer is now on the market as levobupivacaine.

Chemical 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].

Bupivacaine Preparation Products And Raw materials

Raw materials

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