- 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
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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.
- Nielsen, Anders Bach,Buur, Anders,Larsen, Claus
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- HYDROPHOBIC ACID ADDITION SALTS AND PHARMACEUTICAL FORMULATIONS THEREOF
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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.
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Page/Page column 86
(2019/05/22)
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- Preparation method of levobupivacaine hydrochloride
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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.
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- Preparation method of levobupivacaine hydrochloride
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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.
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Paragraph 0053; 0054
(2017/09/26)
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- Preparation method of bupivacaine hydrochloride
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The invention discloses a preparation method of bupivacaine hydrochloride. The preparation method includes the steps of: 1) preparing N-(2,6-xylyl)-2-piperidineformamide; 2) preparing the bupivacaine hydrochloride. The reaction routes in the two steps are described in the specification. The method has high yield, high product quality and low operation cost, allows automation operation of equipment, has good stability, and can satisfy industrial demands.
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- Synthesis of Mepivacaine and Its Analogues by a Continuous-Flow Tandem Hydrogenation/Reductive Amination Strategy
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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.
- Suveges, Nícolas S.,de Souza, Rodrigo O. M. A.,Gutmann, Bernhard,Kappe, C. Oliver
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p. 6511 - 6517
(2017/12/02)
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- Synthesis method of bupivacaine
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The invention belongs to a synthesis method of bupivacaine. The method comprises: adding 2 piperidinecarboxylicacid into aqueous alkali, dropwise adding Cbz and alkaline water, after finishing dropwise adding at normal temperature, reacting for 12 hours, after reaction, extracting with diethyl ether, washing a water layer to be weak-acid with 18% of diluted hydrochloric acid, extracting with the diethyl ether again, combining an diethyl ether layer, drying and filtering, and concentrating to obtain a dried product; adding the dried product into a DMF solvent, then adding a catalyst for reaction for 1 hour at normal temperature, then adding 2,6-dimethylaniline, reacting for 18hours at normal temperature, adding water and ethyl acetate for washing, taking an organic layer, drying and filtering, and concentrating to obtain a dried concentrated product; adding the dried concentrated product into a solvent, then adding a catalyst, pressurizing and introducing hydrogen, filtering after reaction and concentrating to obtain a dried product; adding the product in the above step into a solvent, dropwise adding bromo-n-butane at normal temperature, after dropwise adding, rising temperature to 80 DEG C for reacting for 12 hours, adding diluted hydrochloric acid, slowing cooling to normal temperature, and crystallizing, filtering and drying to obtain the product. The synthesis method has the advantages of higher yield, smaller pollution and low equipment requirement.
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- Preparation process of bupivacaine hydrochloride
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The invention discloses a preparation process of bupivacaine hydrochloride. According to the specific scheme, N-(2,6-xylyl)-2-piperidine formamide is adopted as a starting raw material and dissolved in methylbenzene, then a deacidification agent, a phase transfer catalyst and bromobutane are added, certain temperature is kept for reacting, and after the reaction is finished, filtering is carried out at room temperature, and a bupivacaine solution is obtained; the bupivacaine solution is acidized with an acidification agent, aftertreatment is carried out, and bupivacaine hydrochloride is obtained through drying. According to the preparation process, the solvent can be recycled, the production cost can be reduced, environmental pollution can be reduced, meanwhile, byproducts of other products of the company are fully utilized, refuse reclamation is achieved, and generated waste gas, waste water and industrial residues are reduced.
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Paragraph 0024; 0025; 0026; 0027
(2017/07/20)
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- PROCESS FOR ENANTIOMERIC ENRICHMENT OF 2 ', 6 ' - PIPECOLOXYLIDIDE
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The invention discloses a process for enantiomeric enrichment of 2',6'-pipecoloxylidide using a chiral carbamoyl benzoic acid to provide (S)-enantiomer in high yield and high enantiomeric purity. The invention also discloses novel intermediates formed in the process of enantiomeric enrichment of 2',6'-pipecoloxylidide, preparation of N- substituted amidic acids and alkylation of 2',6'-pipecoloxylidide.
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Page/Page column 18-19
(2014/02/15)
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- Sustained-release liposomal anesthetic compositions
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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.
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Page/Page column 4
(2008/06/13)
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- PHARMACOLOGICALLY ACTIVE SALTS
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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.
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- Racemisation of R-Bupivacaine: A key factor in the integrated and economic process for the production of levobupivacaine
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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].
- Langston, Marianne,Dyer, Ulrich C.,Frampton, Graham A.C.,Hutton, Gordon,Lock, Christopher J.,Skead, Benjamin M.,Woods, Martin,Zavareh, Hooshang S.
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p. 530 - 533
(2013/08/07)
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