- Design of an integrated process of chromatography, crystallization and racemization for the resolution of 2′,6′-pipecoloxylidide (PPX)
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An integrated process for the chiral separation of the industrially relevant substance 2′,6′-pipecoloxylidide (PPX), an intermediate in the manufacture of a number of anesthetics, was developed. By combining three different techniques, chromatography, crystallization, and racemization, high productivity was achieved. All unit operations were executed using a common solvent system, full recycling, and a minimum of solvent exchanges or removals. The target molecule was obtained with an enantiopurity of >99.5 wt %.
- Von Langermann, Jan,Kaspereit, Malte,Shakeri, Mozaffar,Lorenz, Heike,Hedberg, Martin,Jones, Matthew J.,Larson, Kerstin,Herschend, Bjoern,Arnell, Robert,Temmel, Erik,Baeckvall, Jan-Erling,Kienle, Achim,Seidel-Morgenstern, Andreas
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- Synthesis, biological evaluation, and molecular docking of ropivacaine analogs as local anesthetic agents
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Two series of ropivacaine analogs (4a–4q, 7a–7c) were synthesized, and their biological activities were evaluated as local anesthetic agents. Most of the compounds displayed detectable local anesthetic characteristics. Among them, compound 4l showed significant efficacy with sciatic nerve block, infiltration, corneal surface, and spinal anesthetic activities. It was as potent as the reference compound ropivacaine. Dissociation constants of these compounds were 5.9–7.9. In addition, molecular docking modeling on compound 4l and ropivacaine was performed to delineate structural requirements and potential mechanisms for the local anesthetic activity. This study provides valuable new information for our ongoing endeavor to design more potent local anesthetics.
- Li, Wen,Ding, Lina,Liu, Hong-Min,You, Qidong
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p. 954 - 965
(2017/11/29)
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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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Paragraph 0019; 0020; 0021; 0022; 0023; 0030; 0031; 0032-36
(2018/01/12)
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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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Paragraph 0010; 0017
(2016/10/10)
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- Topalgia treatment methods and compositions for treating
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of local pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postheipetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and Sower back pain.
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Paragraph 0093; 0095
(2017/02/23)
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- A process for the preparation of ropivacaine hydrochloride
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The invention provides a method for preparing hydrochloric acid ropivacaine. Part of parameters and conditions in the prior art are improved, and optimization is performed through the following steps that intermediate (I) separation pH and separation extracting solvent are selected; a catalyst and the usage quantity of the catalyst in a resolution agent are selected; refining solvent is selected. In this way, the yield and purity of the prepared hydrochloric acid ropivacaine are high, the purity reaches up to over 99% under the optimal condition, the percentage of dextrorotary isomer is reduced below 0.5%, standard requirements are completely met, and the hydrochloric acid ropivacaine is suitable for industrial production.
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Paragraph 0011; 0123; 0124
(2017/02/24)
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- Compositions and methods for the treatment of local pain
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of local pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain.
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Page/Page column 24-25
(2015/11/27)
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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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- PROCESS FOR PRODUCING PIPECOLIC-2-ACID-2 ',6'-XYLIDIDE USEFUL AS AN INTERMEDIATE FOR THE PREPARATION OF LOCAL ANESTHETICS
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The present invention relates to an improved process for the preparation of pipecolic-2- acid-2',6'-xylidide or derivative thereof wherein it comprises hydrogenation of picolinic-2-acid-2',6'-xylidide in the presence of a Raney-nickel as a catalyst.
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Page/Page column 5-6
(2009/08/16)
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- LOCAL ANESTHETIC COMPOUNDS AND USES
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Novel compounds, pharmaceutical compositions and methods are disclosed for producing local anesthesia of long-duration. The compounds of this invention are multibinding compounds that comprise from 2 to 10 ligands covalently attached to a linker or linkers, each ligand being capable of binding to a ligand binding site in a voltage-gated Na + channel to modulate the biological processes/functions thereof.
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- Local anesthetic compounds and uses
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Novel compounds, pharmaceutical compositions and methods are disclosed for producing local anesthesia of long-duration. The compounds of this invention are multibinding compounds that comprise from 2 to 10 ligands covalently attached to a linker or linkers, each ligand being capable of binding to a ligand binding site in a voltage-gated Na+channel to modulate the biological processes/functions thereof.
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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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- Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants
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A variety of 2-piperidinecarboxamides were synthesized and evaluated for anticonvulsant activity using the MES and sc PTZ tests in mice and rats. Neurotoxicity was determined by the rotorod test. Several N-(benzyl)-2- piperidinecarboxamides exhibited potent MES activity in mice [2-CF3 14, ED50 = 29 mg/kg; 3-F 16, ED50 = 31 mg/kg; and 3-CF3 17, ED50 = 24 mg/kg]. The most active compounds in the MES test in mice were the 2,6- dimethylanilides [(R,S)-34, ED50 = 5.8 mg/kg; (R)-35, ED50 = 5.7 mg/kg; and (S)-36, ED50 = 14.8 mg/kg]. The enantiomer (S)-36 was about two-fold less potent in the MES test than (R)-35 and also was less neurotoxic. Acylation of the piperidine ring nitrogen of 12 anal 34 led to a decrease in the MES activity. In the N-(α-methylbenzyl)-2-piperidine-carboxamides, the stereochemistry at either the 2-position of the piperidine ring or at the α- position of the N-(α-methylbenzyl) group does not significantly affect MES activity.
- Ho, Bin,Venkatarangan, Prabha M.,Cruse, Sharon F.,Hinko, Christine N.,Andersen, Peter H.,Crider, Albert M.,Adloo, Ahmad A.,Roane, David S.,Stables, James P.
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