- A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics
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A novel and enantioselective synthesis of (S)-2-pipecolic acid (5) has been achieved from Oppolzer’s sultam (1) and ethyl N-(diphenylmethylene)glycinate (2) as readily available starting materials. The highly stereoselective alkylation of chiral glycine intermediate (3) with 1,4-dibromobutane afforded the key backbone of (S)-2-pipecolic acid (5) in one-step that was utilized into the preparation of the local anesthetics mepivacaine, ropivacaine and bupivacaine.
- Yang, Yuyan,Li, Hua,You, Zhonglin,Zhang, Xingxian
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p. 3084 - 3089
(2021/08/12)
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- Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof
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The invention discloses bupivacaine and a preparation method of an intermediate (S)-2-piperidinecarboxylic acid of the bupivacaine; wherein the intermediate (S)-2-piperidinecarboxylic acid is prepared by taking (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary agent through amidation, asymmetric alkylation, hydrolysis, cyclization and auxiliary group removal; wherein the prepared (S)-2-piperidinecarboxylic acid is used as a raw material to prepare the local anesthetic (S)-bupivacaine. The method utilizes cheap and easily available organic raw materials, and has the advantages of simple operation, mild reaction conditions, good stereoselectivity, high yield and the like.
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Paragraph 0025; 0072-0076
(2021/06/13)
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- Preparation and purification method of ropivacaine hydrochloride intermediate
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The invention relates to a preparation and purification method of a ropivacaine hydrochloride intermediate. According to the method, single chiral intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide is prepared from single chiral raw mate
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Paragraph 0047; 0048; 0049; 0050; 0051; 0052; 0053-0058
(2019/04/04)
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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 ropivacaine hydrochloride
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The invention discloses a preparation method of ropivacaine hydrochloride. The preparation method comprises steps as follows: (1) preparation of an intermediate (I), (2) preparation of an intermediate (II), (3) preparation of a crude product and (4) refin
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Paragraph 0019-0021; 0027; 0040; 0042
(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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- 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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- Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties
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The modulation of pharmacologically relevant properties of N-alkyl-piperidine-2-carboxamides was studied by selective introduction of 1–3 fluorine atoms into the n-propyl and n-butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non-fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine-2-carboxamide core is chiral, pairs with enantiomeric N-alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.
- Vorberg, Raffael,Trapp, Nils,Zimmerli, Daniel,Wagner, Bj?rn,Fischer, Holger,Kratochwil, Nicole A.,Kansy, Manfred,Carreira, Erick M.,Müller, Klaus
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p. 2216 - 2239
(2016/10/19)
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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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- 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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- 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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experimental part
p. 343 - 352
(2012/06/18)
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- Highly enantioselective catalytic dynamic resolution of N-boc-2-lithiopiperidine: Synthesis of (R)-(+)- N-boc-pipecolic acid, (S)-(-)-coniine, (S)-(+)-pelletierine, (+)-β-conhydrine, and (S)-(-)-ropivacaine and formal synthesis of (-)-lasubine II and (+)-cermizine C
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The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9 in the presence of TMEDA has led to the highly enantioselective syntheses of both enantiomers of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of (R)- and (S)-pipecolic acid derivatives, (+)-β-conhydrine, (S)-(+)-pelletierine, and (S)-(-)-ropivacaine and the formal synthesis of ()-lasubine II and (+)-cermizine C.
- Beng, Timothy K.,Gawley, Robert E.
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supporting information; experimental part
p. 12216 - 12217
(2010/12/25)
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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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- PROCESS FOR THE PREPARATION OF (S)-ROPIVACAINE HYDROCHLORIDE MONOHYDRATE
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Process for preparation of Ropivacaine hydrochloride monohydrate comprising resolution of racemic pipecoloxylidide in non-ketonic solvents to give (S)-pipecoloxylidide followed by N-propylation to in water ass reaction medium give (S)-Ropivacaine base; co
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Page/Page column 9-10
(2009/05/29)
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- Enantioselective total syntheses of ropivacaine and its analogues
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An alternative asymmetric synthesis of ropivacaine and analogues employing the 'cation pool' strategy and host/guest supramolecular co-catalysis approach is presented. In this study, chiral auxiliaries, several soft nucleophiles as well as one-pot conditions for anodic oxidation, followed by nucleophilic addition, have been applied.
- Shankaraiah, Nagula,Pilli, Ronaldo Aloise,Santos, Leonardo S.
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p. 5098 - 5100
(2008/12/21)
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- ROPIVACAINE HYDROCHLORIDE ANHYDRATE AND THE PREPARATION THEREOF
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The invention pertains to a process for preparing stable anhydrous Ropivacaine hydrochloride, the process involving preparing Ropivacaine hydrochloride from Ropivacaine base, wherein Ropivacaine base is provided having a chiral purity of more than 95 %, a
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Page/Page column 9-11
(2008/06/13)
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- Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom
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The present invention describes a novel process of preparation of optically pure L-Pipecolic acid and an improved process for the conversion of L-pipecolic acid to L-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide, its hydrochloride salt and hydrochloride monohydrate.
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Page/Page column 4
(2008/06/13)
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- Studies directed towards asymmetric synthesis of levobupivacaine
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We report herein the first catalytic asymmetric synthesis of levobupivacaine. The key step involves the asymmetric alkylation of N-benzylimine glycinamide (2b).
- Kumar, Sanjeev,Ramachandran, Uma
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- PROCESS FOR PRODUCING PIPECOLAMIDE DERIVATIVE
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A method of manufacturing a pipecolamide derivative, characterized in that pipecolic acid or an acid salt thereof is reacted with an amine in an inert solvent in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl- 2-(2-dimethylam
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Page column 4
(2010/02/07)
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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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- Stereospecific synthesis of the anaesthetic levobupivacaine
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Enantiomerically pure (S)-bupivacaine is synthesized from the chiral pool using cheap and readily available (S)-lysine. The key steps in this efficient synthesis include an oxidative de-amination and stereospecific ring closure to form the pipecolamide core structure.
- Adger, Brian,Dyer, Ulrich,Hutton, Gordon,Woods, Martin
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p. 6399 - 6402
(2007/10/03)
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