98717-16-9Relevant articles and documents
Direct Catalytic N-Alkylation of α-Amino Acid Esters and Amides Using Alcohols with High Retention of Stereochemistry
Yan, Tao,Feringa, Ben L.,Barta, Katalin
, p. 2303 - 2307 (2021/05/11)
The direct functionalization of naturally abundant chiral scaffolds such as α-amino acid esters or amides with widely abundant alcohols, without any racemization, is a demanding transformation that is of central importance for the synthesis of bio-active compounds. Herein a robust and general method was developed for the direct N-alkylation of α-amino acid esters and amides with alcohols. This powerful ruthenium-catalyzed methodology is atom-economic, base-free, and allowed for excellent retention of stereochemical integrity. The use of diphenylphosphate as additive was crucial for significantly enhancing reactivity and product selectivity. Notably, the only by-product was water and both substrates could be potentially derived from renewable resources.
Method for preparing ropivacaine hydrochloride
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Paragraph 0028; 0058; 0063-0064; 0071; 0076-0077, (2021/12/07)
The preparation method comprises the following specific steps: 1) reacting (S)- piperidine -2 - formic acid with propionaldehyde in the presence of a reducing agent and an aprotic solvent to obtain the intermediate 1. 2). N. NIn the presence of -dimethylformamide and an aprotic solvent, the intermediate 1 obtained in step 1) and the acylating agent are subjected to an acylation reaction to give an intermediate 2. 3). N. N[-] The intermediate 2 obtained in step 2) and 2 and 6 -dimethylaniline are subjected to a condensation reaction in the presence of dimethylformamide and basic conditions to give an intermediate 3. 4) The intermediate 3 obtained in step 3) is salified with hydrochloric acid to give the ropivacaine hydrochloride crude product. 5) The ropivacaine hydrochloride is purified to obtain ropivacaine hydrochloride. The method has the advantages that the product purity is higher than 99.99%, the synthesis process is mild in reaction condition, simple in preparation process, low in cost, safe and environment-friendly, and is suitable for industrial production.
A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics
Yang, Yuyan,Li, Hua,You, Zhonglin,Zhang, Xingxian
, p. 3084 - 3089 (2021/08/12)
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.
Industrial preparation method of ropivacaine hydrochloride monohydrate
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Paragraph 0013; 0038; 0041-0042; 0050; 0053-0054, (2021/07/14)
The invention discloses an industrial synthesis method of ropivacaine hydrochloride monohydrate. The method comprises the following steps: dissolving racemized 2-piperidinecarboxylic acid serving as a starting material in an organic solvent, and carrying out alkylation reaction, transesterification, chiral resolution and salification refining to obtain a target product. The raw materials are cheap and easy to obtain, a one-pot method is adopted, organic reagents are easy to recycle and reuse, the reaction safety coefficient is high, the technological operation is simple, few three wastes are generated, and the obtained ropivacaine hydrochloride monohydrate is high in yield and high in purity.
Preparation method of ropivacaine hydrochloride
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, (2017/11/29)
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
Synthesis of Mepivacaine and Its Analogues by a Continuous-Flow Tandem Hydrogenation/Reductive Amination Strategy
Suveges, Nícolas S.,de Souza, Rodrigo O. M. A.,Gutmann, Bernhard,Kappe, C. Oliver
, p. 6511 - 6517 (2017/12/02)
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.
Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties
Vorberg, Raffael,Trapp, Nils,Zimmerli, Daniel,Wagner, Bj?rn,Fischer, Holger,Kratochwil, Nicole A.,Kansy, Manfred,Carreira, Erick M.,Müller, Klaus
, p. 2216 - 2239 (2016/10/19)
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.
A process for the preparation of ropivacaine hydrochloride
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, (2017/02/24)
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.
A Survey of the Borrowing Hydrogen Approach to the Synthesis of some Pharmaceutically Relevant Intermediates
Leonard, John,Blacker, A. John,Marsden, Stephen P.,Jones, Martin F.,Mulholland, Keith R.,Newton, Rebecca
, p. 1400 - 1410 (2015/11/02)
The use of the "borrowing hydrogen strategy" in the synthesis of a number of typical pharmaceutical intermediates has been investigated. The main aim of this work was to investigate the scope and limitations of current methodology using standard laboratory techniques in an industrial context. Some interesting and significant results were achieved across a diverse set of complex substrates; however several drawbacks with this approach were identified, such as the high loading, poor turnover, and susceptibility to substrate inactivation of the catalysts. These are areas which are highlighted for future investigation and improvements.
PROCESS FOR PRODUCING OPTICALLY ACTIVE N-ALKYL-PIPERIDINE-2-CARBOXANILIDE
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Page/Page column 8, (2010/08/08)
Disclosed herein is a process for producing optically active 1-n-propyl-2',6'-dimethyl-2-piperidinecarboxanilide. The process comprises of reacting n-propyl pipecolate ester with 2,6-dimethylanilino magnesium halide. The 1-n-propyl-2',6'-dimethyl-2-piperi
