- Direct Catalytic N-Alkylation of α-Amino Acid Esters and Amides Using Alcohols with High Retention of Stereochemistry
-
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.
- Yan, Tao,Feringa, Ben L.,Barta, Katalin
-
p. 2303 - 2307
(2021/05/11)
-
- Method for preparing ropivacaine hydrochloride
-
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.
- -
-
Paragraph 0028; 0058; 0063-0064; 0071; 0076-0077
(2021/12/07)
-
- A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics
-
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
-
p. 3084 - 3089
(2021/08/12)
-
- Industrial preparation method of ropivacaine hydrochloride monohydrate
-
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.
- -
-
Paragraph 0013; 0038; 0041-0042; 0050; 0053-0054
(2021/07/14)
-
- Preparation method of ropivacaine hydrochloride
-
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
-
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
-
p. 6511 - 6517
(2017/12/02)
-
- Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties
-
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
-
p. 2216 - 2239
(2016/10/19)
-
- A process for the preparation of ropivacaine hydrochloride
-
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
-
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.
- Leonard, John,Blacker, A. John,Marsden, Stephen P.,Jones, Martin F.,Mulholland, Keith R.,Newton, Rebecca
-
p. 1400 - 1410
(2015/11/02)
-
- PROCESS FOR PRODUCING OPTICALLY ACTIVE N-ALKYL-PIPERIDINE-2-CARBOXANILIDE
-
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
- -
-
Page/Page column 8
(2010/08/08)
-
- 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
-
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.
-
supporting information; experimental part
p. 12216 - 12217
(2010/12/25)
-
- Recycling of pipecoloxylidide via racemization
-
A method for the racemization of pipecoloxylidide with a ruthenium catalyst has been developed. This racemization method can be implemented in an integrated process that combines the separation of two enantiomers with racemization of the undesired enantio
- Thalén, Lisa K.,Hedberg, Martin H.,B?ckvall, Jan-E.
-
body text
p. 6802 - 6805
(2011/03/18)
-
- PROCESS FOR THE PREPARATION OF (S)-ROPIVACAINE HYDROCHLORIDE MONOHYDRATE
-
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
- -
-
Page/Page column 10-11
(2009/05/29)
-
- PROCESS FOR THE PREPARATION OF (S)-1-ALKYL-2',6'-PIPECOLOXYLIDIDE COMPOUND
-
The present invention relates to an improved process for the preparation of high chiral purity (S)-1-alkyl-2',6'-Pipecoloxylidide compound such as Ropivacaine, Levobupivacaine or salts thereof, which comprises crystallization of (S)-1-alkyl-2',6'- Pipecoloxylidide acid addition salt in a non-alcoholic and non-ketonic solvent.
- -
-
Page/Page column 3
(2009/08/16)
-
- Enantioselective total syntheses of ropivacaine and its analogues
-
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.
-
p. 5098 - 5100
(2008/12/21)
-
- ROPIVACAINE HYDROCHLORIDE ANHYDRATE AND THE PREPARATION THEREOF
-
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
- -
-
Page/Page column 9-11
(2008/06/13)
-
- A PROCESS FOR THE PREPARATION OF AN INJECTABLE SOLUTION OF (2S)-N-(2;6-DIMETHYL-PHENYL)-1-PROPYL-2-PIPERIDINCARBOXAMIDE
-
A process for the preparation of an injectable solution of (2S)-(-)-N- (2;6-dimethyl-phenyl)-l-propyl-2-piperidincarboxamide (Ropivacaine) starting from Ropivacaine base substantially free from the dextro enantiomer, by dissolution of the same in water fo
- -
-
Page/Page column 3-4
(2008/06/13)
-
- Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom
-
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.
- -
-
Page/Page column 4
(2008/06/13)
-
- Determination of the enantiomeric purity of S-ropivacaine by capillary electrophoresis with methyl-β-cyclodextrin as chiral selector using conventional and complete filling techniques
-
Capillary electrophoresis (CE) methods based on the conventional and complete filling techniques for determination of the enantiomeric purity of S-ropivacaine are described. The complete filling technique is a separation method which can be used instead of the partial filling technique in order to reduce the total analysis time, when the chiral selector solution does not absorb UV light. In the complete filling technique the total length of the capillary is filled with the chiral selector solution, prior to application of the analyte. During the run both ends of the capillary are connected to the background electrolyte, i.e. without chiral agent. An interlaboratory study was performed to validate the method. The limit of detection and quantification for R-ropivacaine were found to be about 0.6 and 1.6 μg/ml, respectively, corresponding to 0.1 and 0.25% enantiomeric purity of S-ropivacaine. Good performances were demonstrated for the repeatability and linearity. The consumption of the chiral selector was about 160 times lower with the complete filling technique compared with the conventional CE technique. Copyright (C) 1999 Elsevier Science B.V.
- Amini, Ahmad,Wiersma, Britta,Westerlund, Douglas,Paulsen-Soerman, Ulla
-
-