- Chiral separation and modeling of baclofen, bupropion, and etodolac profens on amylose reversed phase chiral column
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Chiral resolution of baclofen, bupropion, and etodolac profens was obtained with amylose derivatized chiral reversed stationary phase (carbamate groups). The eluent used for bupropion and etodolac was MeOH–water (20:80, v/v) and for baclofen was water–methanol (95:5, v/v). The eluent run rates, finding wavelength and temperature, were 1.0?mL/min, 220?nm and 27?±?1?°C for all the eluents. The magnitude of the retardation factors for S- and R-enantiomers of baclofen, bupropion, and etodolac were 1.37, 2.62, 2.25, 3.25, 1.8, and 3.0. The magnitudes of separation and resolution factors were 1.90, 1.44, and 1.67 and 2.77, 2.35, and 2.04. Limits of detection and quantitation were 1.0–2.0 and 5.1–10.0?μg/mL. Chiral recognition mechanisms were recognized by simulation and high-performance liquid chromatography (HPLC) experiments. It was seen that hydrogen interactions, hydrophobic interactions, and π–π exchanges were the chief interactions for chiral recognition mechanisms. The described methods may be exploited for the chiral separation of baclofen, bupropion, and etodolac profens in any unknown sample.
- Ali, Imran,Suhail, Mohd.,Alothman, Zeid A.,Alwarthan, Abdulrahman
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- Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography
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Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1′-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.
- Jiang, Hong,Yang, Kuiwei,Zhao, Xiangxiang,Zhang, Wenqiang,Liu, Yan,Jiang, Jianwen,Cui, Yong
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supporting information
p. 390 - 398
(2021/01/13)
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- COCRYSTALS OF (R)-BACLOFEN
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The invention relates to novel cocrystals of (R)-Baclofen and processes for preparation thereof, and in particular to cocrystals of (R)-Baclofen with cinnamic acid, benzoic acid, salicylic acid and ferulic acid. It also refers to pharmaceutical compositions containing said cocrystals and to a use of said cocrystals or pharmaceutical compositions for the treatment of a disease or disorder selected from spasticity due to multiple sclerosis, spinal cord injury or cerebral palsy, and alcoholism.
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Page/Page column 23
(2020/07/21)
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- Method for Resolution of Baclofen Salts
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The invention relates to the field of resolution of chiral compounds existing in the form of two optical antipodes (enantiomers), such as Baclofen. More particularly, the invention relates to the production of the pure enantiomer (R)(?) Baclofen, of chemical nomenclature (R)-4-amino-3-(4-chlorophenyl)-butanoic acid, and the hydrogen maleate salt thereof. More specifically, the invention relates to the resolution of hydrogen maleate salts of racemic Baclofen by preferential crystallisation and particularly by the AS3PC method (auto-seeded and programmed polythermal preferential crystallisation).
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Paragraph 0111; 0113; 0115; 0180-0190
(2019/11/22)
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- Rhodium-catalyzed asymmetric hydrogenation of β-cyanocinnamic esters with the assistance of a single hydrogen bond in a precise position
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With the assistance of hydrogen bonds, the first asymmetric hydrogenation of β-cyanocinnamic esters is developed, affording chiral β-cyano esters with excellent enantioselectivities (up to 99% ee). This novel methodology provides an efficient and concise synthetic route to chiral GABA-derivatives such as (S)-Pregabalin, (R)-Phenibut, (R)-Baclofen. Interestingly, in this system, the catalyst with a single H-bond donor performs better than that with double H-bond donors, which is a novel discovery in the metalorganocatalysis area.
- Li, Xiuxiu,You, Cai,Yang, Yusheng,Yang, Yuhong,Li, Pan,Gu, Guoxian,Chung, Lung Wa,Lv, Hui,Zhang, Xumu
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p. 1919 - 1924
(2018/02/23)
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- Biocatalytic desymmetrization of 3-substituted glutaronitriles by nitrilases. A convenient chemoenzymatic access to optically active (S)-Pregabalin and (R)-Baclofen
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Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access (S)-Pregabalin and (R)-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles (1a) or 3-(4′-chlorophenyl)glutaronitriles (1b) as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of 1a and 1b to form optically active 3-(cyanomethyl)-5-methylhexanoic acid (2a) and 3-(4′-chlorophenyl) -4-cyanobutanoic acid (2b) with high enantiomeric excesse (ee), respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated (R)-2b, whereas BjNIT6402 and HsNIT produced the opposite (S)-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substituent of the substrates also exerted great effect on the enzyme activity and stereoselectivity. (S)-2a and (S)-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of (S)-2a and (S)-2b, followed by the acidic hydrolysis, afforded (S)-Pregabalin and (R)-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted γ-amino acids of pharmaceutical importance.
- Duan, Yitao,Yao, Peiyuan,Ren, Jie,Han, Chao,Li, Qian,Yuan, Jing,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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p. 1164 - 1171
(2014/08/18)
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- METHOD FOR PREPARING CHIRAL BACLOFEN
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The present invention provides a novel method for preparing chiral Baclofen with higher yield, higher e.e. value, and lower cost via chiral Michael addition.
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Page/Page column 4
(2012/02/06)
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- OPTICALLY ACTIVE 4-AMINO-3-(4-CHLOROPHENYL)BUTANOIC ACID
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Provided is a new crystal A of optically active 4-amino-3-(4-chlorophenyl)butanoic acid which is far better in stability, and a process for producing the crystal and a process for producing the crystal A comprising a step of heating the following crystal B in water having a pH of 3 to 9: crystal A: a crystal of optically active 4-amino-3-(4-chlorophenyl)butanoic acid which has diffraction peaks within the range of a diffraction angle 2θ of 8.7 to 9.4°, within that of 2θ of 12.2 to 12.8°, and within that of 2θ of 24.8 to 25.4° in a powder X-ray diffraction measurement of the crystal by use of the Cu—Kα wavelength; and crystal B: a crystal of optically active 4-amino-3-(4-chlorophenyl)butanoic acid which has diffraction peaks within the range of a diffraction angle 2θ of 20.8 to 21.4°, within that of 2θ of 26.7 to 27.3°, and within that of 2θ of 29.7 to 30.3° in a powder X-ray diffraction measurement of the crystal by use of the Cu—Kα wavelength.
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(2011/07/06)
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- METHOD OF PRODUCING PURIFIED OPTICALLY ACTIVE 4-AMINO-3-(SUBSTITUTED PHENYL)BUTANOIC ACID COMPOUND
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A method of producing a purified optically active 4-amino-3-(substituted phenyl)butanoic acid compound which is characterized by comprising a step of making a crude optically active 4-amino-3-(substituted phenyl)butanoic acid compound contact an organic acid in the presence of water.
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Page/Page column 5
(2011/04/18)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 61
(2010/12/31)
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- Method of Producing Optically Active 4-Amino-3-Substituted Phenylbutanoic Acid
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The present invention provides a method of producing a compound (IIa) or a compound (IIb), provides a method of producing a compound (IIIa) or a compound (IIIb), provides a method of producing a compound (Va) or its salt or a compound (Vb) or its salt, provides a method of producing a compound (IIIa) or a compound (IIIb), further, provides a method of producing a compound (Va) or its salt or a compound (Vb) or its salt including these production methods.
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Page/Page column 14
(2009/06/27)
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- An efficient enantioselective method for asymmetric Michael addition of nitroalkanes to α,β-unsaturated aldehydes
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The addition of nitroalkanes to α,β-unsaturated aldehydes under the catalysis of (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine and lithium acetate as additive afforded γ-nitroaldehydes in good yield and up to 97% ee. The Royal Society of Chemistry.
- Wang, Yongcan,Li, Pengfei,Liang, Xinmiao,Zhang, Tony Y.,Ye, Jinxing
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p. 1232 - 1234
(2008/12/20)
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- A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA(Baclofen)
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Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.
- Felluga, Fulvia,Gombac, Valentina,Pitacco, Giuliana,Valentin, Ennio
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p. 1341 - 1345
(2007/10/03)
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- Enantioselective synthesis of (-)-(R)-Baclofen and analogues via rhodium-catalysed conjugate addition of boronic acids
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Highly enantioselective syntheses of the antispastic drug (-)-(R)-Baclofen and analogues have been achieved by using rhodium-catalysed asymmetric 1,4-additions of arylboronic acids to 4-amino-but-2,3-enoic acid derivatives.
- Meyer, Oliver,Becht, Jean-Michel,Helmchen, Günter
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p. 1539 - 1541
(2007/10/03)
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- Process for the optical resolution of 3-(p-chlorophenyl)-glutaramide
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PCT No. PCT/GB96/03103 Sec. 371 Date Jun. 19, 1998 Sec. 102(e) Date Jun. 19, 1998 PCT Filed Dec. 16, 1996 PCT Pub. No. WO97/22578 PCT Pub. Date Jun. 26, 1997A process for the optical resolution of racemic 3-(p-chlorophenyl)glutaramide (GAM) into its R isomer R-COOH and its S isomer S-COOH, which process includes the steps of either: (1) reacting racemic 3-(p-chlorophenyl)-glutaramide dissolved in a suitable solvent with S-(-)- alpha -methylbenzylamine of the formula H2N-S'(2) precipitating out of the solution of step (1) R-CO2-.H3+N-S'; (3) dissolving the precipitate of step (2) in water, with the addition of a suitable acid; and (4) precipitating out of the solution of step (3) R-COOH; or (5) reacting racemic -3-(p-chlorophenyl)-glutaramide dissolved in a suitable solvent with R-(+)- alpha -methylbenzylamine of the formula H2N-R'; (6) precipitating out of the solution of step (5) S-CO2-.H3+N-R'; (7) dissolving the precipitate of step (6) in water, with the addition of a suitable acid, and (8) precipitating out of the solution of step (7) S-COOH. The R isomer of GAM may be used for the production of R-baclofen and the S isomer of GAM may be used for the production of S-baclofen.
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- An efficient synthesis of (R)-(-)-baclofen
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In this report we describe an efficient synthesis of (R)-(-)-baclofen, a selective GABA(B) agonist used as an antispastic agent. Our strategy is based on an enantioselective deprotonation of a cyclobutanone easily obtained by [2+2] cycloaddition of 4-chlorostyrene and dichloroketene.
- Resende, Patricia,Almeida, Wanda P.,Coelho, Fernando
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p. 2113 - 2118
(2007/10/03)
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- Enantioselective synthesis of β-substituted butyric acid derivatives via orthoester Claisen rearrangement of enzymatically resolved allylic alcohols: Application to the synthesis of (R)-(-)-baclofen
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A three step synthesis of (R)-(-)-baclofen is described. The key step is the orthoester Claisen rearrangement of enantiopure allylic alcohol (S,E)-(-)-1a, affording γ,δ-unsaturated ester (S,E)-(+)-6 with high stereoselectivity. This latter derivative is converted into (R)-(-)-baclofen through a high yield one-pot reaction.
- Brenna, Elisabetta,Caraccia, Nicola,Fuganti, Claudio,Fuganti, Daniela,Grasselli, Piero
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p. 3801 - 3805
(2007/10/03)
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- Optical resolution of baclofen via diastereomeric salt pair formation between 3-(p-chlorophenyl)glutaramic acid and (S)-(-)-α-phenylethylamine
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The structures of the diastereomeric salts of (R)-(+)- and (S)-(-)-3-(p-chlorophenyl)glutaramic acid with (S)-(-)-phenylethylamine have been determined by X-ray crystallography. Solubility and melting behaviours of the salts were analysed and correlated with their structural properties in the solid state. The (R)-(+)-3-(p-chlorophenyl)glutaramic acid was converted to (R)-(-)-baclofen via a Hofmann degradation (57% yield, 99.8% ee, enantiomeric excess).
- Caira, Mino R.,Clauss, Rainer,Nassimbeni, Luigi R.,Scott, Janet L.,Wildervanck, Alexander F.
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p. 763 - 768
(2007/10/03)
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- Enantioselective syntheses of (R)-3-phenyl GABA, (R)-baclofen and 4-arylpyrrolidin-2-ones
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Enantioselective synthesis of (R)-4-amino-3-phenylbutyric acid and (R)-baclofen has been achieved through a diastereoselective conjugate addition of cyanide to enantiomerically pure 2-(2-arylethenyl)oxazolines, followed by chemoselective reduction into cyclic amidines.
- Langlois, Nicole,Dahuron, Nathalie,Wang, Hai-Shan
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p. 15117 - 15126
(2007/10/03)
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- Chemoenzymatic enantioselective synthesis of baclofen
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We report two different chemoenzymatic enantioselective syntheses of baclofen based on the distinction between enantiotopic ester groups in compounds bearing a prochiral centre. In the first approach, the key step is the highly stereoselective enzymatic hydrolysis of dimethyl 3-(4-chlorophenyl)glutarate by chymotrypsin in an aqueous medium. In the second approach, the key step is the enzyme-catalyzed esterification of 2-(4-chlorophenyl)-1,3-propanediol by acetic anhydride in the presence of a lipase in an organic medium. We report two different chemoenzymatic enantioselective syntheses of baclofen based on the distinction between enantiotopic ester groups in compounds bearing a prochiral centre. In the first approach, the key step is the highly stereoselective enzymatic hydrolysis of dimethyl 3-(4-chlorophenyl)glutarate by chymotrypsin in an aqueous medium. In the second approach, the key step is the enzyme-catalyzed esterification of 2-(4-chlorophenyl)-1,3-propanediol by acetic anhydride in the presence of a lipase in an organic medium.
- Chenevert,Desjardins
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p. 2312 - 2317
(2007/10/02)
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