scholarly journals Effect of Reaction Parameters on the Lipase-Catalyzed Kinetic Resolution of (RS )-Metoprolol

2020 ◽  
Vol 20 (1) ◽  
pp. 20
Author(s):  
Mariani Rajin ◽  
Asiah Binti Zulkifli ◽  
Sariah Abang ◽  
S.M Anissuzzaman ◽  
Azlina Harun Kamaruddin
Keyword(s):  
Adrenergic Receptor ◽  
Kinetic Resolution ◽  
Beta Blockers ◽  
Enantiomeric Excess ◽  
Acyl Donor ◽  
Market Demand ◽  
Disease Treatment ◽  
Enantiomeric Ratio ◽  
Candida Antarctica B ◽  
Candida Antarctica B Lipase

Racemic metoprolol is a selective ß1-blocker, which is used in cardiovascular disease treatment. It has been found that (S)-metoprolol has a higher affinity to bind the ß-adrenergic receptor compared to (R)-metoprolol. Moreover, the regulatory authorities’ high market demand and guidelines have increased the preference for single enantiomer drugs. In this work, the lipase-catalyzed kinetic resolution of racemic metoprolol was performed to obtain the desired enantiomer. The type of lipase, acyl donor, and solvent were screened out. This was achieved by Candida antarctica B lipase-catalyzed transesterification of racemic metoprolol in hexane and vinyl acetate as the solvent and an acyl donor, which gave maximum conversion of (S)-metoprolol (XS) of 52%, enantiomeric excess of substrate, (ees) of 92% and product (eeP) of 90% with enantiomeric ratio (E) of 62. This method can be considered as green chemistry, which can be applied to produce other enantiopure beta-blockers.

scholarly journals Biocatalytic synthesis of (S)-Practolol, a selective β-blocker

Biocatalysis ◽  
2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Sachin Mulik ◽  
Saptarshi Ghosh ◽  
Jayeeta Bhaumik ◽  
Uttam C. Banerjee
Keyword(s):  
Adrenergic Receptor ◽  
Kinetic Resolution ◽  
Sol Gel ◽  
Enantiomeric Excess ◽  
Green Technology ◽  
Chemoenzymatic Synthesis ◽  
Acyl Donor ◽  
Pseudomonas Cepacia ◽  
Reaction Parameters ◽  
Β Blocker

AbstractThe present study describes an efficient chemoenzymatic synthesis of enantiopure (S)-Practolol, a selective β-adrenergic receptor blocker. Prior to the synthesis of the target, a synthetic protocol for (RS)-N-4-(3-chloro-2-hydroxypropoxy)phenylacetamide, an essential precursor, was developed. Various commercial lipases were screened for the kinetic resolution of (RS)- N-4-(3-chloro-2-hydroxypropoxy)phenylacetamide using toluene as solvent and vinyl acetate as an acyl donor. Among various lipases screened, Pseudomonas cepacia sol-gel AK showed the highest enantioselectivity (96% enantiomeric excess with 50% conversion), affording (S)-1-(4-acetamidophenoxy)-3-chloropropan-2-yl acetate. Optimization of the reaction parameters was carried out in order to find the best-suited conditions for the biocatalysis. Furthermore, the enantiopure intermediate was hydrolyzed and the resulting product was reacted with isopropylamine to afford (S)-Practolol. This biocatalytic procedure depicts a green technology for the synthesis of (S)-Practolol with better yield and enantiomeric excess.

Isolation of an esterase-producing Trichosporon brassicae and its catalytic performance in kinetic resolution of ketoprofen

2001 ◽  
Vol 47 (12) ◽  
pp. 1101-1106 ◽  
Author(s):  
Duan Shen ◽  
Jian-He Xu ◽  
Peng-Fei Gong ◽  
Hui-Yuan Wu ◽  
You-Yan Liu
Keyword(s):  
Ethyl Ester ◽  
Sole Carbon Source ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Catalytic Performance ◽  
Soil Samples ◽  
Enantioselective Hydrolysis ◽  
Resting Cells ◽  
Enantiomeric Ratio ◽  
Hydrolysis Of

A yeast strain CGMCC 0574, identified as Trichosporon brassicae, was selected from 92 strains for its high (S) selectivity in the hydrolysis of ketoprofen ethyl ester. The effective strains of the microorganisms were isolated from soil samples with the ester as the sole carbon source. The ethyl ester proved to be the best substrate for resolution of ketoprofen among several ketoprofen esters examined. The resting cells of CGMCC 0574 could catalyze the hydrolysis of ketoprofen ethyl ester with an enantiomeric ratio of 44.9, giving (S)-ketoprofen an enantiomeric excess of 91.5% at 42% conversion.Key words: ketoprofen, biocatalytic resolution, enantioselective hydrolysis, microbial esterase, Trichosporon brassicae.

Optimization of Chiral Resolution of (+/-)-1-Phenylethanol by Statistical Methods

2011 ◽  
Vol 9 (1) ◽  
Author(s):  
Ganapati D. Yadav ◽  
Jyoti B. Sontakke
Keyword(s):  
Kinetic Resolution ◽  
Batch Reactor ◽  
Immobilized Lipase ◽  
Enantiomeric Excess ◽  
Molar Ratio ◽  
Catalyst Loading ◽  
Acyl Donor ◽  
Reaction Conditions ◽  
Optimum Reaction ◽  
Synthetic Intermediate

Optically active 1-phenylethanol is used as a chiral building block and synthetic intermediate in pharmaceutical and fine-chemical industries. Lipase - catalyzed kinetic resolution of (R,S)-1-phenylethanol with vinyl acetate as an acyl donor and Candida antarctica immobilized lipase as a biocatalyst in a batch reactor was optimized using Response Surface Methodology (RSM). Four-factor-five-level central composite rotatable design (CCRD) was employed to evaluate the effect of synthesis parameters such as speed of agitation, enzyme loading, temperature and acyl donor/alcohol molar ratio, on conversion, enantiomeric excess (ee), enantioselectivity and initial rate. Optimum reaction conditions obtained were; mole ratio of acyl donor: ester of 2:1, temperature of 42.5 °C, catalyst loading of 1.6x10-3 g.cm-3 and speed of agitation of 336 rpm. Analysis of variance was performed to determine significantly affecting variables and interactions between the process parameters.

Optimization of process parameters and kinetic modeling for the enantioselective kinetic resolution of (R,S)-2-pentanol

2017 ◽  
Vol 42 (6) ◽  
Author(s):  
Aslı Soyer Malyemez ◽  
Emine Bayraktar ◽  
Ülkü Mehmetoğlu
Keyword(s):  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Reaction Rates ◽  
Initial Reaction Rate ◽  
Initial Reaction ◽  
Acyl Donor ◽  
Optimum Conditions ◽  
Optimization Of Process Parameters ◽  
Maximum Reaction ◽  
Working Volume

AbstractIntroduction:In order to product (S)-2-pentanol which have been used as a key chiral intermediate required in the synthesis of several potential anti-Alzhemeir drugs, the effects of enzyme, acyl donor, substrate concentration and acyl donor/racemic-2-pentanol mole ratio were investigated on the kinetic resolution of racemic-2-pentanol.Methods:Reactions were performed in a bioreactor of 50 mL capacity with a working volume of 30 mL on an orbital shaker at 150 rpm and at 30°C. Production parameters were investigated with different type of enzyme and acyl donor.Results:The optimum conditions were obtained with Novozyme 435 and vinyl butyrate with the 50% conversion, 99% of enantiomeric excess for the substrate at 30 min. Optimum conditions are 1500 mM substrate and 4 mg/mL enzyme concentrations and 24.88 mM/min maximum initial reaction rate. It was obtained that Ping-Pong bi-bi mechanism was the appropriate reaction kinetic. Kinetic parameters were determined with Polymath 6.1 software as 4.16 mmol/min/g enzyme maximum reaction rates, 103.73 mM Km for (R)-2-pentanol and 51.18 mM Km for vinyl butyrate.Conclusion:(S)-2-pentanol was obtained with 99% of enantiomeric excess. These data will be clear up to product (S)-2-pentanol at larger industrial scales in future.

scholarly journals Substrate Specificity and Enantioselectivity of 4-Hydroxyacetophenone Monooxygenase

2003 ◽  
Vol 69 (1) ◽  
pp. 419-426 ◽  
Author(s):  
Nanne M. Kamerbeek ◽  
Arjen J. J. Olsthoorn ◽  
Marco W. Fraaije ◽  
Dick B. Janssen
Keyword(s):  
Carbonyl Compounds ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
The Other ◽  
Biotechnological Applications ◽  
Complete Conversion ◽  
Aromatic Ketones ◽  
Acetate Ester ◽  
Enantiomeric Ratio ◽  
Villiger Oxidation

ABSTRACT The 4-hydroxyacetophenone monooxygenase (HAPMO) from Pseudomonas fluorescens ACB catalyzes NADPH- and oxygen-dependent Baeyer-Villiger oxidation of 4-hydroxyacetophenone to the corresponding acetate ester. Using the purified enzyme from recombinant Escherichia coli, we found that a broad range of carbonylic compounds that are structurally more or less similar to 4-hydroxyacetophenone are also substrates for this flavin-containing monooxygenase. On the other hand, several carbonyl compounds that are substrates for other Baeyer-Villiger monooxygenases (BVMOs) are not converted by HAPMO. In addition to performing Baeyer-Villiger reactions with aromatic ketones and aldehydes, the enzyme was also able to catalyze sulfoxidation reactions by using aromatic sulfides. Furthermore, several heterocyclic and aliphatic carbonyl compounds were also readily converted by this BVMO. To probe the enantioselectivity of HAPMO, the conversion of bicyclohept-2-en-6-one and two aryl alkyl sulfides was studied. The monooxygenase preferably converted (1R,5S)-bicyclohept-2-en-6-one, with an enantiomeric ratio (E) of 20, thus enabling kinetic resolution to obtain the (1S,5R) enantiomer. Complete conversion of both enantiomers resulted in the accumulation of two regioisomeric lactones with moderate enantiomeric excess (ee) for the two lactones obtained [77% ee for (1S,5R)-2 and 34% ee for (1R,5S)-3]. Using methyl 4-tolyl sulfide and methylphenyl sulfide, we found that HAPMO is efficient and highly selective in the asymmetric formation of the corresponding (S)-sulfoxides (ee > 99%). The biocatalytic properties of HAPMO described here show the potential of this enzyme for biotechnological applications.

scholarly journals Immobilization and Biochemical Properties of the Enantioselective Recombinant NStcI Esterase of Aspergillus nidulans

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Carolina Peña-Montes ◽  
María Elena Mondragón-Tintor ◽  
José Augusto Castro-Rodríguez ◽  
Ismael Bustos-Jaimes ◽  
Arturo Navarro-Ocaña ◽  
...  
Keyword(s):  
Kinetic Resolution ◽  
Storage Stability ◽  
Enantiomeric Excess ◽  
Residual Activity ◽  
Biochemical Properties ◽  
Maximum Activity ◽  
Acyl Donor ◽  
Initial Activity ◽  
Enzymatic Kinetic Resolution ◽  
Repeated Use

The recombinant NStcI A. nidulans esterase was adsorbed on Accurel MP1000, where protein yield and immobilization efficiency were 42.48% and 81.94%, respectively. Storage stability test at 4°C and RT showed 100% of residual activity after 40 days at both temperatures. The biocatalyst retains more than 70% of its initial activity after 3 cycles of repeated use. Biochemical properties of this new biocatalyst were obtained. Maximum activity was achieved at pH 11 and 30°C, while the best stability was observed with the pH between 9 and 11 at 40°C. NStcI thermostability was increased after immobilization, as it retained 47.5% of its initial activity after 1 h at 60°C, while the free enzyme under the same conditions displayed no activity. NStcI preserved 70% of its initial activity in 100% hexane after 72 h. Enzymatic kinetic resolution of (R,S)-1-phenylethanol was chosen as model reaction, using vinyl acetate as acyl donor. After optimization of reaction parameters, the highest possible conversion (42%) was reached at 37°C, aw of 0.07, and 120 h of bioconversion in hexane with an enantiomeric excess of 71.7%. NStcI has selectivity for (R)-enantiomer. The obtained E value (31.3) is in the range considered useful to resolve enantiomeric mixtures.

scholarly journals Lipase-Catalyzed Kinetic Resolution of Dimethyl and Dibutyl 1-Butyryloxy-1-Carboxymethylphosphonates

Catalysts ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 956
Author(s):  
Paulina Majewska
Keyword(s):  
Burkholderia Cepacia ◽  
Kinetic Resolution ◽  
Wide Spectrum ◽  
Candida Rugosa ◽  
Enantiomeric Excess ◽  
Optically Active ◽  
Enantiomeric Ratio ◽  
Catalyzed Reactions ◽  
Hydrolysis Of ◽  
Different Sources

The main objective of this study is the enantioselective synthesis of carboxyhydroxyphosphonates by lipase-catalyzed reactions. For this purpose, racemic dimethyl and dibutyl 1-butyryloxy-1-carboxymethylphosphonates were synthesized and hydrolyzed, using a wide spectrum of commercially available lipases from different sources (e.g., fungi and bacteria). The best hydrolysis results of dimethyl 1-butyryloxy-1-carboxymethylphosphonate were obtained with the use of lipases from Candida rugosa, Candida antarctica, and Aspergillus niger, leading to optically active dimethyl 1-carboxy-1-hydroxymethylphosphonate (58%–98% enantiomeric excess) with high enantiomeric ratio (reaching up to 126). However, in the case of hydrolysis of dibutyl 1-butyryloxy-1-carboxymethylphosphonate, the best results were obtained by lipases from Burkholderia cepacia and Termomyces lanuginosus, leading to optically active dibutyl 1-carboxy-1-hydroxymethylphosphonate (66%–68% enantiomeric excess) with moderate enantiomeric ratio (reaching up to 8.6). The absolute configuration of the products after biotransformation was also determined. In most cases, lipases hydrolyzed (R) enantiomers of both compounds.

Modulation of the enantioselectivity of Candida antarctica B lipase via conformational engineering. Kinetic resolution of (±)-α-hydroxy-phenylacetic acid derivatives

2002 ◽  
Vol 13 (12) ◽  
pp. 1337-1345 ◽  
Author(s):  
José M Palomo ◽  
Gloria Fernández-Lorente ◽  
Cesar Mateo ◽  
Manuel Fuentes ◽  
Roberto Fernández-Lafuente ◽  
...  
Keyword(s):  
Phenylacetic Acid ◽  
Kinetic Resolution ◽  
Candida Antarctica ◽  
Candida Antarctica B ◽  
Candida Antarctica B Lipase

scholarly journals Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases

2021 ◽  
Author(s):  
Kimberly Vega ◽  
Daniel Cruz ◽  
Artur Oliveira ◽  
Marcos da Silva ◽  
Telma de Lemos ◽  
...  
Keyword(s):  
Aspergillus Niger ◽  
Ethyl Acetate ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
The Other ◽  
Chemoenzymatic Synthesis ◽  
Hydrolysis Reaction ◽  
Chiral Alcohol ◽  
Enantiomerically Pure ◽  
Enantiomeric Ratio

The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED‑P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.

scholarly journals Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol

Catalysts ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 503
Author(s):  
Morten Gundersen ◽  
Guro Austli ◽  
Sigrid Løvland ◽  
Mari Hansen ◽  
Mari Rødseth ◽  
...  
Keyword(s):  
Building Block ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Catalytic Amount ◽  
Building Blocks ◽  
Β Blocker ◽  
Β Blockers ◽  
Optical Rotations ◽  
Reported Data ◽  
By Products

Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved.

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