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.

Ensemble Learning Approach with LASSO for Predicting Catalytic Reaction Rates

Synlett ◽  
2020 ◽  
Author(s):  
Akira Yada ◽  
Kazuhiko Sato ◽  
Tarojiro Matsumura ◽  
Yasunobu Ando ◽  
Kenji Nagata ◽  
...  
Keyword(s):  
Ensemble Learning ◽  
Reaction Rates ◽  
Initial Reaction Rate ◽  
Training Dataset ◽  
Initial Reaction ◽  
Learning Approach ◽  
Learning Framework ◽  
Machine Learning Approach ◽  
Reasonable Prediction ◽  
Epoxidation Of Alkenes

AbstractThe prediction of the initial reaction rate in the tungsten-catalyzed epoxidation of alkenes by using a machine learning approach is demonstrated. The ensemble learning framework used in this study consists of random sampling with replacement from the training dataset, the construction of several predictive models (weak learners), and the combination of their outputs. This approach enables us to obtain a reasonable prediction model that avoids the problem of overfitting, even when analyzing a small dataset.

scholarly journals Layer-Like Zeolite X as Catalyst in a Knoevenagel Condensation: The Effect of Different Preparation Pathways and Cation Exchange

Catalysts ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 474
Author(s):  
Jan-Paul Grass ◽  
Katharina Klühspies ◽  
Bastian Reiprich ◽  
Wilhelm Schwieger ◽  
Alexandra Inayat
Keyword(s):  
Catalytic Activity ◽  
Reaction Rate ◽  
Knoevenagel Condensation ◽  
Ethyl Cyanoacetate ◽  
Reaction Rates ◽  
Initial Reaction Rate ◽  
Comparative Investigation ◽  
Morphological Properties ◽  
Initial Reaction ◽  
Zeolite X

This study is dedicated to the comparative investigation of the catalytic activity of layer-like Faujasite-type (FAU) zeolite X obtained from three different synthesis routes (additive-free route, Li2CO3 route, and TPOAC route) in a liquid-phase Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate to ethyl trans-α-cyanocinnamate. It is shown that the charge-balancing cations (Na+ and K+) and the morphological properties have a strong influence on the apparent reaction rate and degree of conversion. The highest initial reaction rate could be found for the layer-like zeolite X synthesised by the additive-free route in the potassium form. In most cases, the potassium-exchanged zeolites enabled higher maximum conversions and higher reaction rates compared to the zeolite X catalysts in sodium form. However, very thin crystal plates (below 100 nm thickness), similar to those obtained in the presence of TPOAC, did not withstand the multiple aqueous ion exchange procedure, with the remaining coarse crystals facilitating less enhancement of the catalytic activity.

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.

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.

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 Promising Immobilization of Industrial-Class Phospholipase A1 to Attain High-Yield Phospholipids Hydrolysis and Repeated Use with Optimal Water Content in Water-in-Oil Microemulsion Phase

2021 ◽  
Vol 11 (4) ◽  
pp. 1456
Author(s):  
Yusuke Hayakawa ◽  
Ryoichi Nakayama ◽  
Norikazu Namiki ◽  
Masanao Imai
Keyword(s):  
Water Content ◽  
Reaction Rate ◽  
Enzyme Reaction ◽  
Initial Reaction Rate ◽  
Industrial Applications ◽  
Molar Ratio ◽  
High Yield ◽  
Initial Reaction ◽  
Phospholipase A1 ◽  
Repeated Use

In this study, we maximized the reactivity of phospholipids hydrolysis with immobilized industrial-class phospholipase A1 (PLA1) at the desired water content in the water-in-oil (W/O) microemulsion phase. The optimal hydrophobic-hydrophilic condition of the reaction media in a hydrophobic enzyme reaction is critical to realize the maximum yields of enzyme activity of phospholipase A1. It was attributed to enzymes disliking hydrophobic surroundings as a special molecular structure for reactivity. Immobilization of PLA1 was successfully achieved with the aid of a hydrophobic carrier (Accurel MP100) combination with the treatment using glutaraldehyde. The immobilized yield was over 90% based on simple adsorption. The hydrolysis reaction was kinetically investigated through the effect of glutaraldehyde treatment of carrier and water content in the W/O microemulsion phase. The initial reaction rate increased linearly with an increasing glutaraldehyde concentration and then leveled off over a 6% glutaraldehyde concentration. The initial reaction rate, which was predominantly driven by the water content in the organic phase, changed according to a typical bell-shaped curve with respect to the molar ratio of water to phospholipid. It behaved in a similar way with different glutaraldehyde concentrations. After 10 cycles of repeated use, the reactivity was well sustained at 40% of the initial reaction rate and the creation of the final product. Accumulated yield after 10 times repetition was sufficient for industrial applications. Immobilized PLA1 has demonstrated potential as a biocatalyst for the production of phospholipid biochemicals.

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.

scholarly journals ω-Amino Acid:Pyruvate Transaminase from Alcaligenes denitrificans Y2k-2: a New Catalyst for Kinetic Resolution of β-Amino Acids and Amines

2004 ◽  
Vol 70 (4) ◽  
pp. 2529-2534 ◽  
Author(s):  
Hyungdon Yun ◽  
Seongyop Lim ◽  
Byung-Kwan Cho ◽  
Byung-Gee Kim
Keyword(s):  
Amino Acids ◽  
Kinetic Resolution ◽  
Specific Activity ◽  
Expression System ◽  
Enantiomeric Excess ◽  
Selective Enrichment ◽  
Alcaligenes Denitrificans ◽  
Keto Acids ◽  
Optically Pure ◽  
High Stereoselectivity

ABSTRACT Alcaligenes denitrificans Y2k-2 was obtained by selective enrichment followed by screening from soil samples, which showed ω-amino acid:pyruvate transaminase activity, to kinetically resolve aliphatic β-amino acid, and the corresponding structural gene (aptA) was cloned. The gene was functionally expressed in Escherichia coli BL21 by using an isopropyl-β-d-thiogalactopyranoside (IPTG)-inducible pET expression system (9.6 U/mg), and the recombinant AptA was purified to show a specific activity of 77.2 U/mg for l-β-amino-n-butyric acid (l-β-ABA). The enzyme converts various β-amino acids and amines to the corresponding β-keto acids and ketones by using pyruvate as an amine acceptor. The apparent Km and V max for l-β-ABA were 56 mM and 500 U/mg, respectively, in the presence of 10 mM pyruvate. In the presence of 10 mM l-β-ABA, the apparent Km and V max for pyruvate were 11 mM and 370 U/mg, respectively. The enzyme exhibits high stereoselectivity (E > 80) in the kinetic resolution of 50 mM d,l-β-ABA, producing optically pure d-β-ABA (99% enantiomeric excess) with 53% conversion.

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