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 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 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 Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

2010 ◽  
Vol 6 ◽  
pp. 823-829 ◽  
Author(s):  
Lisa K Thalén ◽  
Jan-E Bäckvall
Keyword(s):  
Good Yield ◽  
Large Scale ◽  
Kinetic Resolution ◽  
Catalyst Loading ◽  
Acyl Donor ◽  
Dynamic Kinetic Resolution ◽  
Reaction Parameters ◽  
Ru Catalyst ◽  
Isopropyl Acetate ◽  
Acyl Donors

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale. A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst loadings could be used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.

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 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 The production of enantiomerically pure 1-phenylethanol by enzymatic kinetic resolution method using response surface methodology

2020 ◽  
Vol 44 (5) ◽  
pp. 1352-1365
Author(s):  
Ayşe BOZAN ◽  
Rahime SONGÜR ◽  
Ülkü MEHMETOĞLU
Keyword(s):  
Response Surface Methodology ◽  
Reaction Time ◽  
Response Surface ◽  
High Performance ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Reaction Parameters ◽  
Enantiomerically Pure ◽  
Enzymatic Kinetic Resolution ◽  
Optimum Reaction

As the enantiomers of 1-phenylethanol are valuable intermediates in several industries, the lipase catalyzed kinetic resolution of (R,S) -1-phenylethanol is a relevant research topic. In this study, the goal was to determine the optimum reaction parameters to produce enantiomerically pure 1-phenylethanol by lipase (Novozyme 435) catalyzed kinetic resolution using response surface methodology (RSM). Reactions were performed with 40–400 mM (R,S)-1-phenylethanol, 120–1200 mM vinyl acetate and 2–22 mg/ mL biocatalyst concentrations (BCL), at 20–60 °C and with a stirring rate of 50–400 rpm for 5–120 min. The samples were analyzed using high performance liquid chromatography (HPLC) with a Chiralcel OB column. Optimum reaction parameters to reach 100% enantiomeric excess for the substrate (ees) were determined as follows: substrate concentration (Cs): 240 mM, BCL: 11 mg/mL, at 42 °C with a reaction time of 75 min. Model validation was performed using these conditions and ees was calculated as 100%, which indicates the predicted model was efficient and accurate. When compared to the literature, it was observed that the reaction time decreased significantly. This is an important result considering the industrial scale perspective.

Amano Lipase PS from Burkholderia cepacia- Evaluation of the Effect of Substrates and Reaction Media on the Catalytic Activity

2020 ◽  
Vol 24 (7) ◽  
pp. 798-807
Author(s):  
Jacek Dulęba ◽  
Tomasz Siódmiak ◽  
Michał Piotr Marszałł
Keyword(s):  
Burkholderia Cepacia ◽  
Kinetic Resolution ◽  
Lipolytic Activity ◽  
Reaction Medium ◽  
Building Blocks ◽  
Diisopropyl Ether ◽  
Acyl Donor ◽  
Pseudomonas Cepacia ◽  
Reaction Media ◽  
Isopropenyl Acetate

: Lipases in the native or immobilized form have commonly been used as catalysts in the chemical and pharmaceutical industry. One of the widely available enzyme catalysts on the market is lipase from Burkholderia cepacia (BCLs), previously called Pseudomonas cepacia (PCLs). This enzyme is applied, among others, in the stereoselective acylation of molecules to achieve chiral pure enantiomers of drugs or their building blocks. In this study, Amano lipase PS (APS-BCL), which is a commercial lipase from Burkholderia cepacia (BC) was tested. The lipolytic activity of APS-BCL by hydrolysis of vegetable oils and enantioselective activity of APS-BCL by the kinetic resolution of (R,S)-1-phenylethanol with using isopropenyl acetate as an acyl donor were evaluated. An effect of reaction media with different logP values (t-butyl methyl ether, dichloromethane, diisopropyl ether, toluene, cyclohexane, n-hexane, isooctane and n-heptane) on the enantioselective activity of lipase was also studied. The high value of the enantiomeric ratio (E =308.5) with the utilization of isopropenyl acetate was achieved. Whereas, the best reaction medium turned out to be diisopropyl ether, C =47.9%, eep =98%, ees =90%, after 24 h of incubation. Moreover, the influence of ω6/ω9 polyunsaturated fatty acids (PUFAs) ratio in commercial (peanut, camelina, rape, pumpkin seed, walnut, sesame, avocado, rice, corn, black cumin, hemp, safflower, grape seed) oils was investigated for the lipase activity. For the first time, the cut-off limit of ω6/ω9 ratio was proposed. The ratio equal to or higher than 2.3 allows achieving higher lipolytic activity.

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