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

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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Highly enantioselective CALB-catalyzed kinetic resolution of building blocks for β-blocker atenolol

Tetrahedron ◽

10.1016/j.tet.2016.02.018 ◽

2016 ◽

Vol 72 (46) ◽

pp. 7288-7292 ◽

Cited By ~ 12

Author(s):

Ingvild T. Lund ◽

Pål L. Bøckmann ◽

Elisabeth E. Jacobsen

Keyword(s):

Kinetic Resolution ◽

Building Blocks ◽

Β Blocker

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

Biocatalysis ◽

10.1515/boca-2015-0006 ◽

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.

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First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.10.322 ◽

2014 ◽

Vol 10 ◽

pp. 3038-3055 ◽

Cited By ~ 8

Author(s):

Paweł Borowiecki ◽

Daniel Paprocki ◽

Maciej Dranka

Keyword(s):

Building Block ◽

Kinetic Resolution ◽

Enantiomeric Excess ◽

Xrd Analysis ◽

Optically Active ◽

Novozym 435 ◽

Lipozyme Tl Im ◽

Bromo Derivative ◽

Chiral Building Block

Enantioenriched promethazine and ethopropazine were synthesized through a simple and straightforward four-step chemoenzymatic route. The central chiral building block, 1-(10H-phenothiazin-10-yl)propan-2-ol, was obtained via a lipase-mediated kinetic resolution protocol, which furnished both enantiomeric forms, with superb enantioselectivity (up to E = 844), from the racemate. Novozym 435 and Lipozyme TL IM have been found as ideal biocatalysts for preparation of highly enantioenriched phenothiazolic alcohols (up to >99% ee), which absolute configurations were assigned by Mosher’s methodology and unambiguously confirmed by XRD analysis. Thus obtained key-intermediates were further transformed into bromide derivatives by means of PBr3, and subsequently reacted with appropriate amine providing desired pharmacologically valuable (R)- and (S)-stereoisomers of title drugs in an ee range of 84–98%, respectively. The modular amination procedure is based on a solvent-dependent stereodivergent transformation of the bromo derivative, which conducted in toluene gives mainly the product of single inversion, whereas carried out in methanol it provides exclusively the product of net retention. Enantiomeric excess of optically active promethazine and ethopropazine were established by HPLC measurements with chiral columns.

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Thienopyrrolocarbazoles: New Building Blocks for Functional Organic Materials

10.26434/chemrxiv.7777343.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Dorian Bader ◽

Johannes Fröhlich ◽

Paul Kautny

Keyword(s):

Building Block ◽

Organic Materials ◽

Building Blocks ◽

Molecular Properties ◽

The Family ◽

Facile Preparation

The facile preparation of three regioisomeric thienopyrrolocarbazoles applying a convenient C-H activation approach is presented. Derived from indolo[3,2,1-<i>jk</i>]carbazole, the incorporation of thiophene into the triarylamine framework significantly impacted the molecular properties of the parent scaffold. The developed thienopyrrolocarbazoles enrich the family of triarylamine donors and constitute a novel building block for functional organic materials.

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Thienopyrrolocarbazoles: New Building Blocks for Functional Organic Materials

10.26434/chemrxiv.7777343 ◽

2019 ◽

Author(s):

Dorian Bader ◽

Johannes Fröhlich ◽

Paul Kautny

Keyword(s):

Building Block ◽

Organic Materials ◽

Building Blocks ◽

Molecular Properties ◽

The Family ◽

Facile Preparation

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Wine By-Products as Raw Materials for the Production of Biopolymers and of Natural Reinforcing Fillers: A Critical Review

Polymers ◽

10.3390/polym13030381 ◽

2021 ◽

Vol 13 (3) ◽

pp. 381

Author(s):

Alessandro Nanni ◽

Mariafederica Parisi ◽

Martino Colonna

Keyword(s):

Critical Review ◽

Raw Materials ◽

Green Revolution ◽

Building Blocks ◽

Poly Lactic Acid ◽

Butylene Succinate ◽

Reinforcing Fillers ◽

Plastic Industry ◽

Review Reports ◽

By Products

The plastic industry is today facing a green revolution; however, biopolymers, produced in low amounts, expensive, and food competitive do not represent an efficient solution. The use of wine waste as second-generation feedstock for the synthesis of polymer building blocks or as reinforcing fillers could represent a solution to reduce biopolymer costs and to boost the biopolymer presence in the market. The present critical review reports the state of the art of the scientific studies concerning the use of wine by-products as substrate for the synthesis of polymer building blocks and as reinforcing fillers for polymers. The review has been mainly focused on the most used bio-based and biodegradable polymers present in the market (i.e., poly(lactic acid), poly(butylene succinate), and poly(hydroxyalkanoates)). The results present in the literature have been reviewed and elaborated in order to suggest new possibilities of development based on the chemical and physical characteristics of wine by-products.

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PyroMEMS as Future Technological Building Blocks for Advanced Microenergetic Systems

Micromachines ◽

10.3390/mi12020118 ◽

2021 ◽

Vol 12 (2) ◽

pp. 118

Author(s):

Jean-Laurent Pouchairet ◽

Carole Rossi

Keyword(s):

Building Block ◽

Building Blocks ◽

Small Scale ◽

Technological Evolution ◽

Research Groups ◽

Function Block ◽

The Past ◽

New Methods ◽

Safety And Reliability ◽

Electronically Controllable

For the past two decades, many research groups have investigated new methods for reducing the size and cost of safe and arm-fire systems, while also improving their safety and reliability, through batch processing. Simultaneously, micro- and nanotechnology advancements regarding nanothermite materials have enabled the production of a key technological building block: pyrotechnical microsystems (pyroMEMS). This building block simply consists of microscale electric initiators with a thin thermite layer as the ignition charge. This microscale to millimeter-scale addressable pyroMEMS enables the integration of intelligence into centimeter-scale pyrotechnical systems. To illustrate this technological evolution, we hereby present the development of a smart infrared (IR) electronically controllable flare consisting of three distinct components: (1) a controllable pyrotechnical ejection block comprising three independently addressable small-scale propellers, all integrated into a one-piece molded and interconnected device, (2) a terminal function block comprising a structured IR pyrotechnical loaf coupled with a microinitiation stage integrating low-energy addressable pyroMEMS, and (3) a connected, autonomous, STANAG 4187 compliant, electronic sensor arming and firing block.

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Dimerization and oligomerization of DNA-assembled building blocks for controlled multi-motion in high-order architectures

Nature Communications ◽

10.1038/s41467-021-23532-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ling Xin ◽

Xiaoyang Duan ◽

Na Liu

Keyword(s):

Building Block ◽

Degrees Of Freedom ◽

Building Blocks ◽

Single Type ◽

Hierarchical Assembly ◽

Optical Responses ◽

Self Association ◽

Living Organisms ◽

Order Structures ◽

Chiral System

AbstractIn living organisms, proteins are organized prevalently through a self-association mechanism to form dimers and oligomers, which often confer new functions at the intermolecular interfaces. Despite the progress on DNA-assembled artificial systems, endeavors have been largely paid to achieve monomeric nanostructures that mimic motor proteins for a single type of motion. Here, we demonstrate a DNA-assembled building block with rotary and walking modules, which can introduce new motion through dimerization and oligomerization. The building block is a chiral system, comprising two interacting gold nanorods to perform rotation and walking, respectively. Through dimerization, two building blocks can form a dimer to yield coordinated sliding. Further oligomerization leads to higher-order structures, containing alternating rotation and sliding dimer interfaces to impose structural twisting. Our hierarchical assembly scheme offers a design blueprint to construct DNA-assembled advanced architectures with high degrees of freedom to tailor the optical responses and regulate multi-motion on the nanoscale.

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A bicyclic S-adenosylmethionine regeneration system applicable with different nucleosides or nucleotides as cofactor building blocks

RSC Chemical Biology ◽

10.1039/d1cb00033k ◽

2021 ◽

Cited By ~ 1

Author(s):

Désirée Popadić ◽

Dipali Mhaindarkar ◽

Mike H. N. Dang Thai ◽

Helen C. Hailes ◽

Silja Mordhorst ◽

...

Keyword(s):

Building Blocks ◽

Regeneration System ◽

Methyl Donor ◽

By Products

The polyphosphate-driven bicyclic S-adenosylmethionine (SAM) regeneration system uses S-methylmethionine as a ‘2-in-1’ methyl donor without producing by-products and can be run with SAM nucleobase analogues such as S-cytidyl- and S-inosylmethionine.

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Metabolic responses of the whole body, portal-drained viscera and hindquarter to adrenaline infusion: Effects of nonselective and selective β-adrenoceptor blockade

Canadian Journal of Animal Science ◽

10.4141/a94-082 ◽

1997 ◽

Vol 77 (2) ◽

pp. 307-316 ◽

Cited By ~ 3

Author(s):

J. O. O. Miaron ◽

R. J. Christopherson

Keyword(s):

Blood Flow ◽

Oxygen Consumption ◽

Portal Vein ◽

Influencing Factor ◽

External Iliac Artery ◽

Open Circuit ◽

Whole Body ◽

Organ Blood Flow ◽

Β Blocker ◽

Β Blockers

Propranolol, a nonselective β-blocker and selective β-blockers (metoprolol a β1-blocker and ICI 118551 a β2-blocker) were used to investigate the β-adrenoceptor-mediated adrenaline-induced increase in whole-body and organ VO2 in five whether sheep. Transit time blood flow probes were chronically implanted on the portal vein and the external iliac artery and sampling catheters were placed in the mesenteric artery, iliac vein and portal vein. Oxygen consumption by the whole body was measured by open circuit calorimetry, and oxygen consumption by the portal-drained viscera and the hindquarter was determined from A-VO2 differences and organ blood flow. Absolute pre-infusion VO2 values for the whole body, portal-drained viscera and hindquarters were 236 ± 7.4, 61 ± 6.0 and 13 ± 3.1 mL min−1 respectively. The mean changes in VO2 in response to infusion were 74 vs. 11, 26, 10 and 12 mL min−1 (SE = 9.1) for whole body; 31 vs. −2, −15, 13 and −4 mL min−1 (SE = 7.3) for portal-drained viscera and 8 vs. −0.4, 2.1, 1.0 and −2.7 mL min−1; SE = 4.3) for hindquarters during adrenaline, control, propranolol, metoprolol and ICI 118551 treatments, respectively. Adrenaline increased VO2 (P < 0.05) in the whole body and portal-drained viscera, but not hindquarters relative to controls. All β-blockers suppressed (P < 0.05) the adrenaline-induced increase in VO2 except for the portal-drained viscera where metoprolol was less effective and the hindquarters where β-blockers had no effect. The blood flow pattern was similar to VO2 responses for the portal-drained viscera. The nonselective β1 and β2 blockers were effective in reducing the adrenaline-induced increases in blood flow from the portal-drained viscera and to the hindquarters, with more pronounced β-adrenoceptor-mediated haemodynamic effects. The results indicate that the β-adrenoceptor system modulates whole body VO2, clearly establishes that adrenaline induces an increased VO2 in portal-drained viscera which can be reversed by a β2 or nonselective β blocker and implicates β adrenoceptors as an influencing factor in the maintenance energy requirements of ruminants. Key words: Calorimetry, adrenaline, β blockers, blood flow, sheep

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