Biocatalysis for Industrial Production of Active Pharmaceutical Ingredients (APIs)

Arroyo, Miguel; Mata, Isabel de la; García, JoséLuis; Barredo, José-Luis

doi:10.1016/b978-0-12-803725-6.00017-0

Cited by 19 publications

(12 citation statements)

References 102 publications

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“…Moreover, derivatives of (R)-mandelic acid have been also used as chiral synthons in the preparation of some drugs with different therapeutic activities: platelet/antithrombotic agents (clopidogrel [85]), vasodilator (cyclandelate [86]), antitumor (complex of cis-[Pt{2-(α-hydroxy)benzylbenzimidazole))2Cl2] [87], antiobesity [88,89] or CNS-stimulant dopaminergic agents ((R)-pemoline [90]). Conversely, (S)-mandelic acid is used for the production of non-steroidal anti-inflammatory drugs such as deracoxib and celecoxib [91].…”

Section: Resultsmentioning

confidence: 99%

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transesterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

Ramos-Martín¹,

Khiari²,

Alcántara³

et al. 2020

Catalysts

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The use of biocatalysts in organic chemistry for catalyzing chemo-, regio- and stereoselective transformations has become an usual tool in the last years, both at lab and industrial scale. This is not only because of their exquisite precision, but also due to the inherent increase in the process sustainability. Nevertheless, most of the interesting industrial reactions involve water-insoluble substrates, so the use of (generally not green) organic solvents is generally required. Although lipases are capable of maintaining their catalytic precision working in those solvents, reactions are usually very slow and consequently not very appropriate for industrial purposes. Increasing reaction temperature would accelerate the reaction rate, but this should require the use of lipases from thermophiles, which tend to be more enantioselective at lower temperatures, as they are more rigid than those from mesophiles. Therefore, the ideal scenario would require a thermophilic lipase capable of retaining high enantioselectivity at high temperatures. In this paper, we describe the use of lipase from Geobacillus thermocatenolatus as catalyst in the ethanolysis of racemic 2-(butyryloxy)-2-phenylacetic to furnish both enantiomers of mandelic acid, an useful intermediate in the synthesis of many drugs and active products. The catalytic performance at high temperature in a conventional organic solvent (isooctane) and four imidazolium-based ionic liquids was assessed. The best results were obtained using 1-ethyl-3-methyl imidazolium tetrafluoroborate (EMIMBF4) and 1-ethyl-3-methyl imidazolium hexafluorophosphate (EMIMPF6) at temperatures as high as 120 °C, observing in both cases very fast and enantioselective kinetic resolutions, respectively leading exclusively to the (S) or to the (R)-enantiomer of mandelic acid, depending on the anion component of the ionic liquid.

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Section: Resultsmentioning

confidence: 99%

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transesterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

Ramos-Martín¹,

Khiari²,

Alcántara³

et al. 2020

Catalysts

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“…2-Arylpropionic acids represent an important group of nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen, ketoprofen, and flurbiprofen . Although many of them are approved as racemates, the ( R )-enantiomer of naproxen, for example, causes unwanted gastrointestinal disorders while the ( S )-enantiomer is 150 times more active …”

Section: Functional Groups Formed In Biocatalytic Reactions For Api S...mentioning

confidence: 99%

“…Furthermore, only examples that were applied on ideally at least several gram scale or where information on industrial application is available are included. Complementary reviews are suggested. ,,− …”

Section: Introductionmentioning

confidence: 99%

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

et al. 2021

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Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool for the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in the first half of the last century exploited whole-cell microorganisms where the specific enzyme at work was not known. In the meantime, novel molecular biology methods, such as efficient gene sequencing and synthesis, triggered breakthroughs in directed evolution for the rapid development of process-stable enzymes with broad substrate scope and good selectivities tailored for specific substrates. To date, enzymes are employed to enable shorter, more efficient, and more sustainable alternative routes toward (established) small molecule APIs, and are additionally used to perform standard reactions in API synthesis more efficiently. Herein, large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols (if available) regarding the steps, reaction conditions, and scale. The review is structured according to the functional group formed in the reaction.

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“…Moreover, derivatives of (R)-mandelic acid have been also used as chiral synthons in the preparation of some drugs with different therapeutical activities: platelet/antithrombotic agents (clopidogrel [103]), vasodilator (cyclandelate [104]), anti-tumor (complex of cis-[Pt{2-(α-hydroxy)benzylbenzimidazole))2Cl2] [105], antiobesity [106,107] or CNS-stimulant dopaminergic agents ((R)-pemoline [108]). Conversely, (S)-mandelic acid is used for the production of non-steroidal anti-inflammatory drugs such as deracoxib and celecoxib [109] Selection of (R, S)-1 as model substrate was based in many previous studies in which BTL2 (mainly immobilized) had been tested for catalyzing the stereoselective hydrolysis (Figure 1(b)) [61,65,67,72,74]. Thus, Palomo et al [61] reported the hydrolysis of (R, S)-1 using several preparations of BTL2 immobilized on different supports (octadecyl agarose, glyoxyl agarose or polyethyleniminemodified (PEI) sepabeds [63]), at different pH values (5, 7 and 9) and different temperature (4, 25 and 37°C).…”

Section: Introductionmentioning

confidence: 99%

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

Ramos-Martín¹,

Khiari²,

Alcántara³

et al. 2020

Preprint

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Biocatalysis for Industrial Production of Active Pharmaceutical Ingredients (APIs)

Cited by 19 publications

References 102 publications

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transesterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transesterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

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