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4 BASF’s ChiPros®: Optically Active Intermediates on an Industrial Scale In recent years, single-enantiomer drugs and drug candidates have become more and more important in the pharmaceutical and agrochemical industry. Therefore, effi cient methods for the synthesis of small, homochiral intermediates, which are frequently used as building blocks for many pharmaceuticals and crop protection agents like herbicides, fungicides and insecticides, but also resolving agents and chiral auxiliaries, are of central interest. With its ChiPros portfolio 1 , BASF off ers a broad and growing range of chiral amines, alcohols, epoxides and carboxylic acids. The ChiPros toolbox holds the best-in-class technologies of enzyme-based biocatalysis including lipases, dehydrogenases, nitrilases, esterases, oxygenases, etc. In addition, chemical methods such as catalytic asymmetric hydrogenations and CBS reductions are utilized to further strengthen the technology portfolio. 2 ChiPros Chiral Amines Chiral amines play an important role in stereoselective organic synthesis. They are used directly as resolving agents, building blocks or chiral auxiliaries. While classically available through racemic resolution with optically active acids, biotechnological approaches also open a way to chiral amines. 3 BASF’s optimized lipase-catalyzed r<strong>out</strong>e to optically active amines (Scheme 1) can be run at a scale of several thousand tons. Due to the wide range of substrates tolerated by the enzymes, a large variety of diff erent chiral amines and chiral aminoalcohols are commercially available. Aldrich.com NH 2 CH 3 Lipase NH 2 CH 3 Scheme 1: Lipase-catalyzed resolution of racemic amines. Asymmetric Synthesis Daniel Weibel, Ph.D. European Market Segment Manager, Chemical Synthesis daniel.weibel@sial.com + O HN CH 3 CH 3 TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis. H 3C NH 2 NH 2 CH 3 726621 NH2 H3C CH3 H3C CH3 726729 NH2 H3C CH3 H3C CH3 726559 H 2N NH 2 CH3 NH 2 CH3 OCH 3 NH 2 CH 3 CH 3 F H 3C H 3C Cl HN NH 2 O NH 2 O NH 2 NH 2 CH 3 CH 3 CH 3 NH 2 NH2 CH 3 NH 2 CH 3 CH3 H 3CO H 3CO H 3CO H 3CO H 3C CH 3 Br 727229 727288 NH 2 O NH 2 NH 2 NH 2 NH 2 NH 2 CH 3 NH 2 NH 2 CH 3 CH 3 CH 3 CH 3 CH 3 Cl Cl H 3C NH2 H3C CH3 CH3 NH2 H3C CH3 CH3 H2N CH3 727164 726494 726591 727156 726486 727148 727024 727172 726532 727105 726680 726524 726796 726583 726915 726710 726516 726664 726826 726540 726974 726907 726850 726648 NH 2 O NH 2 NH 2 726702 726931 CH3 CH 3 NH 2 726737 NH 2 CH3
H 3C H 3CO Br 726893 NH 2 727083 726842 NH 2 726869 NH 2 NH 2 CH 3 ChiPros Chiral Acids Enantiopure α- and ß-hydroxy acids and esters are versatile building blocks for the preparation of a wide range of active pharmaceutical ingredients by incorporating them as esters, amides or ethers, or after further derivatization, as diols, amino alcohols, thioethers. Hydroxy acids are accessible via a range of biotransformations, among them are the stereoselective hydrolysis of the racemic ester precursor or reduction of the corresponding keto esters. Hydroxynitrile lyase (HNL) processes catalyze the stereoselective addition of HCN to aldehydes and ketones yielding single-enantiomeric nitriles. 3 Application of nitrilases or a combination of nitrile-hydratase plus amidase allows the transformation of the starting material into the desired enantiomer of the corresponding acid in a dynamic kinetic resolution fi nally yielding mandelic acid derivatives. BASF developed proprietary processes based on dehydrogenases to off er access to a wide range of α- and ß-hydroxy esters, starting from readily available keto esters. Due to the large range of enzymes available, both enantiomers can normally be made. Another established technology is enzymatic resolution using lipases which only acylate one enantiomer. Cl OH CH 3 O 727067 H 3C CH3 H3C OH H 3C NH2 CH3 726605 726885 NH 2 726923 727342 NH 2 CH 3 CH3 H3C NH2 CH3 OH 726990 O OH HN NH 2 CH 3 726818 NH2 CH3 726613 727180 727032 NH 2 CH 3 NH3 O H3C OH 727350 Br CH3 H3CO SO 3 CH 3 ChiPros Chiral Alcohols Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com. NH 2 726958 NCO CH 3 726761 726656 CH 3 NH 2 CH 3 Asymmetric Synthesis 5 Chiral alcohols form a versatile class of chiral synthons, since they can be incorporated into the API structures directly as esters or ethers. They can be starting materials for the formation of amines, amides, thiols, thioethers. In addition, after transforming the hydroxyl function into a leaving group by way of mesylation, tosylation or trifl ation, they can be used to form new C–C bonds. Many manufacturing r<strong>out</strong>es make use of asymmetric hydrogenation methods. 4 The two most important biocatalytical processes for the formation of chiral alcohols apply lipases and dehydrogenases, respectively. 3 The latter off ers the advantage that only the requested enantiomer is obtained. Enzyme-catalyzed acylations using lipases, however, achieve the resolution of racemic mixtures of alcohols but with an inherent 50 percent maximum yield of the total amount of starting material. One enantiomer of the racemic mixture remains unchanged while the antipodal enantiomer is esterifi ed (Scheme 2). H 3CO O O CH 3 OH OH + CH3 Lipase CH3 + R Scheme 2: Lipase-catalyzed resolution of aryl-substituted alcohols. R R O O CH 3 OCH 3 Thanks to a variety of commercial and proprietary enzymes at its disposal, BASF off ers a wide range of aliphatic and cycloaliphatic and aryl-substituted single-enantiomer alcohols under the ChiPros brand. H3C OH CH 3 726753 726672 OH 726567 CH 3 H 3C OH CH 3 H 3C OH 727059 CH 3 OH O O 727210 CH 3
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