86087-24-3Relevant articles and documents
Processes for the Preparation of SGLT-2 Inhibitors, Intermediates Thereof
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Paragraph 0161, (2019/01/04)
The present invention relates to novel, improved processes for the preparation of sodium glucose co-transporter 2 (SGLT-2) inhibitors and novel intermediates thereof. More particularly, the present invention relates to a novel, improved process for the preparation of gliflozin compounds such as empagliflozin and dapagliflozin, intermediates thereof. The product obtained from the processes of present invention may be amorphous or crystalline, or in the form of amorphous/crystalline solid dispersions/solutions with pharmaceutically acceptable polymers and preparation process thereof. Also, the products obtained from the present invention may be used for the preparation of medicaments for the prevention and/or treatment of diseases and conditions associated with SGLT-2 inhibition.
Methodology Development in Directed Evolution: Exploring Options when Applying Triple-Code Saturation Mutagenesis
Qu, Ge,Lonsdale, Richard,Yao, Peiyuan,Li, Guangyue,Liu, Beibei,Reetz, Manfred T.,Sun, Zhoutong
, p. 239 - 246 (2018/02/09)
Directed evolution of stereo- or regioselective enzymes as catalysts in asymmetric transformations is of particular interest in organic synthesis. Upon evolving these biocatalysts, screening is the bottleneck. To beat the numbers problem most effectively, methods and strategies for building “small but smart” mutant libraries have been developed. Herein, we compared two different strategies regarding the application of triple-code saturation mutagenesis (TCSM) at multiresidue sites of the Thermoanaerobacter brockii alcohol dehydrogenase by using distinct reduced amino-acid alphabets. By using the synthetically difficult-to-reduce prochiral ketone tetrahydrofuran-3-one as a substrate, highly R- and S-selective variants were obtained (92–99 % ee) with minimal screening. The origin of stereoselectivity was provided by molecular dynamics analyses, which is discussed in terms of the Bürgi–Dunitz trajectory.
A pharmaceutical intermediates (S)-3 - hydroxy tetrahydrofuran preparation method (by machine translation)
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Paragraph 0042, (2017/08/31)
The invention provides a pharmaceutical intermediate (S)- 3 - hydroxy tetrahydrofuran preparation method. The method other than racemic 1, 2, 4 - butanetriol as raw materials synthesis of racemic 3 - hydroxy tetrahydrofuran, then esterification of racemic tetrahydrofuran-yl - 3 - fatty acid ester. By lipase hydrolysis in the racemic mixture of (R)- tetrahydrofuran-based - 3 - fatty acid ester after, in in the hydrolysis product under the condition of separating, using the mitsunobu reaction will be hydrolyzed to obtain the of (R)- 3 - hydroxy tetrahydrofuran is converted into (S)- tetrahydrofuran-based - 3 - carboxylic acid ester, finally under alkaline condition all of the tetrahydrofuran ester hydrolyzed to obtain the final product (S)- 3 - hydroxy tetrahydrofuran. (by machine translation)
THE PRESENT INVENTION RELATES TO PROCESS FOR THE PREPARATION OF D-GLUCITOL, 1,5- ANHYDRO-1-C-[4-CHLORO-3-[[4-[[(3S)-TETRAHYDRO-3-FURANYL] OXY]PHENYL] METHYL]PHENYL]-, (1S) AND ITS CRYSTALLINE FORMS THEREOF.
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Page/Page column 22; 35, (2017/08/22)
The present invention relates to process for the preparation of D-glucitol, 1,5- anhydro-l-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl] methyl]phenyl]-, (1S) formula- 1 and its crystalline forms thereof.
(S)- 3 - hydroxy tetrahydrofuran and (R)- 3 - hydroxy tetrahydrofuran preparation method
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Paragraph 0066; 0067; 0068, (2017/08/02)
The invention discloses a preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran, relating to the technical field of preparation of five-element heterocyclic compounds containing one oxygen atom as the only heterocyclic atom. The method comprises the following steps: by using (S)-carnitine or (R)-carnitine as the initial raw material, carrying out reduction reaction in a reducer and an organic solvent to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine alkali; adding a hydrogen chloride organic solvent solution into an organic solvent to perform salification reaction to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine hydrochloride; and finally, adding alkali into a polar solvent, heating, and carrying out cyclization reaction to obtain the (S) or (R)-3-hydroxytetrahydrofuran. The method has the advantages of low cost, simple technique, high yield, cheap and accessible raw materials, short reaction steps, short period and low pollution, and is suitable for industrial production.
Catalytic Asymmetric Reduction of Difficult-to-Reduce Ketones: Triple-Code Saturation Mutagenesis of an Alcohol Dehydrogenase
Sun, Zhoutong,Lonsdale, Richard,Ilie, Adriana,Li, Guangyue,Zhou, Jiahai,Reetz, Manfred T.
, p. 1598 - 1605 (2016/03/15)
Catalytic asymmetric reduction of prochiral ketones with the formation of enantio-pure secondary alcohols is of fundamental importance in organic chemistry, chiral man-made transition-metal catalysts, or organocatalysts and enzymes of the alcohol dehydrogenase (ADH) type. A distinct limitation is the traditional requirement that the α- and α′-moieties flanking the carbonyl function differ sterically and/or electronically. Difficult-to-reduce ketones such as tetrahydrofuran-3-one and tetrahydrothiofuran-3-one and related substrates are particularly challenging, irrespective of the catalyst type. The ADH from Thermoethanolicus brockii (TbSADH) is an attractive industrial biocatalyst, because of its high thermostability, but it also fails in the reduction of such ketones. We have successfully applied directed evolution using the previously developed concept of triple-code saturation mutagenesis at sites lining the TbSADH binding pocket with tetrahydrofuran-3-one serving as the model compound. Highly (R)- and (S)-selective variants were evolved (95%-99% ee) with minimal screening. These robust catalysts also proved to be effective in the asymmetric reduction of tetrahydrothiofuran-3-one and other challenging prochiral ketones as well. The chiral products, which are generally prepared by multistep routes, serve as synthons in the preparation of several important therapeutic drugs.
PROCESS FOR PRODUCTION OF (S)-(TETRAHYDROFURAN-3-YL)HYDRAZINE
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Paragraph 0085, (2016/04/19)
A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof, comprising hydrolysis or hydrogenation step of protected hydrazine compound of formula VII, wherein Ra is a tert-butyl group or a benzyl group, is disclosed. (S)-(Tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof is a useful intermediate in the preparation of a PDE9 inhibitor.
Use of 'small but smart' libraries to enhance the enantioselectivity of an esterase from Bacillus stearothermophilus towards tetrahydrofuran-3-yl acetate
Nobili, Alberto,Gall, Markus G.,Pavlidis, Ioannis V.,Thompson, Mark L.,Schmidt, Marlen,Bornscheuer, Uwe T.
, p. 3084 - 3093 (2013/07/26)
Two libraries of simultaneous double mutations in the active site region of an esterase from Bacillus stearothermophilus were constructed to improve the enantioselectivity in the hydrolysis of tetrahydrofuran-3-yl acetate. As screening of large mutant libraries is hampered by the necessity for GC/MS analysis, mutant libraries were designed according to a 'small but smart' concept. The design of focused libraries was based on data derived from a structural alignment of 3317 amino acid sequences of α/β-hydrolase fold enzymes with the bioinformatic tool 3dm. In this way, the number of mutants to be screened was substantially reduced as compared with a standard site-saturation mutagenesis approach. Whereas the wild-type esterase showed only poor enantioselectivity (E = 4.3) in the hydrolysis of (S)-tetrahydrofuran-3-yl acetate, the best variants obtained with this approach showed increased E-values of up to 10.4. Furthermore, some variants with inverted enantiopreference were found. A semi-rational approach was applied for the enhancement of the enantioselectivity of an esterase from Bacillus stearothermophilus towards the industrially interesting substrate tetrahydrofuran-3-yl acetate, based on data derived from structural alignment. The design of 'small but smart' libraries led to a 2.4-fold increase of (S)-selectivity compared to wild type enzyme, while some mutants with marginal (R)-selectivity were found.
Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane
Gadakh, Sunita K.,Santhosh Reddy,Sudalai, Arumugam
experimental part, p. 898 - 903 (2012/09/22)
A short and efficient enantioselective synthesis of the HIV protease inhibitor amprenavir 1 (99% ee) as well as a formal synthesis of saquinavir 3 have been achieved in high enantiomeric purity starting from commercially available materials. Our strategy mainly comprises a Co-catalyzed two-stereocentred hydrolytic kinetic resolution (HKR) of racemic 2-(1-azido-2-phenylethyl)oxirane as the chirality inducing step. Also presented is a concise synthesis of (S)-3-hydroxytetrahydrofuran 4, the key structural feature, in high enantiomeric purity (98% ee).
A novel lipase enzyme panel exhibiting superior activity and selectivity over lipase B from Candida antarctica for the kinetic resolution of secondary alcohols
O'Neill, Maeve,Beecher, Denis,Mangan, David,Rowan, Andrew S.,Monte, Agnieszka,Sroka, Stefan,Modregger, Jan,Hundle, Bhupinder,Moody, Thomas S.
experimental part, p. 583 - 586 (2012/08/13)
A novel, commercially available lipase enzyme panel performing kinetic bioresolutions of a number of secondary alcohols is reported. The secondary alcohols that have been chosen are known from the literature to be particularly challenging substrates to resolve. Following initial screening, four co-solvents were investigated for each lead enzyme in an effort to assess their tolerance to common organic solvents. The superiority of these novel enzymes over lipase B from Candida antarctica (CALB) has been demonstrated.
