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Fryszkowska A.,Dr. Reddys Laboratories EU Ltd. | Fryszkowska A.,Merck And Co. | Peterson J.,Dr. Reddys Laboratories EU Ltd. | Davies N.L.,Dr. Reddys Laboratories EU Ltd. | And 18 more authors.
Organic Process Research and Development | Year: 2016

Dehydroepiandrosterone (DHEA, 2) is an important endogenous steroid hormone in mammals used in the treatment of a variety of dysfunctions in female and male health,1 as well as an intermediate in the synthesis of steroidal drugs, such as abiraterone acetate which is used for the treatment of prostate cancer.2-4 In this manuscript we describe a novel, concise, and cost-efficient route toward DHEA (2) and DHEA acetate (3) from 4-androstene-3,17-dione (4-AD, 1). Crucial to success was the identification of a ketoreductase from Sphingomonas wittichii for the highly regio- and stereoselective reduction of the C3-carbonyl group of 5-androstene-3,17-dione (5) to the required 3β-alcohol (2, >99% de). The enzyme displayed excellent robustness and solvent stability under high substrate concentrations (up to 150 g/L). © 2016 American Chemical Society.


Fox M.E.,Dr. Reddys Laboratories EU Ltd | Jackson M.,Dr. Reddys Laboratories EU Ltd | Meek G.,Dr. Reddys Laboratories EU Ltd | Willets M.,Chirotech Technology Ltd.
Organic Process Research and Development | Year: 2011

A synthetic route to an N-BOC d-phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N-acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmeyer condensation, and ring-opening/O-deacetylation with methanol provided the 4-(hydroxymethyl)-substituted dehydrophenylalanine hydrogenation substrate. Asymmetric hydrogenation of this enamide using [((R,R)-Ethyl-DuPhos) Rh(COD)BF 4 proceeded in high enantiomeric excess. Subsequently, the cis-2,6-piperidyl group was introduced by mesylation/displacement, the BOC group was introduced, and acetyl and methyl ester groups were removed by basic hydrolysis. This route was used to manufacture 150 kg of the BOC amino acid 1. © 2011 American Chemical Society.


Cobley C.J.,Chirotech Technology Ltd. | Hanson C.H.,Dr. Reddys Laboratories EU Ltd. | Lloyd M.C.,Chirotech Technology Ltd. | Simmonds S.,Chirotech Technology Ltd. | Peng W.J.,Nantong Cellulose Fibers Co.LTD
Organic Process Research and Development | Year: 2011

The compound, (S)-2-amino-5-[1,3]dioxolan-2-yl-pentanoic acid [(S)-allysine ethylene acetal], is a key intermediate in a number of angiotension-I converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors currently in clinical trials. Through a combination of our hydroformylation and biocatalysis technologies we have developed an efficient five-step synthetic route to this material starting from crotonaldehyde. The development of this process, leading to a large-scale commercial manufacturing campaign, is described in this paper. © 2010 American Chemical Society.


Crampton R.H.,University of Nottingham | Fox M.,Dr. Reddys Laboratories EU Ltd | Woodward S.,University of Nottingham
Tetrahedron Asymmetry | Year: 2013

The sequential reaction of chlorosulfonyl isocyanate with t-BuOH, t-BuNH2 and TFA allows formation of H2NSO 2NHBut. Condensation of the latter with Ar1CHO in the presence of Ti(OEt)4 provides the activated imines Ar 1CHNSO2NHBut (59-89%). Commercially available boronic acids add to these imines with good stereoselectivity (76-98% ee) using readily available diene ligands. Simple deprotection with 5% w/w water in pyridine affords free Ar1CHNH2Ar2. © 2013 Elsevier Ltd. All rights reserved.


Chaplin D.A.,Dr Reddys Laboratories EU Ltd. | Fox M.E.,Dr Reddys Laboratories EU Ltd. | Kroll S.H.B.,Dr Reddys Laboratories EU Ltd.
Chemical Communications | Year: 2014

Dehydrocoronamic acid can be racemised by dehydration of an N-acyl derivative to an azlactone, which undergoes facile racemisation. For the N-trifluoroacetyl derivative, the racemisation process was combined with an enzymatic resolution, to achieve a dynamic kinetic resolution process by which the racemate can be converted to either enantiomer. This journal is © the Partner Organisations 2014.


Tomaszewski B.,TU Dortmund | Lloyd R.C.,Dr. Reddys Laboratories EU Ltd | Warr A.J.,Dr. Reddys Laboratories EU Ltd | Buehler K.,TU Dortmund | Schmid A.,TU Dortmund
ChemCatChem | Year: 2014

Microreactors provide higher mass transfer rates than do conventional batch reactors. A tube-in-tube microreactor was used for the NADH-dependent in vitro conversion of 2-hydroxybiphenyl to 3-phenylcatechol that was catalysed by 2-hydroxybiphenyl 3-monooxygenase. A biphasic reaction system allowed high substrate loadings, whereas the microreactor ensured excellent mass transfer rates between the organic and aqueous phases. Oxygen was supplied continuously by membrane aeration across the whole reaction compartment. The productivities achieved in the tube-in-tube microreactor were 38 times higher than those in previously described batch reactors and almost 4 times higher than for the same reaction in a microreactor in which aqueous, organic, and air phases were delivered through consecutive segments. This set-up is a promising concept for oxygen-dependent biocatalytic reactions in microreactors and is developing as a basis for applications in gram-scale organic biosyntheses. Flow power: A tube-in-tube reactor is presented for a gas-dependent biocatalytic reaction, overcoming typical limitations such as mass transfer, product and substrate inhibition, and challenges with gas delivery with productivities superior to standard batch reactors or conventional microreactors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Appell R.B.,Dow Chemical Company | Boulton L.T.,Dr. Reddys Laboratories Ltd. | Daugs E.D.,Dow Chemical Company | Hansen M.,Dow Chemical Company | And 11 more authors.
Organic Process Research and Development | Year: 2013

The synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various intermediates in a physical form that would readily allow filtration, washing, and ultimately purification underpinned the successful manufacturing campaign. © 2012 American Chemical Society.


Patent
DR. REDDYS LABORATORIES EU Ltd | Date: 2011-10-25

A chemical analysis method for the determination of RO(CH_(2)CH_(2)O)_(n)H, RO(C_(2)H_(4)O)_(n)A, and AO(C_(2)H_(4)O)_(n)A in a mixture thereof, wherein R is an alkyl group, A is a functional group for coupling with a surface or a biologically active material or another thing of use and n is an integer greater than 10. The method includes the derivatizing the A groups of the mixture with a derivatizing agent to form a derivatized mixture comprising RO(CH_(2)CH_(2)O)_(n)H, RO(C_(2)H_(4)O)_(n)AD, and DAO(C_(2)H_(4)O)_(n)AD, wherein AD is the derivatized A group. The second step is chromatographing a sample of the derivatized mixture by liquid chromatography under critical conditions to determine the relative amounts of RO(CH_(2)CH_(2)O)_(n)H, RO(C_(2)H_(4)O)_(n)AD, and DAO(C_(2)H_(4)O)_(n)AD in the derivatized mixture.


PubMed | Dr. Reddys Laboratories Ltd. and Dr. Reddys Laboratories EU Ltd
Type: Journal Article | Journal: The Journal of organic chemistry | Year: 2015

A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C-C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki-Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2-hydroxypropan-2-yl)phenyl)-1-phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki-Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl-BINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1.


Patent
University of Edinburgh and DR. REDDYS LABORATORIES EU Ltd | Date: 2012-04-10

The present application relates to a mutated Amycoiatopsis sp. TS-1-60 NAAAR that shows improved activity of the enzyme compared with the wild type Amycoiatopsis sp. TS-1-60 NAAAR. The mutated NAAAR is almost five times more active than its wild type counterpart. The present application also relates to the use of mutated Amycoiatopsis sp. TS-1-60 NAAAR in the production of enantiomerically pure amino acid from its N-acyl derivative via dynamic kinetic resolution method.

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