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Green…Asymmetric hydrogentation of unfunctionalised olefins/enamines/imines

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Asymmetric hydrogentation of unfunctionalised olefins/enamines/imines

The reaction survey found that the predominant strategy for the introduction of chirality was through classical chemical resolutions as opposed to introductions through biotransformation or transition metal or organometallic catalytic means.

 

Asymmetric hydrogenation provides an elegant methodology for the introduction of chirality, meeting many of the goals of green chemistry and is finding increasing application in API synthesis.47

 

The efficiency of this approach is elegantly exemplified by the Merck second generation synthesis of sitagliptin 5 (Scheme ), where an unprecedented final stage asymmetric hydrogenation of the unprotected enamide 6 resulted in an increase in overall yield of almost 50% and produced 100 kg less waste per kg sitagliptin48 when compared with the first generation approach.49

 

 

The synthesis of sitigliptin.
Scheme  The synthesis of sitagliptin.

There are challenging areas remaining within the field, for example, the hydrogenation of enamides and related substrates in the synthesis of amino acids has numerous examples50 but few examples exist for unsubstitued enamines41 and imines. Some classes of alkene offer additional challenges.51 For the pharmaceutical industry, the limited time for synthetic route identification is an issue and access to catalyst and ligand diversity is required to ensure the application of this approach.52

Some pharmaceutical companies have synthesised their own ligands and have found very effective catalysts.53 The majority of academic asymmetric hydrogenation approaches are based on homogeneous catalysis to overcome issues of activation and mass transfer. For pharmaceutical use, efficient catalyst and ligand recovery, and eliminating heavy metal contamination of the API are significant requirements for the industry.

These controls are often easier to achieve with heterogeneous methodology where there are less examples.50 The demonstration of organocatalytic hydride transfer offers the possibility of future access to metal free asymmetric hydrogenations.54

  1. 47………V. Farina, J. T. Reeves, C. H. Senanayake and J. J. Song, Chem. Rev., 2006, 106, 2734–2793. See also Asymmetric Catalysis on Industrial Scale Challenges, Approaches and Solutions, ed. H.-U. Blaser and E. Schmidt, Wiley-VCH, Weinheim, 2004 Search PubMed  .
  2. 48………..http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa06.html .
  3. 49……K. B. Hansen, J. Balsells, S. Dreher, Y. Hsiao, M. Kubryk, M. Palucki, N. Rivera, D. Steinhuebel, J. D. Armstrong III, D. Askin and E. J. J. Grabowski, Org. Process Res. Dev., 2005, 9, 634–639 Search PubMed  .
  4. 50………..M. Studer, H.-U. Blaser and C. Exner, Adv. Synth. Catal., 2003, 345, 45–65 CrossRef  CAS  Search PubMed  .
  5. 51……..X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272–3296 CrossRef  CAS  Search PubMed 
  6.  52……….I. C. Lennon and C. J. Pilkington, Synthesis, 2003, 1639–1642 CrossRef  CAS  Search PubMed  .
  7. 53………G. Hoge, H.-P. Wu, W. S. Kissel, D. A. Plum, D. J. Greene and J. Bao, J. Am. Chem. Soc., 2004, 126, 5966–5967 CrossRef  CAS  Search PubMed  .
  8. 54……..H. Adolfsson, Angew. Chem., Int. Ed., 2005, 44, 3340–3342 CrossRef  CAS  Search PubMed  .

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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