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Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator



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Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator

K.R. Knudsen, J. Holden, S.V. Ley and M. Ladlow, Adv. Syn. Cat. 2007, 349, 535-538.

A versatile, fully automated flow hydrogenator has been developed that is able to perform sequential flow optimisation experiments, flow library hydrogenation, or iterative scale-up hydrogenation. The behaviour of a palladium catalyst in effecting removal of O-benzyl and N-benzyloxycarbonyl protecting groups has been investigated. Significant observations relating to maintaining optimal throughput are reported. A small library of peptidic derivatives has been deprotected in high yield and purity.


System configuration:
The system used was configured from a Gilson liquid handler (233XL), driven with a 10 mL
syringe pump (402). The syringe pump was connected to the sampling needle via a 2-way 6
position switching valve. This single channel liquid handler was used to perform both substrate
manipulation and fraction collection. The liquid handler was connected via a 2-way 6 position
injection valve to a Thales H-CubeTM flow hydrogenator driven with a KnauerTM A120 high
pressure pump. The collection vials were housed in specially designed gas tight blocks (2 x 7)
which were fitted with PTFA seals to enable penetration by the liquid handler needle, and
continuously purged with nitrogen in order to dilute and vent excess hydrogen safely. The
hardware was controlled using a single graphic user interface (HydroMateTM, Figure 2) which
utilised either RS232 or GSIOC connectivity to interface with the Thales and Gilson devices
respectively. Throughout 30 mm, 4 mm id 10% Pd/C catalyst cartridges (CatCartTM) were used
in conjunction with a 5 mL sample injection loop, although larger cartridges are also available.


The control software exploits software ‘wizards’ to assist the user in compiling a sequence of
optimisation experiments, or alternatively permits the implementation of a series of repetitive
experiments for either: (i) catalyst evaluation, (ii) reaction optimisation, (iii) compound library
synthesis, or (iv) as part of an automated, unattended scale up campaign (Figure 1). Experiments
may be devised with variations in scale, temperature, flow rate, and pressure in addition to
periodicity of fraction collection.
Analysis: RP-HPLC was run on a Hewlett Packard 1050 instrument. Column: Supelcosilä
PLUS column, 3.3 cm, 4.6 mm f, 3 mm. Eluent: A: water, 0.1% TFA, B: acetonitrile 95%,
water 5%, TFA 0.05%. Gradient: 10 to 95% B in A (1 mL min-1
) over 8 min. Detection: UV
(diode array detector).

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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 AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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