A Review of U.S.Patents in the Field of Organic Process Development Published During April and May 2008

摘要

There are 19 patents in the current selection from an original list of 321.Several of these contain experimental details involving many stages,and because of space limitations only very brief details are given here.By a strange coincidence there are several patents in the current selection that are assigned to the same company(Teva),and some explanation may be appropriate.When selecting patents the initial list contains only the title and patent number,and the final selection is made purely on the title of the patent so there is no significance in the presence of so many from one company.Having said that,there is one patent that stands out by virtue of the fact that it describes some novel crystalline polymorphs of the drug fluvastatin sodium.The striking point is that the patent claims to have identified 87 polymorphs,and this must be rather difficult to deal with.Another patent on statins covers a new synthesis of pravastatin.Polymorphs appear in a patent on the anti-insomnia drug indiplon.In this case amorphous forms are described that have improved solubility.Avoiding chromatographic separation methods is common,and an improved method of crystallising calcipotriene gives good particle size distribution and 99.9% pure product.An improved separation method is also reported for recovering levulinic acid by reactive extraction from esterification reactions.This must be deemed to be in commercial use since the patent reports multiton/h production rates.The identification and isolation of impurities and their use as reference standards is reported for the anti-hyperactivity drug atomoxetine and the immunosuppressant mycophenolate mofetil.An improved process is described for tolterodine that is used to treat bladder problems.A safer method for the production Of the intermediate glyceraldehyde acetonide is reported that removes the need for close control of pH.The patent reports large-scale production,thus indicating that it is,indeed,safe.A safer process for the production of LAF-237,a diabetes drug in phase 2 trials,is reported that removes the need for isolation of irritant intermediates.On the subject of safety,a new method of producing aromatic carboxylic acids by oxidation of alkyl groups is reported.It uses catalytic ozonolysis and reports yields of 98%.Multiple fluorination of aryl groups is reported that uses KF and is catalysed by an iminium chloride compound.A very large number of novel pteridinones is reported that have potential in treating tumours,but one step in the process is a reduction that takes nine days.A process for preparing a sterically hindered iV-alkoxyamine involves the reaction of TEMPO and an alkyl borane in the presence of a catalyst and O2.It is no surprise that the reaction was speeded up by bubbling the gas through the solution.In a static atmosphere the reaction takes 48 h but:only one hour when bubbling the gas.The patent coverage suggests that over 180 compounds have been produced.Another very comprehensive patent covers the synthesis of benzazepines that are useful ia treating inflammatory diseases,and multikilo batches are reported.Patents describing large-scale experiments can indicate commercialisation or,at the very least,advanced development.A process for preparing CCR-2 antagonists is very comprehensive and reports using multikilo quantities of reagents.The titles of patents can be misleading,and one describing the synthesis of alkynols actually turns out to be a method of removing protective silyl groups to give the alkynol.The inclusion of a patent does not imply any commercial or legal significance,and the advantages listed are those claimed in the patent unless this reviewer has personal knowledge of the subject.