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Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2014

The current review covers 20 patents from an initial list of 305 that fitted the search criteria. A number of the patents use the well-established Friedel-Crafts reaction as a key step. For example, its use is reported in two patents covering the syntheses of t-butylphenylalkanols that are used in fragrances and aroma chemicals. In addition, fingolimod is used as the HCl salt in the treatment of multiple sclerosis, and a very detailed patent provides three processes for its preparation that involve Friedel-Crafts reactions. A new synthesis of aliskiren, a drug used to treat hypertension, involves a novel Friedel-Crafts reaction between a chiral azide compound and an anisole. Another drug used to treat hypertension is telmisartan, and a new synthesis reduces dimeric byproducts and gives a higher product yield. A patent describes the synthesis of isoquinolinones that are intermediates for other antihypertension drugs. The new process avoids a high-temperature Curtius reaction of an acyl azide that is thermally unstable and difficult to handle. Pyrazoles are often prepared from hydrazines that may be unstable or even carcinogenic. A new method avoids their use and starts from enamines that are coupled with carboxylic acid amides under oxidative conditions. Another patent describes the purification of pyrazoles that are intermediates in the synthesis of herbicides. A simple washing procedure avoids the formation of oligomeric compounds during the preparation of an acid chloride. Although the synthesis of the pyrazoles does involve the use of hydrazine, it is used as an aqueous solution to reduce safety issues. A process for preparing novel diaminoalcohols is described that are of interest as dispersants in coatings. The new compounds are less volatile than alternatives and so are less of a health hazard. However, their synthesis gives quite low yields. A patent describes a new method for the resolution of an isoquinoline derivative used in the synthesis of atracurium tosylate. The procedure uses the anti-inflammatory drug S-naproxen as a resolving agent. The use of ion exchange resins as catalysts is quite common although they can sometimes be unselective. A method of preparing a range of acidic resins that contain fewer SO3H groups than normal is described, and these have a higher activity and selectivity than fully functionalized resins. A patent describes the use of acidic ion exchange resins for the dehydration of tertiary alcohols in the synthesis of arylbutylamine compounds that are intermediates in the preparation of pain-relief drugs. The same patent also uses Pd-doped resins in a hydrogenation step. Efavirenz is used in the treatment of HIV, and the final step of its synthesis involves a carbonylation reaction. A patent reports that this can be carried out using a selection of carbonylating agents that are safer and more efficient than alternatives. Temozolomide is used to treat high grade brain tumours and can be prepared using MeNCO, the handling of which is highly dangerous. A new method uses MeNCO that is prepared in situ, but since this occurs at 250°C, there are still serious safety issues. Alfuzosin is used to treat prostate enlargement problems, and a new synthesis reduces impurity levels and gives a higher purity product in higher yield than alternatives. Chloromethylpyridine compounds, that are intermediates in herbicide synthesis, are prepared by a new route that involves a chlorination reaction with SO2Cl2 catalysed by AIBN. The patent claims to offer a process that is ecologically better than alternatives, but the chlorination step has safety issues that would need to be addressed. A patent describes the preparation of acyloxysulfides using DMSO as the source of the S atom. These compounds are then used in the synthesis of chiral aminoepoxides. Fluorinated diols are used to prepare monomers for photoresist materials, and a patent describes a new process for the hydrogenation of a fluorinated hydroxyaldehyde using less expensive catalysts than alternatives. Several N-substituted benzimidazoles and azabenzimidazoles are prepared by a novel Cu-catalysed coupling reaction under milder conditions than alternative methods. A new method is described for the synthesis of naratriptan that is used to treat migraine and cluster headaches. The process provides high yields in each of steps of the synthesis. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale and thus suggesting an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. © 2014 American Chemical Society.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2012

The current review contains 21 patents from an original list of 277 that fitted the selection criteria. One patent in particular evoked memories of the stories of horrific birth defects that appeared in the 1950s and 60s due to the drug thalidomide. Derivatives of this compound are under investigation for treating cancers, and a patent describes the synthesis of some of these molecules. There is a wide range of subjects in this selection. Some of the patents contain extensive amounts of experimental information, while others have very little. A feature of several patents is that changing solvents gives marked improvement in selectivity and productivity as well as reducing environmental impact. High cholesterol levels lead to coronary problems and are treated by a number of drugs including a range of statins. A comprehensive patent covers the synthesis of the side chain of several statins and contains a number of novel intermediates. Another drug used to treat the same problem is ezetimibe, and a detailed patent describes its synthesis that includes a previously unpublished finding that a side product, from a Ti(IV)-catalysed Mannich reaction, can be converted into a useful intermediate. A detailed patent describes the synthesis of azobicyclohexane esters that are used to prepare drugs for the treatment of hepatitis C. The route proceeds via novel bisulfite compounds that do not need to be isolated. Carbamoyl leucine derivatives are alternative antiviral drugs for treating hepatitis C, and a patent describes how they can be made with minimum byproducts by careful control of pH. A third patent covers a range of aminohydroxycarboxamides that are intermediates for another class of hepatitis C drugs. The process produces crystals that are easy to filter and avoids the use of solvents such as DMF and dioxane that give solid masses. Another antiviral drug is etravirine that is used in treating HIV, and a new process for its synthesis proceeds via a novel ether compound. The ether is formed along with an isomer that can also be converted to the final product, thus increasing overall yield. A process is described for producing sterile batches of the β-lactam antibiotic meropenem trihydrate. The process is claimed to be commercially viable, but in a catalytic hydrogenation step an almost stoichiometric amount of a Pd catalyst is required. A patent covering the preparation of pyrroles involves the synthesis of γ-nitrodicarbonyl and subsequent oxidation to an γ-dicarbonyl with H2O2. Reducing the amount of H2O in the process gives improved selectivity. Two patents describe methods for preparing aminobenzene compounds by processes that reduce the need for solids handling and, thereby, exposure to compounds that are toxic and skin sensitizers. Another patent on amine compounds covers an aminopyridine that is used to produce the fungicide fluazinam. The process uses the same reagents as an original procedure and gives improved selectivity, yield, and productivity by using MIBK instead of DMF as reaction solvent. Imatinib is used for the treatment of leukaemia and is available as the mesylate, under the name Gleevec. An improved synthetic route for a key intermediate is described that avoids some of the complex workup methods of alternative routes. An aldehyde that is used as perfume in soaps, shampoos, and cosmetics can contain unacceptably high levels HOAc that is unsuitable in these applications. An improved synthesis of the compound is reported that does require isolation of intermediates and gives a product with very low HOAc levels. The synthesis of the antidepressant mirtazapine involves the use of concd H2SO4 in a cyclisation step. The subsequent product extraction is improved by using PrnOH or PriOH in place of DCM that can leave unacceptable residues. Ziprasidone is an antipsychotic drug used to treat schizophrenia, and it can contain impurities causing discolouration in the final product. Despite a multistep purification procedure using several solvents and filtration steps the yield and the final purity are both very high. A one-pot process is described for the synthesis of rufinamide, an anticonvulsant used with other drugs for the treatment of seizure disorders. The process is carried out in aqueous solution and avoids the need to isolate or purify intermediates. A detailed patent covers the synthesis of novel cyclopropyl carboxylic acid derivatives that are pharmaceutical intermediates. Dihydropteridione derivatives are useful in treating tumours, and a very detailed patent describes the preparation of crystalline salts but uses a large number of solvents. The cis isomer of a azabicycloalkanol derivative is an intermediate in agrochemical synthesis, but the trans isomer is unsuitable. A new process gives improved yield of the cis isomer and provides an isomerisation step to increase the cis/trans ratio. 2,2-Difluoroethylamine is a useful intermediate, and a patent describes an improved synthesis by amination withNH3 that gives high yields when the amount of H2O in the system is minimised. Several of the patents in this collection describe experiments carried out on a kilo or multikilo scale, and this may suggest an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. © 2012 American Chemical Society.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2015

The current review covers 16 patents from an original list containing 256 patents, and it is hoped that readers will find the wide range of topics to be of some interest. Patents are generally very selective in referring to previous work, and two patents on the synthesis of the mild antidepressant duloxetine provide good examples of this. Both patents ignore an earlier patent that uses the same starting reagent, which often contains a regioisomeric impurity that also takes part in the reaction, forming a byproduct that is difficult to remove. Reducing hazards and handling problems are often cited as reasons for developing processes. One patent refers to an earlier process involving a Friedel-Crafts reaction as having handling and disposal problems. The patent then describes the new process, which also involves a Friedel-Crafts reaction, and ignores the subsequent handling problems. The perception of what is a hazardous or difficult reagent to handle is invariably related to the experience of an individual or a company. One patent comments that using BuLi is hazardous because it is pyrophoric and then proceeds to describe a process that involves adding PhMe to a reaction mixture that is already at the boiling point of the solvent. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale, thus suggesting an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. © 2015 American Chemical Society.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2015

The current review covers only 15 patents from an initial list of 285 that fit the search criteria. However, there is a considerable amount of chemistry that is hopefully of interest to readers. One patent describes in detail the use of an experimental design to determine the factors that control the formation of an impurity in a process for making quinolones. Although such designs are routinely used in process development, it is most unusual to see a detailed analysis of a design being described in a patent. Several patents describe new routes for compounds that avoid the use of expensive reagents, although the definition of expensive is relative and clearly depends on the value of the desired product. The chemistry covered is quite varied, and Wittig reactions are found to be useful in two of the patents: one in the synthesis of isoxazoline agrochemicals and another in the synthesis of an antihistamine compound. Changing reaction solvents can often lead to improved selectivity and yield and is the subject of one patent involving the quaternisation of cyclic tertiary amines that uses a mixture of MeCN and NMP. Using a solvent mixture also proves fruitful in the synthesis of sulfamides where water containing around 10% PriOH is the preferred solvent, and in another patent a mixture of ButOH and water proves to be the best solvent in a reaction forming an azide. Solvent degradation can sometimes be encountered, and one patent reports on a hydrogenation reaction carried out in THF containing an acid ion-exchange resin. This resulted in the formation of C4 compounds that originated from the THF. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale and thus suggesting an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2012

The current review contains 21 patents from an original list of 321 that fitted the selection criteria. It is not often that water improves a process, but that is what happens when it is present during the synthesis of a diaminodinitrobenzene. The water hydrolyses a byproduct formed in a reaction between the solvent and the reactant. On the other hand a new process for the preparation of abacavir, a drug used to treat HIV, requires anhydrous conditions to achieve high yield in a cyclisation step. Improving the physical characteristics of crystals can be important in preparing drug formulations. A comprehensive patent describes a process for the synthesis of the anti-insomnia drug, ramelteon. The method provides crystals that have much lower charge density when crystallised from PhMe compared with crystals of EtOAc, and the lower electrostatic charge improves flow properties of the crystals. In a process for purifying the ant-ulcer drug, rabeprazole sodium, the use of a mixture of solvents provides an amorphous form suitable for preparing formulations. A herbicide intermediate is produced in an asymmetric hydrogenation reaction using cheaper Ru catalysts in place of Rh catalysts. A different range of herbicides is produced by one-step fluorination of lactate esters using a fluorinated amine. The reaction proceeds via inversion with high stereoselectivity. The preparation of the anti-inflammatory drug, meloxicam, can contain byproducts at up to 20% levels, and their removal is difficult. A new process gives high-purity material via formation of the K salt of the drug. A process for the synthesis of sitagliptin, used to treat diabetes, describes a novel route that is claimed to give high yield and high-purity product; the patent contains a lot of experimental information yet no yield and purity details. Another drug used to treat diabetes is repaglinide, and by using B(OH)3 as dehydrating agent in a condensation reaction, the process is simplified, and yield and product purity are improved. Diabetes can also be treated with corosolic acid that is found in plant extracts. A method is reported for extracting this acid in high purity along with the related compound ursolic acid, used to treat wrinkles and help muscle growth. The anticoagulant drug rivaroxaban is produced by a new route involving several novel intermediates, but again purity details are not provided for many compounds. An extensive patent describes a new route to an indole compound that is used to treat bipolar disorders. The patent includes a number of alternative methods and intermediates that can be used. Resveratrol and piceatannol are E-stilbene derivatives that are antioxidants, and a patent describes how they can be obtained in high purity without the Z-isomers. Alprazolam and triazolam are benzodiazepines used to treat depression, and a method of making these drugs is described that improves a cyclisation step. An improved process is reported for producing 14-hydroxymorphinane derivatives that are used as sedatives. The process starts from oripavine, a littleused extract from the poppy plant, in place of thebaine that necessitates protection and deprotection steps in the process Plant extracts are also a source of tocotrienols that are used as dietary supplements and claimed to overcome hair loss. The molecules exist as four isomers with the α-molecule being in demand. The process converts the undesired isomers to intermediates that can be decomposed to the α-isomer but the workup is complicated. An ester salt of 3-phenylisoserine is used to prepare anticancer drugs known as taxanes. These molecules have several chiral centres and a patent provides the desired isomers in an efficient process. Cancer drugs often cause nausea and aprepitant is a drug used to overcome this problem. A detailed patent describes a method for the synthesis of a specific polymorph of the drug. The use of microreactors for the production of hazardous intermediates is described, and these are then used to prepare stable organic molecules, at least on a small scale. Thiobutyrate compounds are intermediates in the synthesis of penem antibiotics, and a new process for their preparation is described that gives such poor yields that it does not seem useful. A biphenyl-cyclopropanecarboxylic acid is used to treat Alzheimer's disease, and an improved synthetic method giveshigher yields and lower levels of byproducts that are formed in a free radical bromination step. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale. This may suggest an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2011

The current review contains 19 patents from an original list containing 267 that fitted the selection criteria. This is slightly fewer than usual although several of the patents reviewed cover a considerable volume of process chemistry. A notable feature in several of the current collection is the lack of analytical detail or reaction yield information. It is quite unacceptable that many patents omit vital process information such as the yield of a reaction and even details regarding its purity or method of analysis. If this information was omitted from papers submitted for publication in the open literature, it is expected that they would be rejected. At the very least, these details would be submitted as Supporting Information. It is a fact of life that patents claims can be excessive, but at the least, some evidence for them should be presented. As an example, an extensive patent reports on the synthesis of an intermediate used to make a drug for treating diabetes. The patent does not contain physical property data apart from the bp of those compounds recovered by distillation. Treatments for inflammatory diseases have a largemarket and are of great value; a process to prepare individual stereoisomers of arylcyclopentane carboxylates is described. The patent contains a large amount of detailed chemistry, but process yields are low. Chemical reactions can often produce sticky solids, syrups, or gels that are difficult to handle on a large scale, and a number of patents report such findings. A patent describes an improved preparation of a range of aniline derivatives, useful in the treatment of thyroid disorders. The original process gave unpredictable yields because of light-sensitive intermediates that were intractable solids. A new process is reported for preparing the active enantiomer of clopidogrel, the drug used to treat blood clots and heart disease. This involves handing four intermediates that are described as syrupy or viscous masses, and the reported yields are generally high. Nebivolol is a beta blocker used to treat hypertension and has four chiral centres. Oily compounds are produced in a new stereoselective synthesis of a key epoxide intermediate. Another drug used to treat blood pressure is trandolapril, and a new process synthesises the molecule in high stereoselectivity. The patent claims that the preferred solvent for the product isolation is MeCN but only describes examples using EtOAc. A new method for making a key epoxide intermediate is described, and this also involves oily intermediates. A new process reports improved yields and efficiency for the preparation of erlotinib, a drug used to treat lung cancer and pancreatic cancer. The new process has a number of improvements including a reduction of the molar excess of HBr used in one step by using 48% concentration in place of 38%. In another step in the process the amount of Ac2Oused for an acylation is reduced by a factor of 18 by adding catalytic amounts of pyridine. Another drug used in chemotherapy for the treatment of ovarian cancer and lung cancer is topotecan. This is a semi-synthetic derivative of camptothecin that is extracted from the bark of certain trees, and an improved process for its preparation is described. A process for carbonylation of amines to give amides uses Pd catalysts as a cheaper alternative to Rh catalysts. Unfortunately, the conditions are rather extreme, and any benefit of a cheaper catalyst may be outweighed. Armodafinil is the (R)-enantiomer of the drug modafinil that is used to treat sleep disorders, and a method for its purification is described. Impurities usually present are a disulfide and an acid, and the new method involving passing a solution of the drug molecule over Al2O3 gives very high-purity product. In the usual synthesis of the reagent N,N0- carbonyldiimidazole the atom yield of the starting material is poor since half acts as a HCl sink. A new process recovers and reuses the HCl salt and thereby gives improved process efficiency. An enzyme catalyst is used in an esterification reaction to stereoselectively produce theaspirane that is a naturally occurring compound used in flavours and fragrances. The process enables both enantiomers to be obtained pure, starting from a commercially available material. Formoterol is used to treat chronic pulmonary diseases, and a new polymorph is reported of the more potent (R),(R)-enantionmer that can be converted to the thermodynamically stable polymorph. A comprehensive patent describes a large-scale synthesis of molecules that are of interest asmale contraceptives and the treatment of prostate-related problems. An efficient method of producing a stable crystalline salt of an aralkyloxypyrrolidine derivative is described, and since the salt is easily handled, this is beneficial because the compound is said to be a pharmaceutical intermediate. Some nitroguanidines have insecticidal activity, and a new synthesis of the compounds is described that uses a stable nitroisourea in place of an expensive isourea. The starting compounds are less likely to decompose and give higher reaction selectivity. Olanzapine is used to treat schizophrenia and bipolar disorders in adults and an improvement on an original process avoids the formation of N-oxides by replacing DMSO as solvent since this appears to oxidise the product. The new solvent is a mixture of 1,3-dimethylimidazolidin-2-one and PhMe. 2-Cyanocinnamic esters are used as UV stabilisers, and an improved synthesis gives high yields and minimises byproducts. The patent involves variable-pressure refluxing to remove water in a condensation reaction without increasing the temperature, and this avoids byproduct formation. Galanthamine can be extracted from the bulbs of snowdrops or daffodils and is approved for treating Alzheimer's disease. A patent describes the synthesis of a compound that can be used to make galanthamine although the patent does not say how this is carried out. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale, and this may suggest that the process is at an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. © 2011 American Chemical Society.


Turner K.,Kappa Tau Consulting
Organic Process Research and Development | Year: 2013

The current review covers 21 patents from an original list of 271 that fitted the search criteria, and these cover a wide range of topics with some interesting chemistry. The extraction of natural products and their use in treating diseases is of longstanding interest. Three patents describe the preparation of synthetic taxanes from natural compounds extracted from tree bark. The compounds are used or have potential in treating various cancers. All three patents focus on protecting hydroxyl groups during the reactions, and one describes the use of lanthanide salts as being highly selective for specific hydroxyl groups. Another patent on anticancer drugs describes a new process for preparing tetrahydroquinoline derivatives in a onepot process that gives enantiomerically enriched compounds without the need to isolate intermediates. Two patents cover the preparation of drugs for the treatment of AIDS and HIV. Interestingly, the patents from different groups describe regioisomers of 1,3-oxathiolanes that are used to treat these diseases. One of these describes a stereoselective method for preparing lamivudine that is used to treat AIDS and hepatitis B. A key aspect of this process is the use of an L-menthol formyl chloride that acts as a chiral auxiliary and improves the stereoselectivity in a glycosylation reaction. The other patent describes a stereoselective method of making a regioisomer of lamivudine that is used to treat HIV and describes optimising a crystallisation step. Two patents describe the synthesis of different drugs for treating epilepsy. One describes a method of preparing high-purity gabapentin enacarbil, and the other describes an asymmetric reduction of oxcarbazepine that is improved if the pH of the reaction is controlled. The synthesis of the antidepressant drug trazodone involves potentially genotoxic reagents, and a patent describes a method for their removal to very low levels. Another antidepressant drug is citalopram that is used as a racemic mixture, and a patent describes a process for preparing the pure (S)-enantiomer that has been claimed to be more effective than the R-isomer. Another drug in which two enantiomers have different activity is atomoxetine that is available as Strattera for the treatment of attention deficit hyperactivity disorder. A process is described in which a novel chiral amino alcohol is prepared and is a key intermediate in the synthesis of the more active enantiomer. A new one-pot process for preparing a dioxotetrahydrofuran as an agrochemical intermediate is described, but its use of chloroacetyl chloride may create environmental problems. Another agrochemical intermediate is an α-fluorocarboxylate, and a fluorination step is described using SO2F2that avoids HF and fluoride salts. A patent describes a process for preparing another fluorinated intermediate that is used to prepare a pyrazole fungicide. The process includes novel piperidine derivatives that are prepared in a one-pot process. Another onepot process covers the preparation of dihalopyridines and aims to provide an improved purification process using less solvents. Tolterodine is used to treat bladder problems, and a patent describes an accelerated method of making hydroxymethylphenols that are intermediates in the synthesis. The patent uses the Turbo-Grignard reagent that is more active than standard Grignards. An improvement in the Ullmann synthesis of multifunctional diaryl ethers is disclosed that uses catalytic quantities of Cu salts. A new process is described for the preparation of paliperidone, a drug used for treating schizophrenia. The process avoids the use of protective group chemistry. A novel class of fused-ring compounds is disclosed that are intermediates in the synthesis of the prostaglandin lubiprostone, a drug used to treat bowel problems. The process includes an unexpected transformation when using the reagent DIBAL that did not proceed as predicted. Varenicline is a drug used to help giving up smoking, and some synthetic routes use hazardous or pyrophoric reagents. A new method is described that gives high yields of intermediates and a high-purity product. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale, thus suggesting an advanced stage of development or even commercial operation. However, there is no legal commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. © 2012 American Chemical Society.

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