e-NEWSLETTERJune 2003 |
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CONTENTSHighlights from the 7th International Conference on Organic Process Research and Development, New Orleans, March 16-19, 2003 Uses and Abuses of Statistical Design Synthesis and Scale Up of Tissue The Impact of a tert-Butyl Group Synthesis and Scale Up of Chiral Alcohols and Epoxides BoPhoz Ligands for Asymmetric Catalysis PLUS Photochemistry – New Light on an Old Problem Variable Residence Time Reactor
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Highlights from the 7th International Conference on
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Synthesis and Scale Up of the Tissue Selective Estrogene ZK 186619Johannes Platzek spoke about the synthesis and scale up of the tissue selective Estrogene ZK 186619 (1) carried out at Schering AG. The medicinal chemistry route (see Scheme 1), 19 steps including 2 chromatographic purifications, had been successfully used to prepare 100g of product with an overall yield of 5%, but a more efficient route was required. Various scale up issues were identified – use of PCl5/SnCl4 for the cyclisation, demethylation with pyridine HCl requires temperature of 180oC, 5 equivalents of 4-methoxyphenylmagnesium bromide were required for the Grignard reaction, demethylation with NaSCH3 generates methane thiol as a by-product, and finally there were several protecting group changes in the synthesis. Scheme 1 An alternative synthetic route was devised where the phenyl group was introduced prior to the cyclisation stage. The same starting material, 3-methoxybenzaldehyde, was used but in the new route was reacted with acetaldehyde to give 3-methoxycinnamaldehyde. The literature yield for this reaction was 10-20%, but initial optimisation studies improved this to 35% and then automated optimisation using a statistical approach gave a fully optimised yield of 80%. The intermediate 3-methoxycinnamaldehyde was not isolate but was reacted directly with phenylacetic acid to give a diene-acid intermediate which was isolated and then hydrogenated to give the cyclisation precursor. Cyclisation was effected by treatment with polyphosphoric acid (PPA), but the work-up of this reaction had to be modified for scale up. Quenching by addition of water was extremely exothermic, but the reaction mixture was too viscous to add to water. The answer was to cool the reaction mixture to 50oC, add 15% methanol to give a pumpable mixture, which could be quenched onto water. Various methods of introducing the 4-methoxyphenyl group were investigated; including Grignard addition, aryl lithium addition, but the best method proved to be a Suzuki coupling with the enol sulphonate derived from the cycloheptanone. Some convergence was introduced to the synthetic route at this point by introducing the side chain in one piece (see Scheme 2) Scheme 2 A number of reagent combinations were evaluated for demethylation to give the phenol (48% HBr, HBr/HOAc, TMSCl/NaI/acetonitrile, AlCl3, BBr3/CH2Cl2) with boron tribromide/base working best. The nature of the base was critical to the success of the reaction. When pyridine was used a yield of 40% was obtained, but utilising a more hindered base, 2,6-lutidine gave much improved yield (85%), but use of an even more hindered base, 2,6-di-tert-butylpyridine was ineffective. Introduction of the pentafluoro side chain was fairly straightforward although two routes were considered – introduction of the sulphide and then oxidation to the sulphoxide, or introduction of the side chain in one unit as the sulphoxide. This latter approach although introducing more convergence to the synthesis was less economic because of the cost of the 4,4,5,5,5-pentafluoropentan-1-ol used as starting material for this leg of the synthesis (the increased convergence meant this material had to be processed through more chemical steps). The final stages were therefore essentially as carried out in the medicinal chemistry synthesis – conversion of pentafluoropentanol in to the tosylate followed by displacement of the tosylate group with potassium thioacetate to give pentafluoropropyl thioacetate. The demethylated chloro intermediate from the Suzuki coupling was converted in to the iodide in a Finklestein reaction in 2-butanone and this was then reacted with the thioacetate ester using sodium methoxide as base. The final oxidation was carried out with sodium metaperiodate. Hydrogen peroxide could also be used as the oxidant, but this gave a product with a poorer impurity profile. Scheme 3 In summary the process route required 12 chemical steps (7 isolated steps) in 25% overall yield (lab, 20% on pilot plant scale) with no chromatography required.
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The Impact of a tert-Butyl GroupMing Guo from Pfizer described the rapid development of a multi kilo scale synthesis of AG 3433, a third generation MMP inhibitor, and in particular the impact a t-butyl group had on the stereoselectivity of an alkylation step and the improved chemical selectivity and chemical stability in subsequent steps. The first two stages of the synthesis are shown in Scheme 1, 4-cyano-4’-aminobiphenyl (prepared by nitration of 4-cyanobiphenyl, with the 2’-isomer being removed by crystallisation) is reacted with the substituted THF (3-MTHF) derivative to form the pyrrole acetic acid (45% overall yield from 3-MTHF), which was coupled with the oxazolidinone auxiliary. Scheme 1 The success of the subsequent alkylation of the oxazolidinone with bromoacetate in THF depended on the choice of base and the ester used for the alkylation. A survey of bases showed sodium hexamethyldisilazide gave the best ee, but the choice of ester had a significant effect on the outcome. The tert-butyl ester gave product with the highest ee followed by the ethyl ester and then the benzyl ester (see table).
The final stages of the synthesis are shown in Scheme 2 – hydrolysis of the auxiliary, which proceeded without any racemisation when the tert-butyl ester was used. The intermediate was purified as the dicyclohexylamine salt and then coupled with the aminolactone to give AG3433 after removal of the tert-butyl ester group. A preliminary polymorph screen (acetonitrile, ethyl acetate, acetone, dichloromethane/methyl tert-butyl ether, heptane in various ratios) had been carried out, but only one form had been found. During the cGMP campaign a problem was encountered with he level of an impurity. The amount of impurity could be reduced to acceptable levels by treatment with toluene, but the subsequent crystallisation (the same procedure that had been used in the pilot runs) revealed a new polymorphic form. Polymorph screening was resumed and a third form was found as well as an acetonitrile solvate. Further work showed form II to the most stable form when crystallisation was carried out from alcoholic solutions and a robust crystallisation process was developed. Various grades of ethanol and other alcohols were examined along with the rate of cooling, the diastereomers content of the crude product, but the crystallisation consistently gave form II. Form I could generally be obtained from ethyl acetate, and form III was produced in acetone.
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Synthesis and Scale Up of Chiral Alcohols and EpoxidesBjörn Schlummer from Bayer discussed the various approaches that can be used to synthesize chiral building blocks, and described a number of these methods that are used at Bayer. Chiral pool approaches can be used to produce chiral polyols amino-alcohols, starting with naturally occurring acids and reducing the carboxylic acid group. Catalytic hydrogenation over ruthenium catalysts is possible at high temperatures and pressures but racemisation occurs under such forcing conditions. Bayer have developed a promoted ruthenium catalyst containing rhenium that allows the catalytic reduction to be operated at lower temperatures where no racemisation is observed. Substrates such as L-lactic acid, L-malic acid and L-tartaric acid give the corresponding diol, triol or tetraol. Similarly amino acids can be reduced to amino-alcohols. For “alkyl” amino acids, such as L-alanine or L-valine the product is the expected amino alcohol (L-alaninol or L-valinol), but for amino acids with aromatic side chains such as L-phenylalanine ring reduction also takes place giving L-cyclohexylalanine. Bayer have also developed number of bisphosphine-derived complexes for asymmetric hydrogenation, such as BIBFUP and Cl-MeO-BIPHEP and the phosphite derived ligand. The (R)-enantiomers of the ligands are shown below, but both enantiomers are available as the ligands are synthesized by a racemic route and then separated by resolution (EP 749,973, EP 1186609, AND DE 101 48 551). The ruthenium complexes of these ligands are extremely effective for hydrogenation of α–ketoesters, b-ketoesters α,β-unsaturated acids to α–hydroxyesters, β-hydroxyesters and α-substituted carboxylic acids. In comparative studies these catalysts give comparable results (chemical yield, ee) to the best alternative ligands, such as BINAP. Finally he outlined developments in the application of the Julia-Colonna asymmetric epoxidation of electron poor olefins such as chalcones. The standard method employs poly-leucine in triphasic conditions. Chemists at Bayer realised that for the reaction to proceed the hydroperoxide anion has to be generated in the aqueous phase and then be transferred to the organic phase to effect the reaction. So adding a phase transfer catalyst should and does improve the rate of reaction dramatically (Bayer patents pending: DE 10136131, DE 10136132, DE 10136485). The method has the added advantage of making the work up of the reaction and recycle of the catalyst simpler.
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BoPhoz Ligands for Asymmetric CatalysisNeil Boaz opened the conference with a presentation on work carried out at Eastman on the synthesis and uses of the BoPhoz ligands. These ligands are similar to the Josiphos ligands developed at Ciba (now Solvias), but the remote phosphorous atom is attached via an amino-phosphorus linkage. The ligands (1) are prepared from the commercially available Ugi amine (2) which is available from ferrocene in 4 steps (see Scheme 1) Scheme 1 In the original synthesis the enantiomers of the Ugi amine were separated by resolution with tartaric acid, but this method was found to be low yielding and not robust on scale up, so the biocatalytic route using a kinetic resolution of the ferrocene alcohols was used to separate the enantiomers. The Rhodium complexes of these ligands have been found to give excellent ee’s and conversions in the hydrogenation of enamides (eq 1), substituted itaconates (eq 2) and a–keto esters (eq 3) with high substrate to catalyst ratios (2500:1 – 10,000:1) and very high catalyst turnover rates (~30,000-50,000h-1).
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| Photochemistry - New Light on an Old Problem
In a presentation given by Malcolm Berry of GlaxoSmithKline at Scientific Update’s one day Symposium on Novel Technologies for Future Manufacture of Fine Chemicals, the emphasis was on the potential of the technology. The group at GSK have concentrated on redesigning the photo-reactor to incorporate modern lasers or systems used in water purification. They have applied the technology to two projects. For the photocyclisation below, it was found that UV light was required to isomerise the compound (1) and a rapid acid catalysed cyclisation then took place. In the early stages of the project, when unpurified (1) was used, no additional acid was required for the cyclisation. When purified (1) was used, the photoisomerisation took place, but would not cyclise until an acid catalyst was added. The process was scaled up and kilogram quantities of (2) were produced. In the second example, the target was to produce a technical synthesis of compound (5) suitable for making 4,000 kg per annum, with a long term expectation of 20,000 kg per annum. The intended synthetic route required a key cyclisation step of the propynyl ether (3). Originally a tin induced radical cyclisation of 3 to 4 had been used but a photochemical cyclisation of the type published by Cossy (Tet. Lett, 1994, 35, 8161) was expected to be more environmentally friendly. A prototype continuous reactor was used to produce 600g/per day (equivalent to 180 kg/annum). |
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Fluorous Phase CatalysisProfessor Dennis Curran, one of the leading figures in the area of fluorous phase catalysis gave an excellent presentation at the Novel Technologies meeting in Manchester, prior to ChemSpec exhibition. Key references to his recent work include: Ryu I et al, J Am Chem Soc., 2002, 124, 12946 Curran has founded a new company Fluorous Technologies to exploit his discoveries.
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| Microwave Technology
Chris Mason fro CEM Microwave Technology Ltd, UK, presented issues related to the scale up of microwave-enhanced reactions at the Novel Technologies meeting in Manchester (June 3, 2003). He presented novel results which indicate that intense microwave heating coupled with simultaneous cooling of the reaction gives best results and allows reactions which would be extremely slow thermally to be carried out quickly under microwave conditions using the Power Max These reactions are carried out in sealed systems so build up pressure (e.g. 250 E>psi for the Alder reaction). The Voyager equipment is available from CEM for large lab studies, the equipment fitting into a standard fume hood.
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| Automation at Degussa
Degussa have designed an automated system comprising 8 x 100 ml reactors with associated instrumentation for use in process development. It has been given the name ALFRED – Advanced Level Fast Reaction Engineering Device. The device seems to offer far better process control than King Alfred had with the cakes! ALFRED offers a high degree of temp control for each reactor, overhead stirring, ability to purge, distillation capability and robotic dosing control and sampling. The equipment is being commercialised with a German equipment manufacturer and will be available soon.
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Variable Residence Time ReactorLee Proctor of Phoenix Chemicals presented a case study of the scale up a key intermediate in the manufacture of atorvastatin (LIPITOR) at the Novel Technologies Symposium in Manchester (3rd June 2003). The Chemistry is shown below.
The E>cyanationreaction, which proceeds via the epoxides, is surprising low yielding when carried out under batch conditions. Using a continuous process, which was optimised using the variable residence time (VRT) reactor and DOE approach, the yield could be improved from 50-55% (batch) to over 80% (after distillation) with a high purity and ee. It was found that small amounts of water enhance the cyanation but also may cause hydrolysis of the product, hence the importance of controlling residence time. Continuous pH control, coupled with continuous extraction of the product ensures a high yield. The VRT reactor has the following advantages:
Scale up from a lab reactor (capable of producing 22 kg/year) to a pilot (5 t/a) and production plant (40 t/a) was relatively straightforward. Having the VRT capability on production could allow further optimisation of the process in the future and preserves flexibility for use in other processes. The VRT was constructed using off-the-shelf components by chemists and engineers at Phoenix/p>
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