Telescoped reaction

Finally, the process design will require crystalline intermediates and the use of telescoped reaction sequences that are robust enough to provide clean intermediates with defined impurity profiles. This is an essential for commercial viability. 

The choice of the carboxylic acid blocking group (R in Scheme 11.2) is very important, as it not only has to survive multiple reactions, it also has to be readily and cleanly removed at the end of the synthesis during the formation of the penultimate intermediate. In addition, there is an important third factor. The physical properties of the isolated intermediates need to be considered. The ideal blocking group will confer sufficient crystallinity on the key intermediates that they can easily be isolated as fairly pure defined compounds from the telescoped reaction sequences needed for commercial efficiency. 

The next series of telescoped reactions is carefully coordinated to produce the highly substituted [3-lactam 24. The thiazoline ring in 21 is easily cleaved to yield the thiol 22, which featmes a... 

Recently, Nyffenegger et al. (07TL5069) have utilised the Sonogashira reaction for the functionalisation of 5[Pg.82]

When considering the solvents used in a synthetic pathway to an API or intermediate, one quick analysis that may be performed is simply to look at the number and types of solvents used. Counting the number of solvent swaps may identify opportunities where steps could be carried out in succession using the same solvent, without the need to isolate the product (telescoping reactions). ... 

Recommendation Alongside the use of solvent selection guides to try to identify as green a solvent for your reaction as possible, consider whether reaction steps could be carried out in the same solvent and hence opening up the possibility for telescoping reactions and easier solvent recycling. 

Telescope the Process by Combining Stages. This has been done successfully in the conversion of propylene to acrylonitrile by direct ammoxidation rather than oxidation to acrolein followed by reaction with ammonia in a separate stage, as was described in the earlier patent literature. The oxychlorination of ethylene and HC1 directly to vinyl chloride monomer is another good example of the telescoping of stages to yield an economic process. 

At the end of the synthesis reactions, the product can be pumped to another vessel or container via transfer lines. If the chemical reactions proceed to completion with negligible trace quantities of impurities, the next stage of production may commence in the same reaction vessel with addition of fresh raw materials. This process is called telescoping. 

No opportunity for telescoping (since the first reaction is conducted in benzene and the second in dichloromethane),... 

Process Improvements. Phase 1 Benzene was replaced with a safer solvent, toluene, which was also used for the [2 + 2] cycloaddition reaction, thus facilitating the telescoping of the two reactions. However, dichloromethane was added during the work-up to prevent product precipitation. The product was ciystallized from 2-propanol in 80% yield. The phase I of development eliminated the use of benzene and allowed for telescoping of the two chemical steps. However, a solvent exchange from toluene-dichloromethane to 2-propanol was still needed to crystallize the product. The color of the product after this modification was dark-brown. 

All process development starts with chemistry. The selection criteria for the most suitable chemistry for a continuous process do not suffer from the same constraints as those for a large-scale batch process. For example, highly exothermic reactions are not only possible in a flow reactor, but are in fact preferred [47]. As operator exposure will be low and so will stock levels, different safety considerations come into play that may allow utilisation of otherwise intolerably toxic reagents. Process telescoping is a necessity to minimise the number of intermediate isolations. Examination of all these factors is facilitated by online analysis because of its speed and maintenance of experimental integrity (i.e. no requirement for sampling). 

Fig. 4.4. All-sky map in the light of the 1.809 MeV gamma-ray hne from radioactive aluminium-26. The galactic distribution of aluminium-26, based on data from the COMPTEL (Compton Telescope) experiment aboard the GRO (Gamma-Ray Observatory), suggests that this isotope is dispersed across the Galaxy by the most massive stars, Wolf-Rayet stars and supernovas. Al is formed by the reaction Mg -b p — A1 -b y. This radioactive isotope has a lifetime of about million years and is ejected into space before it begins to decay.

The sliding filament model describes the mechanism involved in muscle contraction. In this model, sarcomeres become shorter when the thin and thick filaments slide alongside each other and telescope together, with ATP being consumed. During contraction, the following reaction cycle is repeated several times ... 

Reaction efficiency with technologies, such as telescoping. 

Telescoping, selecting reagents, and reaction optimization can afford significant decreases in the COG. The process route initially used to prepare 200 kg of the API intermediate acid 44 involved seven steps, four solvents, bromination, diazotization, and reaction with CO at 120°C, and produced the drug candidate in 20% yield. The optimized route shown in Scheme 2.12 was operationally simpler (using the same vessel for every... 

Direct reduction of an aldehyde or ketone to the corresponding ether could potentially telescope two reactions, reduction and protection, into one step. S. Chandrasekhar of the Indian Institute of Chemical Technology, Hyderabad, reports (Tetrahedron Lett. 2004,45,5497) that in the present of polymethylhydrosiloxane (PMHS) and catalytic B(C6F,), TMS ethers of alcohols will convert aldehydes to the corresponding dialkyl ethers. The reaction works well for both saturated and benzylic alcohols. This may prove to be a useful alternative to Williamson synthesis for the preparation of complex ethers. 

Telescoping of reaction steps, where feasible, can significantly improve the overall efficiency of a target-directed sequence. Zoapatanol 10 features a delicate combination of organic functional groups, in... 

Many continuous processes are used to prepare early pharmaceutical intermediates, but Pfizer recently presented a continuous process to prepare the API itself. A continuous process to prepare the anti-inflammatory drug celecoxib was described (Scheme 11.3) [6]. The batch process for celecoxib consists of two steps (1) a base-mediated Claisen reaction between 4-methylacetophenone and ethyl trifluoroacetate, and (2) an acid-mediated pyrazole condensation between enolate intermediate 8 and hydrazine 9 giving celecoxib (Scheme 11.4) [7]. Continuously flowing the Claisen reaction step 1 into the pyrazole condensation step 2 offers the advantages of directly telescoping continuous processing steps, as described in the introduction to this chapter. 

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