Telescoping of reactions

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... 

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. 

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. 

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. 

Beryllium and beryllium alloys have properties that make them useful for applications in space they are hard, they are lighter than aluminum, and they are stable over a wide temperature range. The Hubble Space Telescope s reaction plate is made of lightweight beryllium. The reaction plate carries heaters that keep the main mirror at a constant temperature. Beryllium is also being used in the Hubble s replacement—the fames Webb Space Telescope (JWST). 

A similar analysis of non-first-order reactions leads to quite cumbersome equations for [ ]n/[ o]- As the order increases, the telescoping functions involved in these equations become progressively more unwieldy, so that a simple expression for [ ]n/Mo] for a series of N reactors similar to Equation 10.15 for a first-order reaction becomes impossible. It is necessary in such cases to resort to step-by-step algebraic calculations. The equation for a single step in any such sequence is known as the recursion equation. Such equations for Mli-i/MJi (for two consecutive stages) for different types of reactions are listed in Table 10.1. 

Telescoping A synthesis tactic often used in process chemistry that involves concatenation of reaction steps so that reaction intermediates are not isolated this is an effective optimization strategy that reduces solvent demand. 

PI has led to the design of a variety of new and innovative reactor designs to overcome mass and heat transfer limitations that are normally encountered in large-scale vessels (Semel, 1997). With these designs it is possible to carry out highly exothermic reactions, speed up the rate of reaction by several orders of magnitudes, totally eliminate side reactions and hence waste formation, combine reactions with unit operations, and telescope several steps into a single step. 

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. 

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.

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... 

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. 

This image of the Crab Nebula taken by the Hubble Space Telescope shows enormous interstellar gas clouds, in which spallation reactions may be taking place. 

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