Telescoping Steps

The second example is the Hayashi [88] plan for oseltamivir phosphate, a neuraminidase inhibitor used to treat influenza. The synthesis scheme is shown in the following and the corresponding 

The next two examples come from academic groups on syntheses of natural products. 

FIGURE 11.24 Synthesis tree for Merck G2 (2005) plan for sitagliptin hydrogen phosphate. 

FIGURE 11.25 Synthesis tree for Hayashi (2009) plan for oseltamivir phosphate. 

FIGURE 11.26 Synthesis tree for Organ G2 (2004) plan for bupleurynol. 

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Figure 17. Steps in the constmction of a datacube of the nucleus of NGC1068 from observations with the integral held unit of the Gemini Multiobject Spectrograph installed on the Gemini-north telescope. The datacube is illustrated by a few spectra distributed over the field and equivalently by a few slices at a given radial velocity in the light of the [OIII]5007 emission line. Only a few percent of the total data content is shown.

Next steps toward experimental works will be particularly exciting the MCAO MAD bench at ESO, the MCAO+LGSs device at Gemini South, experiments at the MMT and at Mt Wilson, the polychromatic LGS demonstrator in France. Also we still have a lot to learn with the feedback from the devices running now or very shortly, at Lick, Keck and ESO. But the biggest challenge of the coming years wdl be to extrapolate this know how to the case of decametric or even hectometric optical telescopes. 

In this chapter we describe a novel, safe and efficient large-scale synthetic approach to tricycle thienobenzazepines. The key steps in the synthesis include a chemoselective hydrogenation of an aryl-nitro functionality in the presence of a 3-bromo thiophene and a subsequent palladium-catalyzed intramolecular aminocarbonylation telescoped sequentially after simple catalyst and solvent exchange. 

Opportunity to combine two or more chemical steps with no intermediate isolation (telescoping to increase throughput). 

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. 

American astronomy holds several trump cards. Until recently, its great optical telescopes, the HST and the twin telescopes Keck I and II set up on Manna Kea in Hawaii, reigned imperially over the visible and near UV sky. Although the European VET has largely counterbalanced this domination, the USA is ready to step into the lead once more. 

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... 

Telescope mirrors are silvered by prepg a soln of K hydroxide and Ag nitrate ammonia and covering the mirror with it. Unless the prepn steps ace followed carefully, SF may form which is very expl. Fof this reason the USBurStds recommends that goggles be worn to avoid an unnecessary risk. The risk is especially great if the "silvering" soln is kept for more than several hours. 

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. 

Carbon-carbon bond formation is fundamental to all of organic chemistry. The emphasis this week is on recently-developed useful transformations that are easily scalable. Notably, these transformations telescope two or more synthesis steps into one-pot procedures. 

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... 

One of the most widely used methods to improve overall process efficiency is to reduce the number of steps and unit operations in a synthetic route. This is more commonly known as telescoping. This can lead to more efficient, less wasteful processes that require fewer solvents because of the smaller number of steps. An example of this technique was illustrated earlier in Section 3.1.6, where the process optimization of the sertraline (Zoloft ) production process by Pfizer was described. In this case the number of process steps (unit operations) was reduced from 3 to 1, which led to huge savings due to higher productivity, fewer inputs, and less waste generation [18]. 

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. 

In aprotic media a l-(acyloxycarbonyl)imidazole such as 16 is formed primarily which reacts to the acylimidazole and carbon dioxide. Imidazole now serves as a good leaving group and so the previously synthesized amine 6 could be added and the desired amide was formed via the usual addition elimination mechanism. One of the advantages of using this more expensive way of activation is the possibility to run the nitro reduction, acid activation and acylation in the same solvent (ethyl acetate) thus all three reactions could be telescoped into a single step during production. 

Shell produces 1,3 PD from ethylene oxide via hydroformylation with synthesis gas (Fig. 8.8 b). The transformation required two separate steps in the past [55], but has been improved [56], which made the large-volume use of 1,3PD in poly(trimethylene terephthalate) economically viable, and the two steps have been telescoped into one [57, 58]. Shell has a capacity to 70 kt a-1 [59]. 

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