Kilogram scale reactions

At this time, I am not aware of any industrial scale solid-state synthetic procedures. However, as described in Chapter 2, kilogram scale reactions of this type have been performed, and with considerable advances being made in the use of ball mills for such reactions on a laboratory scale, it is only a matter of time before these innovations reach commercialization. 

Most biosynthetic reactions used in industry employ hydrolytic enzymes. Many other enzymes could be used in synthesis, but these enzymes require adenosine 5 -triphosphate (ATP) as a source of energy. The synthesis of various Hne chemicals using bioreactors with systems for the regeneration of ATP has been investigated intensively on a research scale. We have produced sugar phosphates in kilogram-scale reactions to demonstrate that bioreactors can be used to produce fine chemicals on an industrial scale. 

In a kilogram-scale reaction-pervaporation unit, the method has been tested extensively. The apphed membranes showed high permeability and selectivity towards water during the whole reaction period. Besides that, the membranes appeared to be thermally and chemically stable for the reaction conditions applied. For this specific application the energy savings as compared to conventional methods are estimated to be more than 40%, and the reactor efficiency can be increased by at least 30% [99, 100]. 

We found that the optimal reaction protocol was to add a solution of a-bromo ketone in THF to the amidine in aqueous THF in the presence of potassium bicarbonate under vigorous reflux. Using this procedure, 2,4-disubstituted imidazoles were isolated in excellent yields with >95% purity without column chromatography. Aromatic and aliphatic a-halo ketones participate in this reaction with a variety of aromatic amidines, as indicated in Table 1. Particularly noteworthy is that reactions involving pyridylamidines or chloroacetone are substantially more robust using this process (entries 3 and 4). We have successfully used this protocol on a multi-kilogram scale. 

The strategies explored and defined in the various examples presented open a way for wider application of microwave chemistry in industry. The most important problem for chemists today (in particular, drug discovery chemists) is to scale-up microwave chemistry reactions for a large variety of synthetic reactions with minimal optimization of the procedures for scale-up. At the moment, there is a growing demand from industry to scale-up microwave-assisted chemical reactions, which is pushing the major suppliers of microwave reactors to develop new systems. In the next few years, these new systems will evolve to enable reproducible and routine kilogram-scale microwave-assisted synthesis. 

Scheme 11.4 shows some other representative Friedel-Crafts acylation reactions. Entries 1 and 2 show typical Friedel-Crafts acylation reactions using A1C13. Entries 3 and 4 are similar, but include some functionality in the acylating reagents. Entry 5 involves formation of a mixed trifluoroacetic anhydride, followed by acylation in 85% H3PO4. The reaction was conducted on a kilogram scale and provides a starting material for the synthesis of tamoxifen. Entry 6 illustrates the use of bismuth triflate as... 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

The completion of the synthesis required removal of the tert-butyl group and crystallization of 1 as the HC1 salt. Reaction of crude 80 with TFA in DCE at 75 °C gave the free base of 1 in near quantitative yield. The free base was not crystalline, but was converted to its crystalline HC1 salt by treatment with 2 M HC1 in MTBE. The product was isolated in 85% yield after filtration and drying. These conditions were also successfully transferred to the kilogram scale, providing 1 in the expected yields. Thus, the final overall optimized route to 1 is summarized in Scheme 7.25. The improved synthesis of 1 proceeded in 14 steps and in 22% overall yield from 35. 

A complete understanding of the mechanistic details of each reaction allowed the successful implementation of the chemistry on a multi-hundred kilogram scale. 

Another synthesis technology which has just started to impact and change the way chemical synthesis is performed in many laboratories is microwave assisted organic synthesis. Using microwave reactors, reaction times often can be reduced from hours or days to minutes or even seconds. Selectivities and yields often can be increased drastically. Therefore, this technology has the potential to increase the output of chemical drug discovery units enormously. An important question in this field is how to scale up these transformations in microwave reactors up to kilogram scale. 

These reactions may give very high enantioselectivities, particularly for structures such as ArS(0)Me and this approach has been used on a multi-kilogram scale in industry. 

The reachon condihons were successfully engineered to allow for operahon in a safe fashion on a mulh-kilogram scale. The reaction was carried out in a 35 wt% aqueous soluhon of hydrazine under rigorously controlled condihons to prevent any thermal events. ) Rather than isolate 7, it was simply extracted at the end of reachon and carried into the next step which involved trifluoroacetylahon with... 

As discussed in this chapter, the scope of demonstrated applications now extends from the sub-milligram level for radio-tracer work to the kilogram scale for preparative chemistry. Commercial microwave batch reactors have been introduced to accommodate such requirements. Continuous reactors have also been produced for use with dry media or liquid-phase reactions and these allow higher throughputs. 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Schering chemists demonstrated that the target molecules 32 and 33 can also be synthesized in a one-pot reaction with enantioselectivity up to 84% ee when using 10-200 mol% proline as catalyst [65, 66], Because of easy access to the steroid precursors 28 and 29 from readily available raw materials, and the use of the economically attractive catalyst L-proline, this intramolecular aldol reaction has attracted commercial attention. At Schering L-proline catalysis has been conducted on a multi-kilogram scale [67]. 

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