Manufacture of fine chemicals

Batch crystallizers are widely used in the chemical and allied industries, solar saltpans of ancient China being perhaps the earliest recorded examples. Nowadays, they still comprise relatively simple vessels, but are usually (though not always) provided with some means of agitation and often have artificial aids to heat exchange or evaporation. Batch crystallizers are generally quite labour intensive so are preferred for production rates of up to say 10 000 tonnes per year, above which continuous operation often becomes more favourable. Nevertheless, batch crystallizers are very commonly the vessel of choice or availability in such duties as the manufacture of fine chemicals, pharmaceutical components and speciality products. 

Hydrogenation reactions, particularly for the manufacture of fine chemicals, prevail in the research of three-phase processes. Examples are hydrogenation of citral (selectivity > 80% [86-88]) and 2-butyne-l,4-diol (conversion > 80% and selectivity > 97% [89]). Eor Pt/ACE the yield to n-sorbitol in hydrogenation of D-glucose exceeded 99.5% [90]. Water denitrification via hydrogenation of nitrites and nitrates was extensively studied using fiber-based catalysts [91-95]. An attempt to use fiber-structured catalysts for wet air oxidation of organics (4-nitrophenol as a model compound) in water was successful. TOC removal up to 90% was achieved [96]. 

In recent years two trends have become visible in the manufacture of fine chemicals (1) custom synthesis, and (2) specialization in groups of processes or products that are derived from specific raw materials (chemical trees). 

Plants for the manufacture of fine chemicals are discussed in Chapter 7 with emphasis put on multiproduct plants. Types of production plants and typical equipment for multiproduct plants with cost considerations are presented in more detail. Problems of designing and scheduling multiproduct and multipurpose plants with particular emphasis given on process data needed to realise this task are discussed. 

Higher selectivity, easier processing, use of inexpensive solvents, use of cheaper chemicals, and ease of heat removal have been realized through phase-transfer catalysis (PTC). It appears that no catalytic method has made such an impact as PTC on the manufacture of fine chemicals (Sharma, 1996). Many times we benefit by deliberately converting a single-phase reaction to a two-phase reaction. Consider catalysis by. sodium methoxide in a dry organic. solvent. This can invariably be made cheaper and safer by using a two-pha.se. system with a PT catalyst. 

In the recent past the potential of zeolites in the manufacture of fine chemicals has received considerable attention. High-Si zeolites can have Hammet s acidity function Ho of -12.8 which is close to those for superacids. MCM (Mobil Catalytic Materials) have opened up new vistas due to larger pore sizes. 

Bakke et al. (1982) have shown how montmorillonite catalyses chlorination and nitration of toluene nitration leads to 56 % para and 41 % ortho derivative compared to approximately 40 % para and 60 % ortho derivatives in the absence of the catalyst. Montmorillonite clays have an acidity comparable to nitric acid / sulphuric acid mixtures and the use of iron-exchanged material (Clayfen) gives a remarkable improvement in the para, ortho ratio in the nitration of phenols. The nitration of estrones, which is relevant in making various estrogenic drugs, can be improved in a remarkable way by using molecular engineered layer structures (MELS), while a reduction in the cost by a factor of six has been indicated. With a Clayfen type catalyst, it seems possible to manipulate the para, ortho ratio drastically for a variety of substrates and this should be useful in the manufacture of fine chemicals. In principle, such catalysts may approach biomimetic chemistry our ability to predict selectivity is very limited. 

The role of reversed micelles in the manufacture of fine chemicals with enzymes also needs to be assessed and analysed. An outstanding example is lipase catalysed interesterification to produce cocoa butter substitute from readily available cheap materials (Luisi, 1985). This example of reversed micelles is sometimes referred to as a colloidal solution of water in organic systems. A number of water insoluble alkaloids, prostanoids, and steroids have been subjected to useful transformations (Martinek et al., 1987). Peptide synthesis has also been conducted. The advantages of two liquid phases are retained to a very great extent the amount of water can be manipulated to gain advantages from an equilibrium viewpoint. 

Electrochemical processes are particularly well suited for the manufacture of fine chemicals in view of their high sjjecificity (almost comparable to that offered by enzymes), the smaller number of steps required, adoption of milder conditions, lack of scale-up problems, avoidance of effluents, etc. The ease with which oxidation and/or reduction can be carried out with the practically mass-free clean electrons makes electrochemical processes well suited for such jobs, including paired synthesis in effect, we use electricity as a reagent . Consider a standard chemical oxidant like manganic or chromic sulphate. Here, a stoichiometric amount of the reduced salt will be formed the disposal of which can be a serious problem. If we adopt an electrochemical process, then the reduced salt is converted into the desired oxidized salt. 

Ogawa et al. (1998b) have shown how 1,4-butanediol to 1,16-hexadecanediol and 1,4-cyclohexanediol, adsorbed on silica gel, can be reacted with acetyl chloride to give nearly 100% selectivity for the mono-acyl derivative. The above examples give an indication of the versatility of this strategy in the manufacture of fine chemicals. There are, however, many aspects associated with the role of mass transfer, which have yet to be studied thoroughly. 

Due to the complexity of the problem, it is generally accepted that we will not reach the optimal reactor design and ojjerating variables, but still we would like to design and operate the reactor safely and near the optimum. Further in this section, we will give a general discussion of. scale-up methods for chemical processes, in particular with respect to chemical reactors suitable for the manufacture of fine chemicals. Next, we will discuss how to obtain reasonable quantitative relationships necessary for optimal and safe scale-up according to the art. The reader can find an extensive treatment of scale-up problems in the book of Bisio and Kabel(1985). 

Above, typical examples of processes have been given, but they are not intended to form a complete list of processes used in the manufacture of fine chemicals. Chapters 2 and 4 provide more examples. 

In practice, nearly all reactors used for the manufacture of fine chemicals are neither isothermal nor adiabatic. The temperature-versus-time (location) profile is determined by the kinetic and physical characteristics of the reaction mixture as well as by the reactor geometry and hydrodynamics. The relationships governing this profile will be discussed in Section 5.4.2. 

Quality control tests or improvement of existing processes. Raw materials from various sources can be used in the manufacture of fine chemicals and pharmaceuticals. The raw materials can contain different impurities at various concentrations. Therefore, before the raw material is purchased and used in a full-scale batch its quality should be tested in a small-scale reactor. Existing full-scale procedures are subject to continuous modifications for troubleshooting and for improving process performance. Laboratory reactors used for tests of these two kinds are usually down-scaled reactors or reactors being a part of the full scale-reactor. 

Transient reactors, such as pulse (chromatographic) reactors, temporary analysis of products (TAP) reactors, multitrack reactors, and temperature-programmed reactors have been developed mainly to study gas-solid (catalyst) reactions. These are rather sophisticated techniques used to study mechanisms of catalytic processes at the molecular level in great detail. Since this is rarely done in the development of processes for the manufacture of fine chemicals and pharmaceuticals, these reactors are not discussed further. The interested reader is referred to works by Anderson and Pratt (1985) and Kapteijn and Moulijn (1997). 

The vast majority of chemical reactions are sufficiently slow not to observe a dramatic influence of mixing on yields and selectivities. Exceptions are polymerizations, interfacial polycondensations, precipitations, and some fast reactions - usually performed in semibatch mode - such as autocatalytic reactions, neutralizations, nitrations, diazo couplings, brominations, iodinations, and alkaline hydrolysis, which are often encountered in the manufacture of fine chemicals. 

Distillation is still the most widely used method of separation in the manufacture of fine chemicals and is often the first choice in view of low costs, wealth of experience, and proven performance. 

There are three basic types of plants for the manufacture of fine chemicals dedicated plants, multiproduct and multipurpose plants, and mixed plants. 

Other factors can also make manufacturers of fine chemicals specializing in certain areas, which is more or le.ss equivalent to constmcting and/or running plants as dedicated ones. For example, experienced people make a company an expert in certain fields. Therefore, the company plant then becomes specialized/dedicated in these fields. 

Jacketed tank reactors, mainly stainless steel reactors and glass-lined reactors equipped with a stirrer, predominate in plants for the manufacture of fine chemicals. Glass-lined reactors are in common use although they are by 30-50 % more expensive than stainless steel reactors. This is because of the high chemical resistance of enamels towards typical chemical media and the much lower possibility of contamination of products with heavy metals, which should not be... 

Tsang, S.C., Caps, V., Paraskevas, I., Chadwick, D. and Thompsett, D. (2004) Magnetically separable, carbon-supported nanocatalysts for the manufacture of fine chemicals. Angewandte Chemie International Edition, 43 (42), 5645-5649. 

The manufacture of fine chemicals and pharmaceuticals generates in the order of 25-100 times more waste than product [52], Inorganic salts account for the bulk of the waste and are most often produced by neutralization of acidic or basic solutions [53]. Salts can pollute soil and ground water, lower the pH of atmospheric moisture and they may contribute to acid dew or acid rain [6]. For cleaner production, their minimization is essential and hence our concentration on new processes, such as the etherification (discussed in Sect. 2.6.3.1) and hydrogen transfer reduction (Sect. 2.6.3.2), that avoid salt formation and the use of salts. 

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