Semi-Synthetic Process

The synthetic process starts with the isopropylation of m-cresol to yield thymol. After catalytic hydrogenation a mixture of stereoisomers is obtained from which (+)-menthol is isolated. The process requires much separation and recycling work. In contrast, the semi-synthetic process of Takasago (Scheme 5.5) leads essentially to stereopure (—)-menthol [19]. 

The semi-synthetic process can be broken down into three sechons to highlight the EHS consequences ... 

The advanced intermediate, 10-DAB, is isolated from the yew cuttings. Comparing the amount of paclitaxel manufactured over a five year period against the PCF process, the semi-synthetic process would generate nearly 1200 tonnes of biomass waste (note 0.1% 10-DAB in needles typically). 

A comparison of the semi-synthetic process with the PCF process can be made, applying the twelve Green Chemistry Principles as outlined by Anastas and Warner [17]. 

Other benefits when changing from the semi-synthetic process to PCF technology include ... 

As the usual in marine natural products development, obtaining sufficient amounts of ET743 has been a significant challenge due to its restricted natural availability (1 g from 1 ton of tunicate). Methods to produce ecteinascidins by in-the-sea culture of E. turbinata have been evolved [130] and much synthetic effort has been directed towards the synthesis of ecteinascidins [82]. Currently, ET-743 for clinical application is produced by a semi-synthetic process in 17 chemical steps developed by Pharma Mar starting from cyanosafracin B, an antibiotic produced by the fermentation of Pseudomonas fluorescens [131]. 

Before we leave our discussion of preparing 6-aminopenicillanic acid for use as a starting material in the manufacture of semi-synthetic penicillins, we should point out that similar processes are used in the manufacture of semi-synthetic cephalosporins. Here tire key intermediate is 7-aminodeacetoxycephalosporanic add (7-ADCA). We have drawn outline schemes comparing the production of semi-synthetic penicillins and cephalosporins in Figure 6.15. You will see that the two schemes are very similar. 

Another important enzymatic process in the production of 7-ADCA, for use in the production of semi-synthetic cephalosporins, is the hydrolysis of 7-aminocephalosporanic add (7-ACA) by the enzyme acetyl esterase. This process, again using immobilisation techniques, is illustrated in Figure 6.16. Hie deacylated product can be used, for example, as an intermediate in the production of the important oral cephalosporin cefuroxime. We will return to cephalosporin antibiotics later in this chapter. 

In section 6.6.1, we described how enzymatic methods have come to dominate the production of the important intermediates used in the manufacture of semi-synthetic -lactams. In principle, the hydrolytic penicillin acylases may be used in the reverse direction to add acyl groups to 6-APA. For example, a two-step enzymatic process has been described for the preparation of ampiciilin (D-(-)-a-aminobenzylpenidllin structure shown in Figure 6.17). 

The p-lactams, mainly penicillins and cephalosporins, are by production volume the most important class of antibiotics worldwide, enjoying wide applicability towards a range of infectious bacteria. Most of the key molecules are semi-synthetic products produced by chemical modification of fermentation products. Production of these molecules has contributed significantly to the development of large-scale microbial fermentation technology, and also of large-scale biocatalytic processing. 

The path from discovery through scale-up of microbial processes has been a huge commercial success. By 1996, the world market for antimicrobials amounted to 23 bilfron and involved some 150-300 products, either natural or semi-synthetic/synthetic. The 8 billion US antimicrobial market... 

Morphine is the major alkaloid in opium, the dried latex obtained from the opium poppy, Papaver somniferum. About 25% of the mass of opium is composed of alkaloids, with morphine constituting about 12-15%. Morphine is a powerful analgesic, and remains one of the most valuable for relief of severe pain. However, most of the morphine extracted from opium is processed further to give a range of semi-synthetic drugs, with enhanced or improved properties. A means of extracting morphine from the other alkaloids in opium is thus desirable. 

Corticosteroids are produced by the adrenal glands, and display two main types of biological activity. Glucocorticoids are concerned with the synthesis of carbohydrate from protein and the deposition of glycogen in the liver. They also play an important role in inflammatory processes. Mineralocorticoids are concerned with the control of electrolyte balance, promoting the retention of Na+ and CC, and the excretion of K+. Synthetic and semi-synthetic corticosteroid drugs are widely used in medicine. Glncocorticoids are primarily nsed for their antirhenmatic and anti-inflammatory activities, and mineralocorticoids are nsed to maintain electrolyte balance where there is adrenal insufficiency. 

For the analogous side-chain removal reaction required for semi-synthetic cephalosporin manufacture more complicated processes have been developed. The side-chain of cephalosporin C can be split off enzymatically, but only after its amino group has been removed by a combined enzymatic and spontaneous reaction sequence (Matsumoto, 1993). Amongst other companies, Hoechst has replaced their chemical process by a two-enzyme process, thus reducing the amount of waste from 31 ton to 0.3 ton per ton of 7-... 

Comparison of Semi-Synthetic versus PCF Taxoi Processes ... 

Reduction in the number of chemical processing steps allows for significant reduchon in the amount of in-process and Quality Control (QC) analysis of raw materials and intermediates required in the semi-synthetic route. Reduced handling and storage/disposal of cytotoxic samples by operators and analysts reduces opportunities for hazardous exposure. 

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