Drug synthesis synthetic routes

In spite of the considerable progress in developing methods for total synthesis, this route to cephalosporins cannot compete with fermentation or penicillin rearrangement (see Sections 5.10.4.1 and 2) for the industrial production of cephalosporin antibiotics. While total synthesis does provide access to nuclear analogs not readily obtainable from fermentation products, none of the totally synthetic materials have displayed sufficient advantages to Warrant their development as new drug products (b-81MI51000). 

The reaction of enamines with iminium salts provides an alternative route to Mannich bases which are an attractive class of compounds, since they have found many applications (synthesis of drugs, pesticides, synthetic building blocks, etc.). This methodology has several basic advantages compared to the classic aminomethylation procedure15-18-24 ... 

One of the first major pharmaceutical biotransformations was the development of the synthesis of hydrocortisone in the late 1940s by whole-cell hydroxylation (Figure 2.2). Up until then a 40-step synthetic route developed by the Noble Prize winning chemist R.B.Woodward was the only source of this important drug substance and intermediate. Nowadays, a biocatalyst exists for the selective hydroxylation of every position on the steroid nucleus. ... 

There are two approaches to producing drugs as a single enantiomer. If a synthetic route produces a racemic mixture, then it is possible to separate the two enantiomers by a process known as resolution (see Section 3.4.8). This is often a tedious process and, of course, half of the product is then not required. The alternative approach, and the one now favoured, is to design a synthesis that produces only the required enantiomer, i.e. a chiral synthesis. 

In addition, new some epoxide hydrolases have also shown a great utility for the desymmetrization of meso-epoxides. An interesting example is the synthesis of nelfinavir-the active pharmaceutical ingredient (API) of the anti-human immunodeficiency virus drug Viracept-where the (R,R)-diol obtained by opening the meso-epoxide is a suitable starting material. Scheme 10.6 shows a synthetic route to nehinavir [14]. 

The purpose of the synthesis also has a bearing on the type of procedure chosen. Thus, in medicinal chemistry, synthetic procedures that allow for the greatest compound diversity as late as possible in the synthesis are desirable, but these may not be the optimum procedures once the final drug candidate is identified. Additionally, procedures that require chromatography for product purification may be perfectly acceptable on a laboratory scale, but are often undesirable on an industrial scale. Legal issues can also influence the choice of synthetic procedure if the preferred route is covered by a competitors patent. Therefore, it is not possible to say categorically that one synthetic route is superior to another until all of the various factors have been fully assessed, and even then the result is only valid for that point in time, as a new or improved procedure may appear at any time. 

The antidiarrhoeal drug ipecac, which was introduced into Europe from Brazil in 1658, contains the amoebicidal alkaloids emetine (12) and cephaeline. Emetine remained the major remedy for amoebic dysentery and amoebic hepatitis for many years. Cephaeline is less active and more toxic. ( j-2-Dehydroemetine, which is made by synthesis, is equiactive with (—)-emetine and less toxic, but other chemical modification has not yielded better amoebicides. From investigations of synthetic routes to the benzoquinolizine moiety the tranquilizer tetrabenazine (13a) was discovered. The very similar compound benzquinamide (13b) is also a tranquilizer and antiemetic. 

Nevertheless, the synthesis of natural products continues to be important. It provides new methodology, new reactions and techniques. It also provides alternative sources of natural compounds and offers routes to related but unnatural analogs. In the case of a useful drug, the synthetic objective is to find a related structure that is more potent at lower dosages with fewer side effects than the natural compound. 

The enantioselective reduction of ketones using oxazaborolidine-borane complexes is a useful synthetic route to chiral alcohols (equation 63). Additives such as simple alcohols have been found to enhance the enantioselectivity of the process, and the reaction has been used in the large-scale synthesis of an important drug with anti arrhythmic properties249. 

A large number of drugs feature a heterocyclic component. Thus, the design, synthesis, and evaluation of heterocyclic libraries have rapidly become a major field of organic chemistry. Over the past decade, we have developed synthetic routes to a wide range of different heterocycles starting from resin-bound amino acids, short peptides, and polyamines. 

A chiral auxiliary is a temporary chiral group on a molecule that directs the stereochemical outcome of a reaction on another part of the molecule. Almost all synthetic routes involving chiral auxiliaries follow three steps (1) covalently attach the auxiliary to the molecule, (2) perform the reaction that forms the new stereocenter, and (3) remove the auxiliary. Under this model, use of a chiral auxiliary adds two steps to a synthesis because the auxiliary must be added and removed. Additional steps in a synthetic scheme require additional time, increase cost, and decrease the overall yield. Despite these disadvantages, chiral auxiliaries are fairly common in drug synthesis. 

Once the structure of a lead has been decided it is necessary to design a synthetic pathway to produce that lead. These pathways may be broadly classified as either partial or full synthetic routes. However, partial synthetic routes tend to be more concerned with the large scale production of proven drugs rather than the synthesis of lead compounds. This chapter is intended to introduce some of the strategies used, and the challenges associated with the design of these synthetic routes. 

With the asymmetric synthesis of the CP compounds completed and the synthetic route to various simpler variants now established, chemists have obtained extensive knowledge about the reactivity of these small but complex natural products. This knowledge may be extremely useful for the development of therapeutically valuable analogues with increased biological activities. Whether or not this search results in the discovery of efficient drugs, the phomoi-drides have already provided a platform for some outstanding, highly inventive science. 

All the optically active terpenes mentioned in this chapter are commercially available in bulk (>kg) quantities and are fairly inexpensive. Although many of them are isolated from natural sources, they can also be produced economically by synthetic methods. Actually, two thirds of these monoterpenes sold in the market today are manufactured by synthetic or semi-synthetic routes. These optically active molecules usually possess simple carbocyclic rings with one or two stereo-genic centers and have modest functionality for convenient structural manipulations. These unique features render them attractive as chiral pool materials for synthesis of optically active fine chemicals or pharmaceuticals. Industrial applications of these terpenes as chiral auxiliaries, chiral synthons, and chiral reagents have increased significantly in recent years. The expansion of the chiral pool into terpenes will continue with the increase in complexity and chirality of new drug candidates in the research and development pipeline of pharmaceutical companies. 

---