Intermediates Synthesis
What are Chemical Intermediates?
In chemistry, a chemical intermediate is a molecular entity that is formed during a chemical reaction and subsequently reacts further to give the final product. Chemical intermediates are important in many areas of chemistry, including organic synthesis, materials science, and biochemistry. They are highly reactive and often unstable species that require special handling and storage conditions.
Importance of Intermediates in Drug Discovery
Owing to chirality is a pivotal factor in the safety and efficacy of many drug products, the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. It has been seen that the increasing awareness of the potential of microorganisms and enzymes derived from the transformation of synthetic chemicals with intermediates. There has been a high demand of intermediates and fine chemicals from the pharmaceutical for the preparation of bulk drug substances. Biocatalytic processes have been described for the synthesis of intermediates for medicine, such as antihypertensive drugs, drugs to treat Alzheimer's disease and so on.
Properties of Chemical Intermediates
Chemical intermediates are a peculiar species in the realm of chemistry. They possess some noteworthy properties that distinguish them from their starting materials and final products. These properties include a high degree of reactivity, which renders them highly unstable and precarious. Handling and storing these volatile entities can be an arduous task, as they tend to react with other chemicals in the environment, leading to decomposition or even an explosion.
In addition to their unpredictability, chemical intermediates are also characterized by a fleeting existence. They are short-lived species, existing only briefly during the reaction process before being consumed in further reactions to form the final product or decomposing into other compounds. This ephemeral nature makes it challenging to isolate and characterize them, as they are present in low concentrations during the reaction process.
Despite their evanescent nature, chemical intermediates can possess unique structural features that are not found in either the starting materials or the final products. These structural features can offer invaluable insights into the reaction mechanism and facilitate the design of new chemical reactions.
Types of Chemical Intermediates
These chemical intermediates can be broadly classified into two major categories: reactive and non-reactive intermediates, based on their stability and reactivity.
Reactive intermediates are the more tempestuous and volatile of the two categories, consisting of a variety of species that possess unpaired electrons or partial charges, such as free radicals, carbocations, carbanions, and other reactive entities. These species are characterized by their high degree of reactivity, which renders them highly unstable and prone to rapid decay. They can initiate or participate in a wide range of chemical reactions, including chain reactions, radical reactions, and substitution reactions.
Non-reactive intermediates, on the other hand, are comparatively more stable and unreactive, held together by covalent bonds, hydrogen bonds, or van der Waals interactions. This category includes zwitterions, organometallic compounds, and radicals that lack the inherent reactivity of their reactive counterparts. These species can play a crucial role in catalysis, as they can facilitate and stabilize reactive intermediates, or act as reaction intermediates themselves in certain chemical transformations.
Applications of Chemical Intermediates
The use of chemical intermediates as building blocks for synthesis is a well-established and fundamental concept in organic chemistry. These species can serve as precursors for the construction of more complex molecules, allowing for the efficient and selective assembly of a diverse range of compounds. The strategic use of chemical intermediates in synthesis has enabled the development of new drugs, materials, and other useful products.
In addition to their role in synthesis, chemical intermediates can also function as catalysts or reagents in various chemical transformations. These species can facilitate and accelerate reactions, lower activation energy barriers, and enhance selectivity and efficiency. The use of chemical intermediates as catalysts or reagents can lead to new reaction pathways, the discovery of novel chemical reactions, and the development of more sustainable and efficient chemical processes.
Moreover, chemical intermediates can also be employed as probes for investigating reaction mechanisms, providing invaluable insights into the underlying processes and pathways involved in chemical transformations. By understanding the behavior and properties of chemical intermediates, researchers can gain a deeper understanding of chemical reactions, enabling the development of new chemical reactions and the improvement of existing ones.
BOC Sciences has very copious experience in regard to intermediates for the synthesis of chiral drug substances. We can provide the synthesis of intermediates for drugs including antihypertensive drugs, drugs to treat Alzheimer’s disease, β3-receptor agonists and so on.
Intermediate for synthesis of drug intermediates of antihypertensive drugs
It is well known that Omapatrilat is an antihypertensive drug that acts by inhibiting angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). S-6-Hydroxynorleucine is an important intermediate in the synthesis of Omapatrilat and C7-substituted azepinones, which are intermediates for other antihypertensive metalloprotease inhibitors. Reductive amination of ketoacids using amino acid dehydrogenases has long been known as a useful method for the synthesis of natural and unnatural amino acids. The synthesis and complete conversion of 2-keto-6-hydroxyhexanoic acid to S-6-Hydroxynorleucine has been described by reductive amination using phenylalanine dehydrogenase (PDH) from S. porosarcina sp. or beef liver glutamate dehydrogenase. Beef liver glutamate dehydrogenase was used for preparative reactions at 100g/l substrate concentration. As depicted, (Figure.2) the sodium salt of 2-keto-6-hydroxyhexanoic acid, in equilibrium with 2-hydroxytetrahydropyran-2-carboxylic acid sodium salt, was converted to S-6-Hydroxynorleucine. The reaction requires ammonia and NADH. NAD produced during the reaction was recycled to NADH by the oxidation of glucose to gluconic acid using glucose dehydrogenase from Bacillus megaterium. The reaction was complete in about 3h with reaction yields of 92% and an ee of >99% for 18.
Figure 2. The synthesis of S-6-Hydroxynorleucine (intermediate for antihypertensive drugs)
Intermediate for synthesis of drug intermediates of anti-Alzheimer’s drugs
S-2-Pentanol is an intermediate in the synthesis of several potential anti-Alzheimer’s drugs that inhibit β-amyloid peptide release and its synthesis. The enzymatic resolution of racemic 2-pentanol and 2-heptanol by lipase B from C. antarctica has been demonstrated. Commercially available lipases were screened for the enantioselective acetylation of racemic 2-pentanol in an organic solvent (hexane) in the presence of vinyl acetate as an acyl donor. C.antarctica lipase B efficiently catalyzed this reaction, giving yields of 49% (theoretical maximum yield 50%) and 99% ee for (S)-2-pentanol. Among acylating agents tested, succinic anhydride was most favored due to easy recovery of the (S)-2-pentanol at the end of the reaction. Reactions were carried out using racemic 2-pentanol as solvent as well as substrate (Figure 3).
Figure 3. The synthesis of S-2-Pentanol (intermediate for anti-Alzheimer’s drugs)
Intermediate for synthesis of drug intermediates of β3-Receptor agonists
β3-Adrenergic receptors are found on the cell surface of both white and brown adipocytes and are responsible for lipolysis, thermogenesis and relaxation of intestinal smooth muscle. The following bio-catalytic syntheses of chiral intermediates required for the total synthesis of β3-receptor agonist have been investigated. The microbial reduction of 4-benzyloxy-3-methanesulfonylamino-2′-bromoacetophenone to the corresponding (R)-alcohol has been demonstrated using Sphingomonas paucimobilis SC 16113. Reaction yields of >85% and enantiomeric excess (ee) values of >98% were obtained; for example, the isolation of (R)-alcohol from a 200 l batch gave 320 g (80% yield) of product with an ee of 99.5%.
Figure 4. The synthesis of (R)-alcohol (intermediate for β3-Receptor agonists)
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References
- Robl. J.A, Sun. C, Stevenson. J, Ryono. D.E, Simpkins. L.M, Cimarusti. M.P, Dejneka. T, Slusarchyk. W.A, Chao. S, Stratton. L et al. (1997) ‘Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensinconverting enzyme and neutral endopeptidase’, J. Med. Chem, 40, 1570-1577.
- Patel. R.N, Banerjee. A, Nanduri. V, Goswami. A, Comezoglu. F.T. (2000) ‘Enzymatic resolution of racemic secondary alcohols by lipase B from Candida antarctica.’ J. Am. Oil. Chem. Soc., 77, 1015-1019.
- Ramesh. N. P. (2001) ‘Biocatalytic synthesis of intermediates for the synthesis of chiral drug substances.’ Curr. Opin. Biotech, 12, 587-604.