Fluorine compounds surge
Thursday, October 25, 2007 08:00 IST
There has been a huge amount of interest in the production of fluorinated molecules with applications in the pharmaceuticals and agrochemicals fields in recent years.
Very few compounds occurring in nature contain fluorine, however, so it may seem strange that molecules containing fluorine have been used in preparing drugs and agrochemicals. The surge in popularity of compounds containing fluorine can be explained based on its properties.
The high electronegative charge of fluorine causes a large electronic effect on neighboring carbon centres and has an appreciable effect on the molecule's dipole moment and the acidity or basicity of other groups nearby, not to mention the molecule's overall reactivity and stability.
The fluorine atom is larger than the hydrogen atom. However, the additional steric demand caused by replacing a hydrogen atom with fluorine at receptor sites is low.
The length of the C-F bond is not much greater than that of the C-H bond, which leads to little change in the steric bulk of the molecule. As far as drug molecules are concerned, fluorine is usually more lipophilic than hydrogen, which makes the fluorinated compounds more fat-soluble. This allows them to partition into membranes more easily and they also have higher bioavailability.
Several examples from recent literature show that molecules useful as pharmaceuticals and agrochemicals have both fluorine and nitrogen atoms incorporated in their framework. Even with the additions of new fluorinating agents that have been developed over the past decades, however, the selective introduction of fluorine into molecules is far from easy, especially on the large scale necessary for the production of pharmaceutical and agrochemical compounds.
The most economical fluorinating agents are hydrogen fluoride (HF) and elemental fluorine (F2) itself. Because of their volatility, reactivity and toxicity hazards, these are both difficult to work with, unless the work is carried out by experts skilled in the art.
There are some newer reagents, reactions involving them can be carried out under relatively mild conditions, require no special equipment and are designed to be simpler to handle by comparison with HF and F2, but they are significantly more expensive.
The advantage of having nitrogen atoms in drug molecules is well known and Halocarbon has now developed several fluorinated molecules that also contain a nitrogen functionality. This group of compounds now gives the drug designer the ability to incorporate the roles of both fluorine and nitrogen into the pharmaceutical structure in a single step.
These groups of molecules serve as building blocks for the preparation of more complex molecules. An added advantage is that the difficult fluorination step is done by experts who are well versed in the art.
Halocarbon, for example, manufactures various fluorinated amines, amides, amino crotonates and nitriles. These fluorinated molecules have been used to prepare compounds shown to possess interesting biological properties and their use has been cited in the recent literature. This article briefly describes a few examples.
One approach to making fluorinated amines involves the reductive amination of the corresponding carbonyl compounds. This process was demonstrated in a patented process by ICI.1 Trifluoroacetaldehyde is reacted with ammonia or a primary amine and the corresponding imine is hydrogenated using suitable hydrogenation methods to produce 2,2,2-trifluoroethylamine.
Another method to prepare this compound involves the reduction of 2,2,2-trifluoroacetamide. This transformation can be accomplished using several reducing agents, such as LiAlH4. A molecule that has the potential to treat Alzheimer's disease has recently been synthesised using 2,2,2-trifluoroethylamine.
Another example where trifluoroethylamine has been used to prepare biologically active compounds is in the preparation of substituted piperazine derivatives which act as inhibitors of microsomal triglyceride transfer protein and are useful in decreasing the plasma level of atherogenic lipoproteins.
2,2,2-trifluoroethylamine has also been used as a raw material to prepare agricultural products. For example,molecules containing 4,6-diamino-s-triazines have been prepared for use as fluorinated herbicides.
Another key fluorine-containing intermediate is 2,2-difluoroethylamine. A recently developed process uses this difluoro molecule to prepare compounds with activity on the 5-hydroxytryptamine receptor, a neurotransmitter that modulates a wide variety of physiological and pathological processes in the central nervous system and its periphery including anxiety, sleep regulation, aggression and depression.
Another building block available from Halocarbon is ethyl-3-amino-4,4,4-trifluorocrotonate. This has been used to synthesise insecticidal and acaricidal agents and herbicides. Previously, it has been used to prepare 6-trifluoromethyl-pyrid-2-one, a pharmaceutical and agrochemical intermediate.
2,2,2-Trifluoroacetamide is another useful intermediate for the synthesis of fluorinated molecules. It can be treated with a variety of dehydration reagents to give the corresponding trifluoroacetonitrile or can be reduced with suitable reducing agents to afford the corresponding trifluoroethyl amine.
This intermediate has been used to prepare herbicides, molecules which function as receptor agonists for treatment of metabolic disorders related to insulin resistance or hyperglycemia, pharmaceutical fungicides and phosphodiesterase IV inhibitors.
Other substituted trifluoroacetamides have been employed as intermediates in the synthesis of compounds that function as cannabinoid receptor agonists. These compounds exhibit anti-inflammatory and immunomodulatory activity. The substituted trifluoroacetamides are prepared by reacting a suitable amine with trifluoroacetic anhydride.
Trifluoromethyl nicotinic acid, a useful precursor for the synthesis of agrochemicals and pharmaceuticals, can be prepared from 4-amino-1,1,1-trifluoro-3-butene-2-one, which itself can be prepared from 4-alkoxy-1,1,1-trifluoro-3-butene-2-one. The alkoxy-1,1,1-trifluoro-3-butene-2-one can be prepared by the reaction of trifluoroacetyl chloride with ethyl vinyl ether in the presence of a suitable organic base.
Another useful compound is trifluoroacetonitrile, which has been prepared by the dehydration of 2,2,2-trifluoroacetamide. Trifluoroacetonitrile has been used to prepare various agrochemicals. Examples of its use are the preparation of thiazole derivatives that are useful as fungicides and insecticides.
The above examples demonstrate the use of nitrogen containing fluorinated molecules as building blocks for biologically active molecules. In addition to the trifluoro compounds shown in these examples, Halocarbon also prepares the difluoro and bromo and chloro-difluoro analogues.