Strong bond with fluorine chemistry


Neville Pavri, research chemist at Halocarbon, looks at some of the benefits of incorporating trifluoromethyl groups in medicinal chemistry

Neville Pavri, research chemist at Halocarbon, looks at some of the benefits of incorporating trifluoromethyl groups in medicinal chemistry

Trifluoromethyl groups are surprisingly common in drug compounds, despite the fact that fluorine atoms are extremely rare in naturally occurring organic molecules. But fluorine has become an invaluable tool for medicinal chemists because of the properties it confers on molecules that contain it, and the biological activity it can create as a result. Fluorine is the most electronegative element, so incorporating it into a potential drug molecule alters the electronic effects, and this can extend to altering the properties of neighbouring functional groups, too. It can also have steric effects, changing the shape of the molecule.

Furthermore, because of its rarity in nature, it is less likely to be degraded by naturally occurring enzymes, so it can help improve a drug’s metabolic stability. And it can have direct effects on the drug’s binding to the target site in the body, as it is able to form strong interactions with hydrogen bond donors and lipophilic side-chains, including aromatic groups.

The trifluoromethyl group, having three fluorine atoms and not just one, is one of the most lipophilic functional groups known. Its electronegative nature also gives it a much more dramatic effect on the drug molecule’s electronic character, with little more bulk than a normal methyl group.

Trifluoromethyl substituents are most common on aromatic groups, where they have an impact on the electronic characteristics of the aromatic rings. Some of the best known drugs have aromatic trifluoromethyl substitution, including Lilly’s SSRI anti-depressant fluoxetine (Prozac), the COX-2 inhibitor celecoxib (Celebrex) from Pfizer – the only one of the class that remains on the market in the wake of the Vioxx debacle – and the antimalarial drug mefloquine (Roche’s Lariam), which has two trifluoromethyl groups on its naphthalenic core. Other examples include Boehringer Ingelheim’s HIV protease inhibitor tipranavir (Aptivus), anticancer drug bicalutamide (Casodex from Astra-Zeneca), and Merck’s antiemetic drug aprepitant (Emend).

Aliphatic trifluoromethyl groups are less common, but again several drugs that contain them are on the market. Perhaps the best known of these is the proton pump inhibitor antiulcer drug lansoprazole (Prevacid from TAP Pharmaceuticals), which contains a trifluoro-ethyl ether moiety. The anti-arrhythmic flecainide (Tambocor from 3M Pharmaceuticals) contains two of these groups. Meanwhile, the non-nucleoside inhibitor efavirenz (Sustiva from Bristol-Myers Squibb) contains a chiral quaternary trifluoromethyl functionality, and the anticancer agent valrubicin, a semisynthetic derivative of doxorubicin, has a trifluoroacetyl group.

While a variety of different fluorin-ating agents exist, when it comes to aliphatic trifluoromethyl compounds it is generally simpler – and safer – to use an intermediate that contains a CF3 group to make them. Suitable intermediates include 1,1,1-trifluoroacetone and its derivatives, such as chloro- and bromo- derivatives and the reduced alcohol form. All of these have been recently introduced to Halocarbon’s portfolio of fluorinated intermediates.

The protons on the ketone’s methyl group are more acidic than they are in the non-fluorinated analogues, and thus the enolate can be formed under fairly mild basic conditions. This means that it is well set up for carrying out aldol addition reactions. One example is the synthesis of a histone deacetylase inhibitor from Errant Gene Therapeutics, which was formed by the aldol coupling of 1,1,1-trifluoroacetone with an aromatic alkenic aldehyde (Scheme 1).1

Another recent example comes from Pfizer, which used the monobromo analogue in the synthesis of a CETP inhibitor, designed to increase levels of ‘good’ cholesterol in the body. While this programme was discontinued because of side-effects in the lead compound, torcetrapib, it exemplifies the usefulness of these intermediates. The ketone was first reduced to the alcohol in a chirally selective reaction, and then cyclised to form a chiral trifluoromethyl epoxide. This intermediate was used to introduce the CF3 moiety in the molecule (Scheme 2).2

Bayer has used the chloro derivative as an intermediate in the synthesis of trifluoromethyl derivatives, which act at CB1 cannabinoid receptors, and have potential in the treatment of neuro-degenerative diseases and pain. The key reaction of the CF3 intermediate is where it is added to an aromatic amide derivative and then cyclised in the presence of phosphorus oxychloride to give the desired bicyclic compound.3

Trifluoroacetic acid is another intermediate that is useful in the synthesis of aliphatic trifluoromethyl containing drugs. Its ethyl ester used as a F-containing intermediate in the synthesis of the antiretroviral agent efavirenz. The step, shown in Scheme 3, involves the formation of a dianion from a pivolyl amide using n-BuLi, along with TMEDA and MTBE to avoid the competitive attack of the lithium on the solvent THF. The dianion is then quenched with ethyl trifluoroacetate, and the resulting adduct is hydrolysed in situ. After further elaboration, the fragment is set up for the pivotal chiral addition step that introduces the cyclopropyl acetylene functionality.4

Another trifluoroacetic acid derivative – 1,1,1,-trifluoroethanol – was used by Par Pharmaceutical in the synthesis of the anti-arrhythmic agent flecainide. Numerous other syntheses of this compound have been developed, but these tend to use reactants that are either unstable or not readily available. Here, the fluorinated intermediate is coupled with a bromochlorobenzoic acid derivative in a copper catalysed reaction in the presence of sodium hydride. The acid group was then transformed into its cyanomethyl ester, before coupling with a piperidine derivative to give the desired drug compound (Scheme 4).5

Fluorine continues to be a favourite tool of medicinal chemists, and as a result, the importance of intermediates to introduce fluorinated fragments in an efficient and safe way will only increase in the coming years.