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新闻中心 Pharmaceutical and Pesticide Intermediates> CF3I as trifluoromethyl radical source for the synthesis of the drugs intermediates

CF3I as trifluoromethyl radical source for the synthesis of the drugs intermediates

2022-02-14 14:14

Trifluoromethyl substituent is one of the most frequently used groups in the drug development. The CF3 group helps to improve metabolic stability of the drugs due to the high C–F bond strength and due to its increased oxidative stability. The CF3 moiety often shows relatively increased binding selectivity at the enzyme active site and is frequently buried in the hydrophobic pocket of the enzymes. As it is relatively highly lipophilic, the trifluoromethylated compounds are generally permeable through the cell membranes, and thus trifluoromethylated compounds have improved bioavailability. A majority of the trifluoromethylcontaining pharmaceuticals have the CF3 moiety incorporated into the aryl rings, while some others contain a trifluoromethyl ketone pharmacophore.[1] Trifluoromethylated aromatic, hetero-aromatic and pseudoaromatic compounds are also important intermediates for synthesis of pharmaceuticals.

Efficient transfer of the trifluoromethyl group from a reagent to a target molecule is key for the reaction, and the reagents are classified according to their radical, nucleophilic or electrophilic character. Direct trifluoromethylation is simple and therefore promising as an industrial process. A trifluoromethyl radical is widely used in direct trifluoromethylation. Radical trifluoromethylation can be achieved from various sources of trifluoromethyl radicals that include trifluoromethyl iodide, trifluoromethylacetyl and trifluoromethylsulfonyl derivatives, S-trifluoromethyl xanthates and others[2]. CF3I, which is one of the available radical sources of a trifluoromethyl radical, was also utilized for radical trifluoromethylation.

1.Preparation of 5-trifluoromethyluracil

Tetsu Yamakawa’s research team found that trifluoromethyl radicals can be generated from CF3I with a reagent composed of FeSO4, H2O2 and dimethylsulfoxide (DMSO), which is the alkylation reagent of aromatic and hetero-aromatic compounds with alkyl and perfluoroalkyl iodides, and that various nucleobases were able to be trifluoromethylated by CF3I and this reagent. Because this reagent for trifluoromethylation is very versatile, it can provide an industrial trifluoromethylation process. In fact, a single-step process for the manufacture of 5-trifluoromethyluracil from uracil and CF3I on an industrial scale has been realized by the use of this reagent.[3]

2.Preparation of trifluoromethyl aldehydes

Redox photocatalysis mediated by iridium or ruthenium catalysts and a household fluorescent light bulb enables α-trifluoromethylation of aldehydes, using the commercially available trifluoromethyl iodide. Through this elegant photoredox catalysis, and using a chiral imidazolidinone catalyst, MacMillan and coworkers have obtained moderate to high yields of the α-trifluoromethyl aldehydes, with high enantioselectivity (Figure 28). These chiral aldehydes could be oxidized or reduced to the carboxylic acids or alcohols, respectively, or they could be transformed into other functional derivatives, such as α- or β-trifluoromethylamines, with high enantioselectivity.[1]

3.Preparation of trifluoromethylthiols (S–CF3)

S–CF3 bonds are important structural motifs in various pharmaceutical and agrochemical compounds. Timothy Noel‘s research team report the development of a mild and fast photocatalytic trifluoromethylation of thiols. The combination of commercially available Ru(bpy)3Cl2, visible light and inexpensive CF3I gas proved to be an efficient method for the direct trifluoromethylation of thiols. The incorporation of a trifluoromethylthio (S–CF3) motif in a drug molecule results in an extremely high lipophilicity and improves the stability of the molecule in acidic media. Access to such compounds is crucial since they constitute a key intermediate for the synthesis of biologically active (trifluoromethyl)-sulfoxides and sulfones.[4]

4.Hydrotrifluoromethylation and iodotrifluoromethylation of alkenes and alkynes

Eun Jin Cho‘s research team study a simple, efficient and environmentally benign strategy for the hydrotrifluoromethylation of unactivated alkenes and alkynes through a radical-mediated reaction using an inorganic electride, [Ca2N]+ e-, as the electron source. In the transformation, anionic electrons are transferred from [Ca2N]+ e-, electrides to the trifluoromethylating reagent CF3I to initiate radical-mediated trifluoromethylation. The role of ethanol is pivotal in the transformation, acting as the solvent, an electron-releasing promoter and a hydrogen atom source.[5]

5.Trifluoromethylation of boronic acid derivatives with radical trifluoromethylation reagents

The trifluoromethylation of boronic acid derivatives through a radical pathway was explored since the CF3 radical can be generated under mild, neutral conditions from commercially available and relatively inexpensive CF3I. Besides, the easy conversion of CF3I to CF3 radical at room temperature with visible light developed by MacMillan. The group of Sanford designed the cross-coupling of arylboronic acids with CF3I via the merger of photoredox and Cu catalysis (Scheme 21). In this protocol, the CF3 radical was generated by visible light photoredox, then Cu aryl species were generated through Cu catalysis. Aromatic boronic acids bearing either electron-donating or electron-withdrawing substituents underwent trifluoromethylation smoothly to give the corresponding products in high yield. It represented a example of combining transition metal and photoredox catalysis to achieve the trifluoromethylation of (hetero)aromatic boronic acids.

Trifluoromethylation of arylboronic acids via the merger of photoredox and Cu catalysis

Organic molecules bearing trifluoromethyl groups are widely used in pharmaceuticals, such as the antidepressant fluoxetine, the anti-ulcer drug lansoprazole and so on. These huge successes of fluorine-containing drugs continue to stimulate research on fluorine in medicinal chemistry for drug discovery. It would not be an exaggeration to say that currently every new drug discovery and development program without exception explores fluorine – containing drug candidates.

Representative examples include efavirenz (CF3) (HIV antiviral), and epothilone B analogue (anticancer), torcetrapib (a potent inhibitor of cholesterol ester transfer protein) possesses three CF3 groups (Pfizer), and sitagliptin (an antidiabetic for type 2 diabetes) has three fluorine atoms and one CF3 group (Merck). [See the following figures] [6]

Selected examples of drugs and drug candidates containing the trifluoromethyl group.

Referrence:

[1] Organofluorine Compounds in Biology and Medicine. http://dx.doi.org/10.1016/B978-0-444-53748-5.00003-4.

[2]Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996. doi:10.1016/j.jfluchem.2007.04.026.

[3]Trifluoromethylation of various aromatic compounds by CF3I in the presence of Fe(II) compound, H2O2 and dimethylsulfoxide. Tatsuhito Kino, Yu Nagase, Yuhki Ohtsuka, Kyoko Yamamoto, Daisuke Uraguchi, Kenji Tokuhisa and Tetsu Yamakawa. A Journal of Fluorine Chemistry 131 (2010) 98–105.

[4] A mild and fast photocatalytic trifluoromethylation of thiols in batch and continuous-flow.

Natan J. W. Straathof, Bart J. P. Tegelbeckers, Volker Hessel, Xiao Wang and Timothy No¨el. DOI: 10.1039/c4sc01982b. www.rsc.org/chemicalscience.

[5] Hydrotrifluoromethylation and iodotrifluoromethylation of alkenes and alkynes using an inorganic electride as a radical generator. Sungkyu Choi, Ye Ji Kim, Sun Min Kim, Jung Woon Yang, Sung Wng Kim and Eun Jin Cho. DOI: 10.1038/ncomms5881. www.nature.com.

[6] Fluorine in Medicinal Chemistry and Chemical Biology: Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology. Takashi Yamazaki, Takeo Taguchi and Iwao Ojima Edited by Iwao Ojima. ISBN: 978-1-405-16720-8.

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