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Fluorine-Substituted Building Blocks

The number of commercial pharmaceutical compounds which contain at least one fluorine substituent noticeably increased since 1950th, when the first fluorine-containing drugs were introduced. At present, about 20% of the commercial drug substances are fluorine-substituted organic compounds[1]. As the prominent examples, top-selling anti-depressant Fluoxetine (Prozac), the cholesterol-lowering drug Atorvastatin (Lipitor), the antibacterial Ciprofloxacin (Ciprobay) could be named.

In this issue, we present Fluorine-Substituted Building Blocks - a selection from the current stock of Enamine Building Blocks.

Noteworthy, Ukrainian chemists were among those who pioneered the field of organofluorine chemistry. The work in this area started in Institute of Organic Chemistry of the Ukrainian Academy of Science in early 1950th by Lev Yagupolskii[2] and his co-workers and culminated in the development of Riluzole in 1963 - a drug used to treat amyotrophic lateral sclerosis[3]. Much experience was gained by the Ukrainian chemists in the field since then, which is advantageously used today to synthesize new products for drug discovery.

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Understanding the importance of the fluorine-substituted compounds for the pharmaceutical industry, we put much effort in adapting known and developing new synthetic methodologies allowing fluorine introduction by the use of different fluorine reagents. Apart from classical perfluoroalkyl-containing reagents (e.g. Ethyl trifluoroacetate, Trifluoroacetaldehyde, 1,1,1-Trifluoroacetone, 1,1,1-Trifluoroacetyl­aceto­ne, Ethyl 1,1,1-trifluoro­acetoacetate etc.) the arsenal of starting materials includes:

  • DAST, MorphDAST and Sulfur tetrafluoride;
  • Hydrogen fluoride;
  • Metal fluorides and TBAF;
  • Tetrafluoroboric acid (for Schiemann process);
  • Trifluorotrimethylsilane;
  • Trifluoromethyl iodide;
  • Trifluoromethyl diazomethane;
  • Phenyl(thifluorometyl)mercury;
  • Trifluoroacetonitrile;
  • Perfluoropropene and its epoxide.

The compounds obtained in such way are original, in many cases unavailable from any other supplier. Many of them were obtained by stereoselective routes; therefore, they are enantiomerically pure or enriched. The procedures employing the reagents mentioned above allow production of original fluorine-containing building blocks at 1–10 g scale; novel compounds of the requested structure can be obtained in 4–8 weeks.

Enamine chemists have developed many synthetic procedures allowing synthesis of isomeric sets containing -F, -CF3, -CHF2, -OCF3, -SCF3, -CF2- groups. These isomeric sets are particularly useful in SAR studies.

Below, we show some examples of diverse Fluorine-Substituted Building Blocks set. Complete Enamine Fluorine-Substituted Building Blocks selection (more than 2400 compounds) is available at  Databases section of our site.

For example, all possible isomers of the sulfochlorides shown below are available:

EN300-04155 EN300-17432 EN300-17447
EN300-17526 EN300-17009 EN300-11017
EN300-27076 EN300-29504 EN300-09800

Apart from the –SO2Cl group, other functional groups in the building blocks can be used for further functionalization, for example, the carboxylic group:

EN300-00475 EN300-00862 EN300-04125
EN300-06505 EN300-07134 EN300-07344
EN300-07706 R=CHF2,
EN300-12936
R=CH2CF3,
EN300-27294
EN300-13542
EN300-28261 EN300-29209 EN300-36688

Amino group is present in fluorinated building blocks as well:

EN300-02545 EN300-08775 EN300-09173
EN300-11001 EN300-12043 EN300-35691
EN300-37461 EN300-36959 EN300-28771
EN300-25406 EN300-31108 EN300-30470
EN300-02317 EN300-27636 EN400-15339
EN400-15895 EN400-15925 EN400-15926
EN300-32020 EN300-40766 EN300-08916
EN300-24301 EN300-39459 EN300-26926
EN400-13100 EN300-39250 EN300-37126
EN400-14479 EN300-35929 EN300-36124
 
EN300-29978 EN400-15894  

 

A number of building blocks with aldehyde functionality are available:

EN300-01124 EN300-07353 EN300-27486

Epoxide moiety is also introduced in some fluorinated building blocks:

EN300-27297 EN300-31522 EN300-16485

Alkylating and arylating agents with fluorine substituents are offered:

EN300-01679 EN300-05604 EN300-05909
EN300-06806 EN300-17182 EN300-19151
EN300-39690 EN300-30691 EN400-14010
EN300-27783 EN400-15922 EN400-15923
EN400-12145 EN300-38967 EN300-42415

Selected thiols, phenols and alcohols with are included in Enamine Fluorine-Substituted Building Blocks:

EN300-03227 EN300-03229 EN300-28920
EN300-13619 EN300-13700 EN300-13809

 

Trifluoromethyl ketones:

EN300-42858 EN300-23116 EN300-01416
EN300-23121 EN300-07063 EN300-31078

 

Trifluoromethyl β-dicarbonyl compounds:

EN300-01274 X=Cl EN300-03907
X=Br EN300-03908
X=COOEt EN400-15678
EN400-15359

 

Amino acids:

EN400-12625 EN400-13996 EN400-13997
EN400-15927 EN400-15928 EN400-13968
EN400-08702 EN400-13442 EN400-13941
EN400-13936 EN400-15929 EN400-15930

 

Cyclic amides:

EN400-15924 EN300-11971 EN300-29977

Download complete Enamine Fluorine-Substituted Building Blocks set (more than 2400 compounds).


[1] Fluorine in Pharmaceuticals: Looking Beyond Intuition. Klaus Muller, Christoph Faeh, Francois Diederich. Science 317, (2007). 1881-1886.

[2] Honoring Lev Moiseevich Yagupolskii, on the occasion of his 80th birthday. Yu. Yagupolskii, V. Petrov. Journal of Fluorine Chemistry 2002, 117, 2, 83-84



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