Steroids fluorinations

Betamethasone is a fluorinated steroid. Fluorination is substitution with an electron-attracting group and increases potency. 

Difluoroiodo)-and (dichloroiodo)arenes Chlorination. Remote Functionalism, of Steroids. Fluorination. Further Transformations. 

Progress in the field received further impetus with the development of synthetic steroids exhibiting activities far greater than that of the natural hormones. The synthesis of 9 a-fluorocortisol (3), described in 1953 by Fried and Sabo (3), opened the way for development of many more highly active antiinflammatory agents, and indeed some of today s most active antiinflammatory agents (ca 1997) bear some resemblance to this 9a-fluorinated steroid. 

It is also used ia the preparation of biologically active steroids where the fluorine is added in a cis configuration to the double bond (13,14). 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

A -dien-3-ol ethers gives rise to 6-substituted A" -3-ketones. 6-Hydroxy-A" -3-ketones can be obtained also by autooxidation.Structural changes in the steroid molecule may strongly affect the stability of 3-alkyl-A -ethers. Thus 11 j5-hydroxyl and 9a-fluorine substituents greatly increase the lability of the enol ether/ while halogens at C-6 stabilize this system to autooxidation and acid hydrolysis. 

The modification and enhancement of biological activity of drugs and hormones by fluorination represent one of the most fruitful recent developments in medicinal chemistry. Its first successes and most interesting subsequent developments were in the steroid field. Almost every new technique of introducing fluorine into organic compounds has been applied in this area and, as a result of both the gross and subtle chemical differences which steroids display at different locations of the nucleus, has produced a wealth of new chemistry. 

The discovery in 1954 that fluorination of the glucocorticoid hormone cortisol could bring about remarkable changes in the biological properties of the hormone was entirely unexpected and violated the then prevalent belief that synthetic variants could not surpass a naturally occurring hormone in its biological activity. Because of the impact that fluorination of steroids has had on subsequent developments in this area the history of the discovery of fluorocortisol will be briefly recounted. 

As a result, the intervening 15 years have witnessed the development of procedures for the introduction of fluorine in practically every available position of the steroid nucleus. Moreover, fluorine-containing groups such as CF2 and CF3 have been substituted at various positions. A number of recent books and reviews deal extensively with this subject. ... 

The observation by Yarovenko and Raksha " in 1960 that diethyl (2-chloro-1,1,2-trifluoroethyl) amine (hereafter called fluoroamine ) could replace hydroxyl groups by fluorine was first applied in the steroid field byAyer and Knox and co-workers. These workers found that a methylene... 

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