Tertiary Amines from Alcohols without Oxidants, Reductants or Alkyl Halides

Lead Research Organisation: University of Bath
Department Name: Chemistry


In order to make pharmaceutical drugs and related compounds, it is sometimes necessary to use toxic chemicals as starting materials in their synthesis and manufacture. One example of this is a class of compounds known as alkyl halides, which are often used to react with amines (nitrogen-containing compounds which are found in many pharmaceutical drugs). Alkyl halides are often toxic because they not only react with amines, but also with our own DNA. This alkylation of DNA means that alkyl halides are often mutagens and carcinogens. Not surprisingly, there is increasing legislation to ensure that these alkyl halides are not present in the final drug molecule, and that the manufacturing processes are carefully contained. The proposed research in this project involves replacing the alkyl halides with alcohols as alternatives for these reactions. Normally, the problem is that alcohols are very unreactive in comparison with alkyl halides and would be unsuccessful in achieving the desired reaction. However, using catalysts, we have designed a method that involves temporarily removing hydrogen from the alcohols to form much more reactive aldehydes as intermediates. The catalyst returns the hydrogen after the aldehyde has reacted with the amine. Overall, the same products are formed as with alkyl halides, but safer, cheaper alcohols are used in their place. The only byproduct from the reaction is water, making these processes clean and environmentally benign.In order to be appealing as a useful industrial process, we will demonstrate that it is possible to run these reactions on a larger scale. In order to do this, a collaboration between Chemistry and Chemical Engineering is proposed. The small scale reactions will be adapted to a larger scale using purpose built reactors that will model reactions that would be necessary for the manufacture of drug molecules on a large scale.


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Description This grant allowed the further development of what is now generally termed 'Borrowing Hydrogen Methodology'. This allows amines to be alkylated by alcohols with water as the only byproduct. The reaction works by temporary removal of hydrogen from the alcohol to give a more reactive carbonyl compound. This then condenses with the amine, and after return of the borrowed hydrogen affords the alkylated amine product.
Exploitation Route The chemistry allows the user to alkylate amines using alcohols rather than more conventional alkylating agents such as alkyl halides. This is already been used in the pharmaceutical industry as a less toxic procedure for achieving this synthetic method.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

URL http://people.bath.ac.uk/chsjmjw/page5.html
Description The borrowing hydrogen approach to the synthesis of amines by reactions of amines with alcohols is a major new approach in synthesis and has been widely used by researchers in industry and in universities.
First Year Of Impact 2008
Sector Chemicals,Pharmaceuticals and Medical Biotechnology,Other
Description Syngenta
Amount £92,500 (GBP)
Funding ID JW/acylation 
Organisation Syngenta International AG 
Sector Private
Country Switzerland
Start 10/2010 
End 03/2014