Friday, April 18, 2014

Chemistry by Design: Celebrex

Celebrex

Treats pain, including pain caused by arthritis in children and adults, ankylosing spondylitis or menstrual cramps. This is a non-steroidal anti-inflammatory medicine (1).

Chemistry by Design found in Journal of Medicinal Chemistry. The authors and departments are listed below:
Departments of Chemistry, Inflammatory Diseases Research, and Molecular Pharmacology, Searle Research and Development (2). 

There are 3 total steps to make Celebrex from 4-[(aminooxy)sulfinyl]aniline

Reagents needed for synthesis:
Step 1: HCl then NaNO2 with H2O (-5 °c) – All these reagents are commercially available
Step 2: SnCl2 (H2O) 86% (happens in 2 steps) – All these reagents are commercially available but SnCl2 purist commercially available solution contains at least 5% of Sn(IV) (3).

Step 3: EtOH at 75 °c (46%)- This step is synthesized in the steps shown below (2):



Reactions learned in class:
Step 1- 

The NH2 is changed into a diazonium ion N2+. This is described as the Sandmeyer reaction (4). This exact reaction has not been discussed in class before but, diazonium ions as a whole have been discussed in class before! The link below explains the Sandmeyer reaction in more detail:
http://web.mnstate.edu/jasperse/Chem365/Sandmeyer.doc.pdf

Step 2- 

Is a substitution reaction of a diazonium ion. This was also discussed in class. The link below give a few examples of substitution reactions of diazonium ions (5). 
 http://www.chemguide.co.uk/organicprops/aniline/propsdiazo.html

Step 3- 

Has not been taught in class yet. 

Mechanistic Explanation of step 1: 

Nitrous acid (also known as nitric (III) acid) has the formula HNO2. The phenylamine is first dissolved in hydrochloric acid, and then a solution of sodium nitrite is added. The reaction between the hydrochloric acid and the nitrite ions produces the nitrous acid. The nitrite is then added to the phenylammonium chloride solution. The end product is a solution containing benzenediazonium chloride (4). The Mechanism is shown below. 

References: 
1.   Celecoxib. U.S. National Library of Medicine. [online] 2012, 
                 http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699022.html

  2.   Njardarson, J.T. Chemistry By Design. http://chemistrybydesign.oia.arizona.edu/app.php
                 (accessed April 17, 2014). 
  
3          3.   Zolle, I. Technetium-99m Pharmaceuticals: Preparation and Quality Control in Nuclear
                 Medicine. [online] 2007, 62-63.http://books.google.com/books?
i                d=o2pPP81jWDYC&pg=PA62&lpg=PA62&dq=Is  
                 +SnCl2+commercially+available&source=bl&ots=wX9w_6KjYd&sig=rfqDzRSVV
                 ZDg70DQesrrD8lEoNc&hl=en&sa=X&ei=d2dNU9TqHK238gGMxoAg&ved=0CC 
                YQ6AEwAA#v=onepage&q=Is%20SnCl2%20commercially%20available&f=false

    4.  Minnesota State University. The Sandmeyer Reaction: Substitution for an NH2 on an Aromatic 
                  Ring: Specialized Information Services.  
                  http://web.mnstate.edu/jasperse/Chem365/Sandmeyer.doc.pdf

   5.   Reactions of Diazonium Salts.
           http://www.chemguide.co.uk/organicprops/aniline/propsdiazo.html (accessed April 17, 
           2014).