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:

Thomas D. Penning ,* John J. Talley ,*^† Stephen R. Bertenshaw ,^† Jeffery S. Carter ,^† Paul W. Collins , Stephen Docter , Matthew J. Graneto ,^† Len F. Lee ,^‡ James W. Malecha , Julie M. Miyashiro , Roland S. Rogers ,^§ D. J. Rogier ,^† Stella S. Yu , Gary D. Anderson ,^† Earl G. Burton ,^‡ J. Nita Cogburn ,^‡ Susan A. Gregory ,^† Carol M. Koboldt ,^‡ William E. Perkins , Karen Seibert ,^‡ Amy W. Veenhuizen ,^† Yan Y. Zhang ,^† and Peter C. Isakson ^†

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 HNO_2. 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).