Synthesis of Cetirizine (Zyrtec Egis)

"Cetirizine is used to temporarily relieve the symptoms of hay fever (allergy to pollen, dust, or other substances in the air) and allergy to other substances (such as dust mites, animal dander, cockroaches, and molds). These symptoms include sneezing; runny nose; itchy, red, watery eyes; and itchy nose or throat. Cetirizine is also used to treat itching and redness caused by hives. However, cetirizine does not prevent hives or other allergic skin reactions. Cetirizine is in a class of medications called antihistamines; It works by blocking the action of histamine, a substance in the body that causes allergic symptoms". (Medlineplus)

Histamine

The synthesis of Cetirizine is shown below. It includes five steps, 1) first the starting material 4-chlorobenzophenone is reduced to an alcohol with sodium borohydrate. 2)Then the alcohol form is converted to its acid chloride form by reaction with thionyl chloride. 3) The acid chloride is converted into an amine by reacting it with 2-piperazine-1-ylethanol in toluene solvent at 80^oC, which gave a new primary alcohol group to the molecule (ethanol). 4) The ethanol part of the molecule was then reacted with 2-chloroacetamide in toluene and NaOMe at 85^oC, which gave an ester/amide. 5) then the amide was hydrolyzed with sodium hydroxide to give a carboxylic acid. 

And it's worth mentioning that all of the steps for the reaction were covered in the Organic Chemistry I and II courses. 

Reagent Availability 

4-chlorobenzophenone: Commercially available: 100 g - 31.20

4-chloroacetamide: Commercially available: 100 g - $25.30

1-(2-Hydroxyethyl)piperazine: Commercially available: 100 g - $29.90

Sodium Methoxyde: Commercially available: 100 g - $37.30

The general mechanism followed by the first step of the synthesis of Cetirizine, which is a reduction of a ketone to a secondary alcohol with the reducing agent sodium borohydryde is shown below. on this mechanistic scheme a proton from the nucleophile borohydryde attacksthe carbonyl group, causing the sp2 carbon to go to an sp3 hybridization. Therefore, giving an alcohol as the product. 

Names of the authors of the article "New Manufacturing Process of Cetirizine" 

József Reiter †, Péter Trinka †, Ferenc L. Bartha ‡,László Pongó *†, Balázs Volk †, and Gyula Simig †

a EGIS Pharmaceuticals Plc., †Chemical Research Division, and ‡Small Scale API Production Plant. Publication Date (Web): June 1, 2012

References

U.S National Library of Medicine, MedlinePlus, Cetirizine.  http://www.nlm.nih.gov/medlineplus/druginfo/meds/a698026.html. Online. 27 March 2014. Accessed 04/19.2014.

Sharpley, Patricia, Borohydryde Reduction, University of Illinois; 2012. http://butane.chem.uiuc.edu/pshapley/GenChem2/B8/2.html. Online. accessed 4/19/2014.

Blog #3 - Artificial Amino Acid

In this assignment we drew the structure of an artificial, fictional aminoacid and its systematic name. The structure of a pentapeptide inclding the structures of four known aminoacids attached to the artificial aminoacid was also sketched. this, with the object of practicing the synthesis of aminoacids and formation of polypeptides.

SYNTHESIS OF THE AMINOACID

STRUCTURE

PENTAPEPTIDE CG-X-HA

References:

ACD/Chemsketch (freeware)

Smith J. G., Organic Chemistry, 3rd ed.; McGraw-Hill: New York, 2006. 

ASR - Enzymatic Chlorination of Tryptophan

Naturally occurring halogenated organic compounds are rare in most biological systems. However, these are commonly used same in many marine organisms, fungi, and bacteria; and several thousand different naturally occurring halogenated compounds have been isolated and identified from these species. Although rare, there are a few examples of biological halogenated compounds produced by humans; one of them is tetraiodothyronine, an endocrine hormone. 

 Halogenase enzymes use metal centers to accomplish halogen insertion (usually iron or vanadium).  The basic strategy of these enzymes is to use the metal center to oxidize a halide anion to a cation species (a two-electron oxidation) or radical species (a one-electron oxidation) so that the halogen cations can react with alkenes and benzene rings and the radicals attach to the unactivated alkyl group.

X^- → X⁺ + 2e^-

X^- → X• + e^-

However,  a metal-free halogenase has been discovered. This halogenase uses only FADH₂ to introduce a chlorine to the aromatic ring of tryptophan. The reaction mechanism relies on the generation of flavin hydroperoxide from FADH₂ and molecular oxygen, just like the two flavin-dependant monooxygenases discussed earlier.  Chloride ion attacks the hydroperoxide, generating ClOH, or hypochlorous acid.

After traveling through a 10 angstrom long tunnel inside the enzyme, the HOCl intermediate comes into contact with C₇ of tryptophan, and reacts as the electrophilic molecule in an electrophilic aromatic substitution.

 Tryptophan :
IUPAC: (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid
MW: 204.225g/mol
Formula: C11H12N2O2

7-chlorotryptophan :
IUPAC: 7-chloro-L-tryptophan
MW: 238.67
Formula: C11H11ClN2O2

References:

Chlorination of tryptophan http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/. (Accessed on March 11, 2014)

http://www.chemicalbook.com/

Biologically Ocurring Deals-Alder Reactions- Lovastatin - 

Lovastatin is a fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent, inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme which catalyzes the conversion of HMG-CoA to mevalonate. Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a competitive inhibitor for HMG-CoA which binds to the HMG-CoA reductase which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver.


Lovastatin, is inactive in the native form, the form in which it is administered, is hydrolyzed to the β-hydroxy acid form in the body and it is this form which is active. Presumably, the reductase acts on the hydrolyzed lovastatin to reduce the carboxylic acid moiety.

IUPAC Name: [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

Molecular Formula: C24H36O5   Molecular Weight: 404.53964

Other Common names are : Mevinolin, Mevacor, Monacolin K, Altoprev, Lovalord, Mevinacor, Nergadan, Altocor, Artein

 In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the  idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

References

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=53232&loc=ec_rcs

http://chem257.pbworks.com/w/page/15645822/Lovastatin