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

Blog post #4 -- Last Gen Chem 112post

 

1. Most valuable lesson?

I learned that chemistry and science in general tend to be selfish, they usually require a lot of time and effort; but then after all the efforts you get to see what you were able to accomplish. However, I enjoyed it because it is challenging and a very complete course.

 

2. Most challenging concept?

 For me the more challenging part of this course is using succesive approximations to find the concentraton of ions, and to work with ice equations.

 

3.  Advice: Do read the chapters and work the "For Practice Problems" that are in the book. 





Blog Post #3 --- Thoughtful question

Here is my question: If the heat from burning 7.800 g of C6H6 is added to 2.387 kg of water that is initially at a temperature of 21 degrees C, what is the final temperature of the water? The specific heat of liquid is 4.184 J/g*Degrees C.

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Data:                                                                                Find:  Tf: ? of the water
   Benzene (C6H6) : 7.800 g
   H2O : 2.387 Kg
   Ti : 21.0 *C
   Specific heat of water : 4.184 J/g . C


1) First we have to find the amount of heat released by the burning of  7.800 g of benzene. To find the it, we need to first write down the balanced equation for the combustion of benzene. Then use the ∆hf* of the reactants and products  to find the ΔH°_{rxn using Hess' Law:}

ΔH°_rxn = Σ ΔH°_f (products) - Σ ΔH°_f (reactants)

  2 C6H6(l) + 15 O2(g) ----> 12CO2(g) + 6H2O(g)      ΔH°_rxn = - 6271 K

ΔH°_rxn =  12(CO₂) + 6( H₂O) – 2(C₆H₆) + 15(O₂)

ΔH°_rxn = 12(-393.5 KJ/mol) + 6 ( -241.8 KJ/ mol) – 2(49.1 KJ/ mol) + 15 (0 KJ/ mol) = -6271 KJ

2) Once we have the ΔH°_{rxn  for the balanced equation of the combustion process, we can find the amount of heat released by the burning of 7.800 g of C6H6 by simply converting from grams to moles of benzene and calculating the heat produced by the burning of that many moles of reactant.} 

7.800 g C₆H₆ x (1 mol C₆H₆ / 78.108 g) = 0.09986173 mol C₆H₆

(-6271 KJ / 2 mol C₆H₆ ) x 0.09986173 mol C₆H₆ = - 313.1165 KJ 

3) Now that we know the amount of heat produced by the  combustion of 7.800g of benzene, we are ready to plug in the values we were given and the heat we just found to solve for the ∆T  of the water using the formula q = m x C_s x ∆T; where q is the amount of heat in J, m is the mass of the substance (water) in g, C_{s is the specific heat capacity, and} ∆T is the change in temperature in °C (Nivaldo J. Tro 241). Notice that q is positive because the heat is being absorbed by the water, therefore is an endothermic process. 

q = m x C_s x ∆T

313116.5 J = (2387 g) x (4.184 J/ g . °C) x ∆T

313116.5 J/ (2387 g) x (4.184 J/ g . °C)  = ∆T

 ∆T = 31.35 °C

∆T = T_f - T_i 

∆T + T_i = T_f

T_f =  31.35 °C + 21.0 °C = 52.35 °C 

• http://www.mychemistrytutor.com/questions/calculating-delta-hrxn-combustion-benzene-using-enthalpy-formation-values
• http://www.saplinglearning.com/ibiscms/mod/ibis/view.php?id=492792
• https://sites.google.com/site/chempendix/thermo
• http://www.chemteam.info/Thermochem/HessLawIntro2.html
• Tro, Nivaldo J. “Chemistry A Molecular Approach.”Pearson. 2^nd Ed. pp. 612-655.Print.2008.

ENZYMES : Ribulose-1,5- bisphosphate carboxylase/ oxygenase

Ribulose-1,5- bisphosphate carboxylase/ oxygenase

Active site/ reactions carried out

2D structure 

                         

Ribulose-1,5- bisphosphate molecule structure

Ribulose-1,5- bisphosphate carboxylase oxylase

•  chemical formula:  CH2OHCO(CHOH) 2CH2OH    
•  molar mass: 310.09 g/mol
• ligands: Mg+2 ion 

This enzyme is commonly known by the shorter name RuBisCO,  and is an enzyme involved in the Calvin cycle that catalyzes the first major step of carbon fixation, which is the process by which the atoms of atmospheric carbon dioxide are made available to organisms in the form of energy-rich molecules such as glucose. RuBisCO is very important in terms of biological impact because it catalyzes the primary chemical reaction by which inorganic carbon permanently enters the biosphere.

 RuBisCO catalyzes either the carboxylation or the oxygenation of ribulose-1,5-bisphosphate (also known as RuBP) with carbon dioxide or oxygen.

.

Carboxylation reaction

Oxygenation reaction

The rate of reaction for this enzyme is really slow compared to most enzymes. RuBisCO fixes only about three carbon dioxide molecules per second while most enzymes can process thousands of molecules per second. However plants compensate this slow rate by building lots of it. This enzyme also shows an unfortunate lack of specificity, since molecules of oxygen and carbon dioxide are similar in shape and properties, RuBisCO enzymes occasionally fix oxigen molecules to the sugar chain, forming faulty oxigenated  products.

references:
http://en.wikipedia.org/wiki/Ribulose-1,5-bisphosphate
http://guweb2.gonzaga.edu/faculty/cronk/biochem/R-index.cfm?definition=rubisco
http://guweb2.gonzaga.edu/faculty/cronk/biochem/R-index.cfm?definition=rubisco (3D ribbon structure)
http://www.climatewiki.org/wiki/Rubisco
http://www.rcsb.org/pdb/101/motm.do?momID=11