March 22, 2023

Hello and good day i am ginger king and i will be discussing the synthesis of levothyroxine for my learning task 2.1 and the course organic chemistry the content of my presentation is taken from the book entitled synthesis of essential drugs by vardanyan and ruby so let’s start levothyroxine also known as l-thyroxine is a manufactured form of the thyroid

Hormone thyrophy it is used to it is used to treat thyroid hormone deficiency including the severe form known as mexidema coma it may also be used to treat and prevent certain types of thyroid tumors so let’s proceed with the mechanism the first step starts as the lone pair of the nitrogen atom in the reagent attacks the sulfur atom in the first compound so

Reacting this with benzene sulfur chloride and pyridine gibbs lee corresponding benzene sulfonate asciine and the resulting compound so pyridine here acted as a solvent and abstracted the protons it also acted as an acid catcher in this case it catched hydrochloric acid by doing this pyridine prevented hydrochloric acid from reacting further with the resulting

Compound the second step proceeds with the displacement of the benzene sulfonyl glue so as that group detaches from the corresponding benzene sulfonate the four methoxy phenyl oxygroup from the reagent which which is called formethoxyphenyl then takes its position this reaction formed the product form the resulting product and step three of the synthesis it

Is going to be divided into more specific substeps let’s begin with step 3a in this step a novenical reaction will start to take place so the resulting compound from step two reacts with an acetylglycine in the presence of sodium acetate to produce an illidine compound which was cyclicized to an oxazolone’s oxygen derivative and the final stop substance so

Step 3a proceeds with the protonated carbon atom attacking the aldehyde i mean the deprotonated carbon atom afterwards and acetyl glycine attaches to the aldehyde and an ilidine compound is four so here in step three b the circulation of the ilidine compound begins with the hydroxyl group attacking the substituted amine so then a phenyl is formed and in that

Phenol a hydroxyl group is attached along with ch2 the final sub step of the stabilization of the illidine compound proceeds with the formation of double bonds and the detachment of hydroxyl groups so since hydroxyl groups are not considered good leaving groups as they are strong bases uh it is converted into h2o as it detaches from the resulting compound

So the hydroxyl groups needed to detach to stabilize the resulting compound and in step four we can either use sodium methoxide or methanol as reagent by using sodium methoxide the oxazolone ring of the compound opens up as the oxygen attacks the carbon the carbon and and through this the methoxide then attaches to the compound and this reaction formed our

Desired ceramic acid derivative moving on to step five the nitro group of the previous compound is reduced to an amino group in step 5 of this synthesis and in the presence of the rainy catalyst a catalytic hydrogenation reaction was made possible and here the nitro group is successfully reduced to nh2 and since we now have this amine it is easier to attach

Other compounds onto the benzene ring and this step is unnecessary since we will be undergoing two iodinations the first iodination will occur and and the next step or so and the less hydrogenation i mean the last iodination is going to be essential for the formation of our final product since it occurs in the last step proceeding to step six there this step

Is also subdivided into more specific subsets in in this step we’ll be following a process similar to the sand near reaction since we already we are already done with nitration and reduction we can proceed directly to convert in the nh2 group into a protonated n2 so the reaction in 6a uses sodium nitride and sulfuric acid at very low temperatures so um we

Are able to convert nh2 into an antigroup through through diazetization and through diazetization we also produce excess hydrogen sulfate so it started with the 8 nh2 group attacking the no2 and then the oh group detaches and attacks the ataxi hydrogen and the sulfuric and the hydrogens of the amino and sulfuric acid and and yeah that’s how it receives so

Moving on to step 6b 6b starts with the heterolytic cleavage of potassium iodine and then a lone pair from the deprotonated iodine then attacks the benzene ring as the mechanism undergoes further ion iodination so this is the first iodination and as as iodination occurs the n2 detaches from the benzene ring and the final step and for step 6 occurs as hydrogen

Sulfate attacks the potassium ion which produce potassium bisulfi moving on to step seven the resulting compound from the previous step undergoes a simultaneous reaction with hydrogen iodide and phosphorus in acetic acid so during this reaction the double bond in the cartonic acid is reduced and the methoxy protection is removed from the phenol ring so this is

The methoxy protection that i am talking about and and this is the cratonic acid and along with this a simultaneous hydrolysis of the acetyl group on the nitrogen atom also took place so here the hydrolysis moving on and step eight the ac the amino group and this product is once again protected by the reaction with formic acid in the presence of acetic anhydride

So this gave us dl-n-formula-35-ioda thyroni so these isomers in this racemic mixture is separated by using brucine and gave the resulting compound so this is this is the formal protecting group as at first attached to to this amino group it is not yet stabilized so so stabilization is achieved by the protonation and protonation so here we can see that nh2

Was the protonated o h was protonated or this um i mean a the protonated oxygen atom is protonated and then that formed h2o so that is now a good leaving group and then we have here o-h and that is stabilized this in this part and we have a stable formal for formal protective moving on to step nine the protecting formal group is hydrolyzed using hydrobromic

Acid and as that is hydrolyzed the formal protecting group is also eliminated from the compound and here is the resulting compound so this resulting compound is going to go through iodination in the next step so finally the resulting compound from step 9 undergoes direct iodination using iodine in the presence of potassium iodide in aqueous methylamine so so

The double bond here attacks this iodine and this um and before it forms this the bond here attacks this other iodine so that is a deprotonated iodine and this is the protonated iodine so as that attached here we have now have a protonated carbon in this benzene ring and since that needs to be stable this bond attacks here and the hydrogen attached to the ch

In this benzene ring is attacked by the aqueous methylamine so that metal amine is then neutralized and then we undergo heterolytic cleavage for potassium iodide and the deprotonated iodine attacks the ch here and the h the hydrogen in ch detaches and i forgot to include arrows but that hydrogen is is the protonated and it will attack the protonated potassium

Ion so after that the iodine is already attached here so we form our desired product which is vivocyros and we’re done with the synthesis of levothyroxine thank you for listening to my presentation and i hope you have a great day ahead of you

Transcribed from video
Synthesis of Levothyroxine By Ginger King