Synthesis Hydroxychloroquine PDF

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Synthesis of Hydroxychloroquine Hydroxychloroquine – Racemic mixture of R and S enantiomers. Both appear to be usable as an antiviral medication; however, the S enantiomer is metabolized about twice as fast as the R enantiomer. 3D Structure https://www.drugbank.ca/structures/small_molecule_drugs/DB01611 2D Structure

Current Batch Reaction Process For the synthesis of hydroxychloroquine, an important intermediate is an aminoketone (species 6 in the two reaction schemes below). Reaction Scheme 1.a. is a three-step process using cyclohexane as a solvent and p-toluenesulfonic acid (PTSA) as the catalyst in the first step. The second step uses toluene (PhMe) as the solvent. The final step uses water as the solvent and HCl as the catalyst. Each step then requires purification of the reaction intermediate by removing both the solvent and the catalyst.

Where: 3  Chloroketone (1-chloro-4-pentanone) 7  Aminoethanol (2-ethylaminoethanol) 6  Aminoketone (5-(ethyl(2-hydroxyethyl)amino)pentan-2-one) The PTSA and HCl are both homogenous catalysts (i.e. same phase as the reactants – liquid in this case), making the separations a bit more difficult. Generally, acid catalyzed reactions are stopped using a base (i.e. sodium hydroxide, NaOH) to form a salt. Suppose that after the third reaction, aqueous NaOH is used to stop the reaction. The reaction mixture is stirred to ensure adequate contact between the HCl and NaOH, thus neutralizing the reaction. HCl + NaOH  NaCl + H2O Then a solvent is used for a liquid – liquid extraction separation (see Lecture 7). The trick is finding a solvent that readily absorbs the aminoketone, yet, is immiscible with water. The salt (NaCl) will remain in the aqueous phase. Another parameter to consider in solvent selection is that it must be easily separable from the aminoketone. If you are considering distillation for this step, then be sure that the aminoketone is not thermally labile (i.e. decomposes under distillation temperatures). Or, solvent stripping could be used. Solvent stripping uses a gas (i.e. N 2) to remove the solvent, perhaps under a vacuum to make the solvent more volatile. If neither of those are applicable, then consider supercritical fluid extraction (SFE). SFE using CO 2 would be attractive since mild conditions are needed and CO2 can readily be vented to the atmosphere. The final consideration for a solvent is environmental, health, and safety. Chlorinated solvents (i.e. dichloromethane, chloroform, and carbon tetrachloride) are not considered suitable for pharmaceutical use for these reasons. As you can see from Reaction Scheme 1.b., there is a one-step (much simpler) synthesis method for the aminoketone. This process uses a solid catalyst consisting of cobalt nitrate, nickel nitrate, magnesium oxide, and calcium oxide. This process is called heterogeneous reaction since

the catalyst is in a different phase than the reactants (solid vs liquid), creating a heterogeneous reaction mixture. The beauty of heterogeneous reactions is that the catalyst is easily removed from the reaction mixture. In this case, a Stirred Tank Reactor (batch) may be used, and the catalyst can be filter post reaction. The aminoketone will need to be separated from the unreacted material as well as a solvent if a solvent was used. In any event, once you have the purified the aminoketone, you are then ready to synthesize the much-needed hydroxychloroquine. That reaction uses the heterogeneous Raney – nickel catalyst.

Raney-nickel catalyst

+ H2, NH3 + solvent 6

8

9

Where: 8  Dichloroquinilone (4-7-dichloroquinione) 9  Hydroxychloroquine (7-chloro-4-[4-[ethyl(2-hydroxyethyl)amino]-1-methylbutylamino] quinoline) Solvent  THF (poor NH3 solubility but used in prior steps)  Alcoholic media (higher NH3 solubility but requires solvent purification from previous steps) THF: Tetrahydrofuran

Not to sound like a pitchman on a commercial (ok maybe I am), but we are not done yet. We still have decisions to make.

Backstory on reactions: Nearly all reactions are governed by reactant concentrations. The higher the concentration 1) the further to the right you can push the reaction (equilibrium) 2) the faster the reaction proceeds (kinetics)

Now, let’s define our problem:

Poor solubility of a key reactant, NH3, with the solvent media Brainstorm Possible Solutions (no pun intended): 1. Proceed with THF (poor conversion of reactants to products, slower reaction) 2. Remove THF solvent from previous reaction steps (costly, possible loss of product) 3. Change reactants As a chemical engineer, you are (or will be) faced with such dilemmas. All three solutions will work. YOU must decide which is the best. But, how do you define “ best?” What is “best” for today, may be different than “best” a month from now, or even a year from now. Perhaps, the market demand for one of your key starting materials increases, and the price skyrockets, making one method non-profitable. Or, maybe the synthesis/purification process for your chosen method is deemed to be environmentally unfriendly. What then?

For now, we will look at option (3) and propose a different process.

A Proposed Steady State Reaction Process...