The Half- Addition In-Process Check (IPC)

 Smart laboratory practice can save process development time and make a chemist more valuable to his or her employer. What kind of synthetic organic chemist would be taking a thin-layer chromatography sample when only 1/2 of the reagent has been added into a reaction? As KiloMentor will explain below: a smart one.

The gradual addition of one of the reactants into a reacting system is typical. The purpose is to avoid an exothermic runaway reaction. 

If the analysis of a quenched reaction mixture at the half-addition point shows both significant product along with either a substantial temperature increase inside the reactor or the need for cooling to prevent such an exotherm, then the need for the precaution is proven.

When this is observed, it signals that the processing is likely sensitive to the rate of addition of the reactant being added because a lot of the reacting is occurring under conditions where the reactant being added is depleted in the reactor compared to its stoichiometry as represented in a balanced equation. If the actual average ratio of reactants is different from that specified by the balanced equation for the desired transformation then in some instances a different chemical outcome can arise from a different mode of reacting. This is convoluted to put in words but simple to illustrate.

Suppose one is attempting to execute the transformation

 1.0 A + 1.0 B reacts to form 1.0 A-B 

where the integers identify the number of moles of A, B, and the adduct A-B.  The transformation issuing conducted by adding gradually, drop by drop A into the entire mole of B. The reaction is exothermic and external cooling must be applied to keep the mixture at a safe temperature. As small portions of A mix together with all of B, A—B is quickly formed, in fact so quickly that essentially no A remains in the mixture between aliquots of addition. All that is in the mixture one could conclude is the formed A—B and the remaining B.

The actual average ratio A: B at any point is far from 1:1!

Now suppose that another reaction in solving A—B is possible. Suppose A—B can react with a second molecule of B:

A—B reacts with B to give B—A—B. Then this overall transformation can be represented as

1.0 A reacts with 2.0 B giving 1.0 B—A—B

This is more consistent with what the actual stoichiometry is and is likely promoted by this need for the gradual addition of A.

What we can conclude is that the gradual addition of one reactant to the other may favor side reactions with other stoichiometries more consistent with the actual average ratio of reactant that occurs in the reactor. Substantial formation of product at the 1/2 addition point is a warning that this may be occurring.  

If the gradual addition is to control the heat of mixing or some other preliminary reaction equilibration then it is OK to see no product at this half-addition stage.

If this misfortune is occurring what can be done? In the example we have looked at the gradual addition of B to A is likely to minimize the formation of B—A—B. In other instances, the gradual simultaneous addition of both A and B at the same rate may be examined. This way the actual ratio of A to B is held more closely constant near 1:1 through the reaction time.

But these solutions are made pertinent only after the 1/2 addition IPC has warned the researcher that they may be particularly needed.

Building Organic Chemistry Synthetic Processes Retrosynthetically

 To develop a synthetic process the chemist needs a sequence of chemical reactions and their work-ups, isolations, and intermediate purifications that can be scaled up.  

This is obvious. 

What is less obvious or unrecognized is that the sequence should most advantageously be planned so that the final intermediate before the transformation that gives the target final product, should be one that can be flexibly purified by some rugged methodology so  that

1. Off-spec material can be upgraded and

2. New impurities introduced by changing prior steps in the reaction sequence will not make it into the final product where they could change the product’s characteristics, require new impurity identifications, change the analytical methods that have been developed or require, most critically, that clinical trials be repeated.

Although the functionality in this last intermediate can be anything that can meet this readily purified criterion, having an ionizable acidic and/or basic functionality is the most predictable way to achieve this. However, many targets will not have such a functionality, though most pharmaceutical products will, since salt forms are most desired for making oral tablets.

In US 6204383B1 issued to Torcan Chemical Ltd. for a new synthesis of Sildenafil, the route was planned so that the basic nitrogen functionality was inserted at the end of the synthesis and the final intermediate was a neutral species.

In fact, the patent reads in its introduction:

 

“As a relatively complicated synthetic organic chemical molecule, sildenafil requires a multi-step chemical synthesis. Any organic synthesis step, which is part of a complex multi-step synthesis, results in contamination of the intermediate with solvents, catalysts, starting materials, and by-products and so introduces the requirement for purification. If a pharmaceutical grade of the final product is to result, this cleaning must be done either as the contamination is caused, that is in the work-up of the particular step, or at some subsequent point in the process. A rugged process is desirable which is not demanding with regard to the purity of the intermediates and which allows for a very efficient cleaning during the isolation of the final drug product.

It is an object of the present invention to provide novel processes for preparing sildenafil which simplifies the purification procedures and which produces sildenafil in substantially pure form without involving complex purification procedures.

It is a further object of the present invention to provide intermediates useful for the preparation of sildenafil by such novel processes.”  

The reason this patent’s stated objective so matches my own thinking is that I was the company patent officer who wrote those words and conceived the strategy!

When there is no appropriate functionality to simplify purification in the product it would be very advantageous if the last step removes one that has been built into the last intermediate! This makes reactions that remove an acid or basic group from a molecule very important.

The chemist, working out his scheme retro-synthetically, can replace the ultimate target with a penultimate target which is the target molecule with such a removable acidic or basic function appended!

An example of this can be found in my US43574730A, a patent for making omeprazole. Omeprazole is neither acidic nor basic; that is, it can’t be extracted reversibly into an aqueous liquid layer by adjusting the pH of the water.  I set as my actual synthetic target therefore an intermediate that had a carboxylic acid bound to the omeprazole substructure in a fashion so that the final transformation would be an easy decarboxylation. This intermediate had the advantage that before decarboxylating to give omeprazole this precursor could be phase-shifted into water leaving any non-acidic materials, whether starting materials, byproducts, or unreacted starting materials, behind in the organic phase. Then adjusting the pH this intermediate would transfer back into fresh organic solvent and be decarboxylated to give clean omeprazole. The idea worked just as contemplated. In practice, it turned out that a preliminary secondary amide was the best way to work with the extra carboxyl functionality.