PTC N-Alkylation Using 1-Bromo-3-Chloro Propane

I wrote an article in 2005 shown at http://www.phasetransfer.com/PTCIssue18.pdf that described the potential for using phase-transfer catalysis in the manufacture of generic pharmaceuticals and agricultural chemicals (please disregard our old mailing address and E-mail address in that article). The first compound discussed in the section entitled “Using Multiple Consecutive PTC Steps to Achieve Advantage” was Verapamil.

In that article, I encouraged process chemists developing a process for Verapamil to perform two consecutive PTC C-alkylations of a benzyl cyanide derivative since PTC excels is C-alkylations, including forming quaternary carbons, as is required for Verapamil.

Piramal just patented several process steps for the manufacture of Verapamil and they used phase-transfer catalysis for an N-alkylation to form the alkylating agent for the second C-alkylation. It is surprising that the inventors used expensive sodamide to perform the second C-alkylation instead of continuing to use NaOH with PTC as they did for the N-alkylation.

There are several interesting features of the PTC process condition the inventors chose for the N-alkylation. The inventors did not disclose the reasons for their choice of reaction conditions and I will speculate here the reasons for those choices.

First, the use of bromochloropropane as an alkylating agent under basic conditions can sometimes be tricky. I have experience with this in a PTC N-alkylation using bromochloropropane for the synthesis of imipramine that I published in the early 1980’s. The side reactions to be avoided include dehydrohalogenation of bromochloropropane with NaOH to form allyl halide, dehydrohalogenation of the N-propyl halide product to form the N-allyl impurity and the selectivity of the reaction at the chloride or bromide.  Another potential issue is the formation of dibromopropane from bromochloropropane as the reaction proceeds that liberates bromide since PTC quats such as tetrabutylammonium have a strong affinity for bromide relative to other anions and bromide is a reasonably good nucleophile.

In the case of Verapamil, the formation of dibromopropane in-situ could potentially be an advantage since the second bromide is displaced anyway in the C-alkylation. In other words, if the N-propyl bromide is formed instead of the N-propyl chloride shown in the diagram, the bromo compound can serve as a faster alkylating agent than the chloride compound in the subsequent C-alkylation. The same is true if bromide anion attacks the N-propyl chloride to form the N-propyl bromide after the N-propyl chloride is formed.

Then again, since the N-propyl bromide is more reactive than the N-propyl chloride, it could react with the secondary amine reactant shown in the diagram and form a propyl-bridged dimer before the product has a chance to get to the C-alkylation step. We must be aware that as the N-alkylation proceeds to higher conversion, more free bromide ion is available, so the PTC quat could conceivably promote the formation of the N-propyl bromide from the N-propyl chloride and maybe form dimer.

The inventors added the bromochloropropane over 3 hours, probably to maintain more control over the reaction, but they also probably had to avoid too slow of an addition since if there is no bromochloropropane to react with secondary amine, dimer could potentially be formed.  The inventors highlight the advantage that their process produces Verapamil in higher than 99% purity and with an overall yield of 74% over three steps, even after handling losses.

Anything that reduces the energy of activation of the desired N-alkylation and subsequent C-alkylation, is advantageous. The inventors also highlight overcoming the challenge to minimize demethylation of the N-methyl group and the anisole groups. This is partially responsible for the high purity they achieved.

It is reasonable to assume that the reason the inventors chose to work at 25 C-28 C was to minimize side reactions. An advantage of PTC is the ability to reduce energy of activation and in turn work at lower temperatures.

Another advantage of PTC is the ability to work without added solvent since a phase-transfer catalyst can transfer almost any anion into almost any organic liquid. As long as some organic liquid is present, possibly excess bromochloropropane, PTC N-alkylation can work.

Another feature of the process conditions chosen was to use 22% NaOH. While it is possible that the inventors wanted more water to contribute to fluidity in the absence of an organic solvent, it is also possible that the use of 50% NaOH or solid NaOH would be such a strong base that dehydrohalogenation would be a problem for both the bromochloropropane as well as the N-propyl chloride product. I found dehydrohalogenation to be a major problem when using 50% NaOH in the N-alkylation of dibenzazepine with bromochloropropane. In fact, we observed complete conversion of the N-propyl chloride to the N-allyl undesired byproduct when using 50% NaOH. For this reason, I speculate that the Piramal inventors diluted the NaOH well below 50%.

Lastly, the inventors added 1.2 mole% TBAB at the outset of the processes, then they added another 0.9 mole% in three portions at 2 hour intervals that started after the 3 hours addition of the bromochloropropane. Usually, when we see reports of additional portions of phase-transfer catalyst as the reaction progresses, that is almost always an indication of catalyst decomposition, especially if NaOH is involved since that causes quat decomposition by Hofmann Elimination.

However, in this case, the reaction is run at 25-28 C and with 22% NaOH. Under these conditions of mild temperature and avoiding high NaOH concentration, we do not expect significant quat decomposition over the 11 hours of the additions of bromochloropropane and TBAB. One could speculate that the reason behind adding additional TBAB in portions as conversion increases might be to push the reaction to completion as the concentration of starting material dwindles, while trying to avoid overly vigorous reaction by adding too much catalyst at the outset in order to maintain controlled reactivity which often results in higher selectivity.

In summary, it appears that the inventors carefully chose a combination of reaction conditions for this PTC N-alkylation to achieve a balance of reactivity and selectivity while facing multiple challenges of potential side reactions.

I am still surprised that the inventors used sodamide as the base for the subsequent C-alkylation instead of using PTC with NaOH. It is possible that the steric hinderance of the isopropyl group on the benzyl cyanide derivative reactant in the subsequent C-alkylation required a stronger nucleophilic attack. If so, maybe they needed to avoid any hydration of the nucleophilic carbanion that could have been a problem if they used NaOH that generates one equivalent of water. Even if that was the case, there are specialized PTC techniques to deal with that water generated.

If your company has a challenging strong base reaction, including C-alkylations and N-alkylations, now contact Marc Halpern of PTC Organics to benefit from the highly specialized expertise in industrial PTC to achieve low-cost high-performance green chemistry.