The PTC etherification of the phenol shown in the diagram was followed by hydrolysis and acidification to the acid, then a series of purification and crystallization steps to produce a product with the desired polymorph. The reaction was performed on a 5 kg scale (50 gallon reactor) and resulted in a yield of 89% from the starting material (“triol” phenol) and a purity of 99.9%.
This is a solid-liquid PTC system. The choice of acetone as the solvent is rather unusual for a large-scale PTC etherification. In most solid-liquid PTC nucleophilic substitutions, a water-immiscible solvent such as toluene or heptane is usually chosen so that during workup, the inorganic byproduct salts (KCl and KHCO3 in this case) can be removed by dissolution in water while the organic product remains in the organic phase followed by simple phase separation. The product can either be isolated by stripping the solvent or carried forward to the next reaction in the solvent without isolation.
In this application, the KCl and KHCO3 byproducts were separated from the ether product by filtering the acetone solution (“with/without a Celite pad”). After washing with additional acetone and stripping the acetone, the product was a crude viscous liquid used without further purification. In other words, the workup was relatively simple as long as filtration is acceptable on a large scale (often filtration is not acceptable on a large scale).
The next steps in this application are [1] hydrolysis of the nitrile to the acid using KOH in methanol/water at 72.2 deg C for 5 h, [2] acidification, [3] formation of the diethanolamine salt in a slurry with heptane and [4] recrystallization. These next steps involved multiple solvent exchanges and filtrations.
The results were obviously very good with a high overall yield and excellent product purity. At the same time, there are a lot of unit operations including multiple filtrations that can be engineering headaches. We wonder if heptane (or toluene) could have been chosen as the solvent instead of acetone for the solid-liquid PTC etherification which should easily dissolve the organophilic substrate and cyanomethyl ether intermediate and enable separation of the inorganic byproduct salts by a simple water treatment. The choice of heptane is based on the use of heptane later in the process for the formation of the diethanolamine salt. Heptane could also be used for the next step if solid-liquid PTC-OH hydrolysis was used, without isolation of the cyanomethyl ether intermediate already dissolved in heptane from the etherification step.
It is possible that telescoping all of these steps in heptane was not feasible if the impurities could not be removed. But the thought of removing the inorganic salt byproducts by filtration after the solid-liquid PTC etherification due to the use of acetone as the solvent followed by multiple solvent exchanges and filtrations, only to wind up with a heptane slurry in the second-to-last purification step, suggested that heptane should have been considered (and maybe WAS considered) as the solvent for two solid-liquid PTC steps and the formation of the diethanolamine salt.
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