Patent Watch

May 6, 2013

Make a purer hydrazide intermediate by changing processing conditions. Inventors G. A. Chiarello and A. Sahli describe a method for preparing hydrazides from hydrazine and an acyl chloride, and they applied the process to the synthesis of compound 1. This intermediate is used to synthesize gemtuzumab ozogamicin, a drug used to treat myeloid leukemia. The current process for manufacturing 1 is shown in the figure. The inventors used the same route but made several improvements to it.

The first step is a Michael addition of thiol 2 and carboxylic acid 3 in the presence of piperidine to form acid 4 (no yield reported). In the next step, 4 is converted to acid chloride 5 by treating it with two portions of (COCl)2. The isolated acid chloride and anhydrous hydrazine react to form hydrazide 6. This is the key step in the process.

Synthesis of hydrazide 1 and formation of byproduct 7

The inventors state that the current commercial process produces 6 that contains ≈20% byproduct 7. Diacylated hydrazide 7 is formed by the reaction of 5 with 6.

In the next step, thioether protection is removed from 6 by treating it with CF3SO3H in the presence of anisole in CF3CO2H solvent. After the reaction is complete, the solids are removed; the mixture is washed, treated with an anionic ion-exchange resin (IER), and acidified with HCl to recover salt 8. Free base 1 is obtained by a lengthy procedure that involves treating the salt with an IER, washing it in water and EtOH, dissolving it in EtOH and then CH2Cl2, treating the solution with silica gel, and precipitating the product with heptane. Purified base 1 is isolated in an overall yield for the five-step process of >33%.

Although the inventors use the same route to 1, they carry out the hydrazine reaction in a more dilute system (14% vs 24–32%). This is one of several process changes that results in the formation of smaller amounts of byproduct 7. In another key process change for the same step, the flask is scraped while 5 is added continuously to a cooled slurry of hydrazine in CH2Cl2. This prevents the hydrazine from crystallizing onto the flask walls and allows 5 to react with hydrazine to make 6 rather than with the already produced 6 to give 7.

In a series of reactions run to investigate the effect of process variables, the yield of 7 ranged from 4.13 to 9.69%. The inventors provide comprehensive details of all of the steps in the process for preparing compound 1. They describe the effects on product purity and yield of mixing speed, temperature, and batch size (20 and 400 g). Drawings show the fate of all solid and liquid components of each reaction step. The process gives purer product than its predecessors without changing the process chemistry. (Wyeth [Madison, NJ]. US Patent 8,383,857, Feb. 26, 2013; Keith Turner)

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