July 9, 2012
Improve the production of a valuable fungicide. S. Cohen and S. Zamir report the synthesis and purification of fluazinam (3), a broad-spectrum contact fungicide. The synthetic route to 3 (Figure 1) involves the base-catalyzed reaction of highly substituted pyridine 1 with equally highly substituted dinitrobenzene 2. This reaction was originally reported by R. Nishiyama et al. in US Patent 4,331,670 (1982).
The original process used THF or DMF as the solvent and a reactant concentration of <8.2% w/v. The reactants were not completely converted, and the product yield was 75% in THF and 22% in DMF. A competing side reaction is the hydrolysis of the chloride atom in 2 to form a phenol. The inventors state that because THF and DMF are water-miscible and form azeotropes with water any recycle of the solvent increases the degree of hydrolysis of 2.
Another problem with the original process is that workup includes extraction with EtOAc and purification with silica gel. These methods are unsuitable for commercial operations.
The inventors’ improvement is the use of methyl isobutyl ketone (MIBK) as the solvent. This allows a reactant concentration of ≈40% w/v and gives yields as high as 98%. The patent contains a data table that shows the effects of a selection of neat and wet solvents on reactant conversion and selectivity. The data show that neat and wet MIBK are superior to other solvents.
Using the MIBK–H2O azeotrope (1.6% H2O), 1.8% of hydrolysis byproduct is produced; neat MIBK gives only 1.2%. This compares well with neat DMF (8.5%) and neat DMSO (14.1%).
In the preparation of 3, a portion of KOH is added every 20 min to a solution of 1 and 2 in MIBK; the temperature is maintained at <30 °C. The crude 3 (95%) is purified by crystallization from hot EtOH and isolated in 90% yield with 98% purity.
The reaction is very sensitive to temperature: A significant amount of tar is produced when the reaction is run at >40 °C. With MIBK, the temperature sensitivity is reduced, and the yield is increased. The inventors suggest that the low miscibility of MIBK and H2O is responsible for the observed improvements.
The inventors also show that fluazinam can exist as two polymorphs and include this finding in their claims. Form I polymorph is obtained by crystallization from EtOH, CH2Cl2, and MeCN, and from Et2O by slow evaporation. Form II is obtained by rapid evaporation from Et2O or by allowing an EtOH solution of 3 to evaporate in air. A mixture of I and II is obtained from i-PrOH or toluene. The patent contains X-ray diffraction, differential scanning calorimetry–thermogravimetry, and electron microscopy data for both polymorphs.
The inventors also outline the preparation of reactants 1 and 2, but they do not give full details. Figure 2 shows how amine 1 is obtained from dichloride 4 and aq NH3 by a process reported by I. Yokomichi et al. in Eur. Patent 0031218 (1981). The same figure shows what appears to be a standard nitration of dichloride 5 to form 2, but no details are provided. (Makhteshim Chemical Works [Beer Sheva, Israel]. US Patent 8,163,930, April 24, 2012 Keith Turner)