Process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate and its analogs

摘要

The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-caboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using Na2CO3 and/or K2CO3 to promote the ring-closure reaction to produce the alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoromethyl-2-methyl-1H-pyrazole-4-caboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

主权项

1. A process for producing a compound of Formula XVI comprising: (a) reacting compounds of Formula III, XIII, and XIV to produce an enolate salt of Formula XV and alkyl alcohol; followed by (b), wherein (b) consists essentially of distilling the enolate salt of Formula XV wherein the distillation removes residual Formula XIII and the alkyl alcohol to provide a purified enolate salt of Formula XV; and then (c) acidifying the purified enolate salt of Formula XV to provide the compound of Formula XVI wherein: R1 is CF2H, CFH2, CF3, CCl2H, CClH2, or CCl3; R2 is C1-C6 alkyl; R3 is methyl or ethyl; and M is sodium, potassium, or lithium.