Safe Scale-Up of a Hydrazine Condensation by the Addition of a Base

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• 作者：Zhe Wang ; Steven M. Richter ; Jorge Gandarilla ; Albert W. Kruger ; Michael J. Rozema
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：December 20, 2013
• 年：2013
• 卷：17
• 期：12
• 页码：1603-1610
• 全文大小：644K
• 年卷期：v.17,no.12(December 20, 2013)
• ISSN：1520-586X

文摘

Herein we describe an observation where an exothermic event encountered during the safety evaluation of the scale-up of the synthesis of 4-chloro-1H-indazol-3-amine was mitigated upon the addition of a base. The 100 掳C adiabatic temperature rise was attributed to the hydrazine condensation reaction, which could cause the batch to self-heat beyond the onset temperature of the exothermic decomposition of the reaction mass. Switching from 1-methyl-2-pyrrolidinone to a lower-boiling-point solvent was explored, but that alone did not guarantee the safe operation in the event cooling is lost. The reaction byproduct, HCl, was identified as a possible cause for the decreasing onset temperature of hydrazine monohydrate. The addition of a base to the reaction mixture increased the onset temperature and decreased the severity of the observed decomposition of the reaction mass. By the introduction of sodium acetate as a base in combination with a lower-boiling-point solvent, safe operating conditions for the process were identified. This base-stabilizing effect has been observed with other hydrazine condensation reactions in our laboratory.