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US-20260125342-A1 - SYNTHESIS OF ACID HYDRAZIDES USING FLOW CHEMISTRY

US20260125342A1US 20260125342 A1US20260125342 A1US 20260125342A1US-20260125342-A1

Abstract

A continuous process for preparing a compound of Formula (III) or a salt and/or solvate thereof, includes forming a first reaction stream comprising a compound of Formula (I) dissolved in an alcohol; flowing the reaction stream from step (a) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min; contacting the reaction stream from step (b) with a second reaction stream comprising a hydrazine source to form a combined reaction stream; and (d) flowing the combined reaction stream from step (c) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min.

Inventors

  • Matthew W. Halloran
  • Michael D. Burkart
  • Caitlin Hudecek

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date
20260507
Application Date
20251231

Claims (19)

  1. 1 . A continuous process for preparing a compound of Formula (III) or a salt and/or solvate thereof, the process comprising: (a) forming a first reaction stream comprising a compound of Formula (I) dissolved in an alcohol; (b) flowing the reaction stream from step (a) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min; (c) contacting the reaction stream from step (b) with a second reaction stream comprising a hydrazine source to form a combined reaction stream; and (d) flowing the combined reaction stream from step (c) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min; wherein R 1 is Y or R 3 is Y or Y is an aryl, heteroaryl, alkyl, cycloalkyl, or heterocycloalkyl group; Z is a divalent group selected from arylene, heteroarylene, alkylene, cycloalkylene, and heterocycloalkylene groups; and R 1 and R 3 are both Y, or R 1 and R 3 are both not Y.
  2. 2 . The continuous process of claim 1 , wherein the alcohol in step (a) has a formula of R a OH, wherein R a is a C 1 -C 6 alkyl.
  3. 3 . The continuous process of claim 2 , wherein the compound of Formula (I) is converted to a compound of Formula (II) in step (b), wherein: R 2 is Y or and when R 1 and R 3 are both Y, R 2 is Y; when R 1 and R 3 are both not Y, R 2 is not Y.
  4. 4 . The continuous process of claim 1 , wherein the first reaction stream further comprises an acid, and wherein the acid is present in an amount of less than 0.5 equivalent relative to the amount of a compound of Formula (I).
  5. 5 . The continuous process of claim 1 , wherein the temperature in step (b) is about 135° C.
  6. 6 . The continuous process of claim 1 , wherein the flow rate in step (b) is about 2 mL/min or wherein the flow rate in step (b) is about 1 mL/min.
  7. 7 . The continuous process of claim 1 , further comprising cooling the reaction stream from step (b) to about 0° C. before step (c).
  8. 8 . The continuous process of claim 1 , wherein the second reaction stream in step (c) comprises an alcohol solvent.
  9. 9 . The continuous process of claim 1 , wherein the hydrazine source in step (c) is hydrazine hydrate.
  10. 10 . The continuous process of claim 1 , wherein the temperature in step (d) is about 125° C. or about 135° C.
  11. 11 . The continuous process of claim 1 further comprising (e) flowing the reaction stream from step (d) through a backpressure regulator; and (f) cooling the reaction stream from step (e) to about 60° C.
  12. 12 . The continuous process of claim 1 , wherein the cooling step comprises flowing the reaction stream from step (e) through a continuous flow reactor at a temperature of about 60° C., and with a residence time of less than about 1 minute.
  13. 13 . The continuous process of claim 1 further comprising collecting a reactor effluent exiting from the continuous flow reactor.
  14. 14 . The continuous process of claim 1 , wherein the compound of Formula (I) is a compound having a formula of and the compound of Formula (III) is a compound having a formula of
  15. 15 . The continuous process of claim 1 , wherein Y is isoxazolyl, phenyl, alkyl, or cycloalkyl.
  16. 16 . The continuous process of claim 1 , wherein Y is
  17. 17 . The continuous process of claim 1 , wherein: the compound of Formula (I) is a compound having a formula of and the compound of Formula (III) is a compound having a formula of
  18. 18 . The continuous process of claim 1 , wherein Z is phenylene, alkylene, or cycloalkylene.
  19. 19 . The continuous process of claim 1 , wherein Z is wherein x is an integer from 1-7.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. Continuation of PCT International Patent Application No. PCT/US2024/036541, filed Jul. 2, 2024, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Ser. No. 63/512,050 filed Jul. 5, 2023, the contents of each of which are hereby incorporated by reference into the present disclosure in their entirety for any and all purposes. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under DE-EE0008246 awarded by the U.S. Department of Energy. The government has certain rights in the invention. BACKGROUND Acid hydrazides are a versatile class of organic compounds which serve as fundamental building blocks in a number of pharmaceutical, agrochemical, and material science applications. In addition, they function as valuable chemical intermediates in the synthesis of ketones, hydrazones, amides, and heterocyclic rings. As a subset of this family, acid dihydrazides find significant applications in a variety of industrial and academic settings owing to their benchtop stability and unique reactivity profile. Accordingly, they are commonly used as curing agents for epoxy resins, corrosion inhibitors, biomimetic hydrogels, or as precursors for the synthesis of acyl azides and diisocyanates. SUMMARY OF THE DISCLOSURE The present disclosure provides methods of preparing hydrazides from carboxylic acids in continuous flow. In a first aspect, the present disclosure provides a continuous process for preparing a compound of Formula (III) or a salt and/or a solvate thereof, comprising: (a) forming a first reaction stream comprising a compound of Formula (I) dissolved in an alcohol; (b) flowing the reaction stream from step (a) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min; (c) contacting the reaction stream from step (b) with a second reaction stream comprising a hydrazine source to form a combined reaction stream; and (d) flowing the combined reaction stream from step (c) through a continuous flow reactor at a temperature of about 100° C. to about 160° C. and at a flow rate of about 0.2 mL/min to about 5 mL/min; wherein R1 is Y or R3 is Y or Y is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; Z is a divalent group selected from arylene, heteroarylene, alkylene, cycloalkylene, and heterocycloalkylene groups; and R1 and R3 are both Y, or R1 and R3 are both not Y. In some embodiments of this first aspect, the compound of Formula (I) is converted to a compound of Formula (II) in step (b), wherein: R2 is Y or and when R1 and R3 are both Y, R2 is Y; and when R1 and R3 are both not Y, R2 is not Y. In some embodiments of this first aspect, the flow rate in step (b) provides a residence time of about 2 minutes to about 15 minutes. In some embodiments of this first aspect, the flow rate in step (b) provides a residence time of about 5.3 minutes or about 9 minutes. In some embodiments of this first aspect, the continuous process further comprises cooling the reaction stream from step (b) to about 0° C. before step (c). In further embodiments of this first aspect, the cooling step comprises flowing the reaction stream from step (b) through an ice bath with a residence time of less than about 1 minute, or less than 0.5 minutes. In some further embodiments of this first aspect, the residence time in the cooling step is about 0.25 minutes. In some embodiments of this first aspect, the hydrazine source in step (c) is hydrazine hydrate. In some embodiments of this first aspect, the hydrazine source is present in the second reaction stream in an amount of about 2 equivalents to about 5 equivalents relative to the amount of —COOH functional group in the compound of Formula (I). In some embodiments of this first aspect, the flow rate is step (d) provides a residence time of about 2 minutes to about 15 minutes. In some embodiments of this first aspect, the flow rate in step (d) provides a residence time of about 6.6 minutes or about 13.2 minutes. In some embodiments of this first aspect, the continuous process further comprises (e) flowing the reaction stream from step (d) through a backpressure regulator; and (f) cooling the reaction stream from step (e) to about 60° C. In some further embodiments of this first aspect, the cooling step comprises flowing the reaction stream from step (e) through a continuous flow reactor at a temperature of about 60° C., with a residence time of less than about 1 minute. In some embodiments of this first aspect, the continuous process further comprises collecting a reactor effluent exiting from the continuous flow reactor. In some further embodiments of this first aspect, the continuous process further comprising cooling the reactor effluent existing from the continuous flow reactor, thereby forming precipitates of a compound of Formula (III). In some embodiments of this first aspect, t