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CA-3046650-C - METHOD OF PREPARING BENZYL 4-AMINO-3-CHLORO-5-FLUORO-6-(4-CHLORO-2-FLUORO-3-METHOXYPHENYL)PICOLINATE

CA3046650CCA 3046650 CCA3046650 CCA 3046650CCA-3046650-C

Abstract

A method of preparing benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (I) from benzyl 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (II) is described. The method includes the use of amination and chlorination process steps to provide the compound of Formula I. (see formula I)

Inventors

  • Jason S. Fisk
  • David J. Couling
  • Abraham D. Schuitman
  • Megan E. DONALDSON
  • Brian Murdoch
  • Ronald B. Leng

Assignees

  • DOW AGROSCIENCES LLC

Dates

Publication Date
20260505
Application Date
20171206
Priority Date
20161213

Claims (20)

  1. 85332884 19 CLAIMS: 1. A method for preparing the compound of Formula I: comprising the steps of: a) combining a compound of Formula II, anhydrous ammonia, and a solvent selected from the group consisting of acetonitrile, propionitrile, benzonitrile, toluene, a xylene, a mixture of xylenes, THF, dioxane, mono- and diethyleneglycol ethers, and mono- and dipropyleneglycol ethers, wherein the combination of step a) is maintained at a temperature of about 60 oC to about 130 oC and a pressure of about 40 to about 150 pounds per square inch gauge (psig) with anhydrous ammonia; b) isolating a compound of Formula III from the combination of step a); c) combining the isolated compound of Formula III from step b) with anhydrous HC1 to form an HC1 salt of Formula IV; 85332884 d) isolating the compound of Formula IV from step c) and combining the isolated compound of Formula IV with a base to reform the compound of Formula III; e) adding a chlorinating agent to the combination of step d); and f) isolating the compound of Formula I.
  2. 2. The method of Claim 1, further comprising reisolating the compound of Formula III after step d) prior to adding the chlorinating agent in step e).
  3. 3. The method of Claim 1, wherein the solvent is acetonitrile.
  4. 4. The method of any one of Claims 1-3, wherein the combination of step a) is maintained at a pressure of about 70 to about 100 pounds per square inch gauge (psig) with anhydrous ammonia.
  5. 5. The method of any one of Claims 1-3, wherein the combination of step a) is maintained at a temperature of about 80 to about 120 °C.
  6. 6. The method of any one of Claims 1-5, wherein step b) comprises removing ammonium fluoride and substantially all of the residual ammonia from the combination of step a).
  7. 7. The method of Claim 6, wherein the ammonium fluoride is removed by filtration or centrifugation.
  8. 8. The method of Claim 6, wherein the residual ammonia is removed by distillation or by sparging with an inert gas.
  9. 9. The method of any one of Claims 1-8, wherein isolating the compound of Formula IV in step d) comprises isolating the compound of Formula IV by filtration or centrifugation. 85332884 21
  10. 10. The method of Claim 2, wherein reisolating the compound of Formula III further comprises a water immiscible solvent.
  11. 11. The method of Claim 10, wherein the water immiscible solvent is an aromatic hydrocarbon selected from toluene, a xylene, a mixture of xylenes, or benzonitrile.
  12. 12. The method of any one of Claims 1-11, wherein the base in step d) comprises a trialkylamine compound.
  13. 13. The method of Claim 12, wherein the trialkylamine compound is triethylamine.
  14. 14. The method of Claim 2, wherein reisolating the compound of Formula III comprises washing with water.
  15. 15. The method of any one of Claims 1-14, wherein the chlorinating agent in step e) is a l,3-dichloro-5,5-dimethylhydantoin.
  16. 16. The method of any one of Claims 1-15, wherein the combination in step d) comprises a one-phase solvent system.
  17. 17. The method of Claim 16, wherein the one-phase solvent system includes one or more solvents selected from the group consisting of toluene, a xylene, a mixture of xylenes, acetonitrile, benzonitrile, ethyl acetate, THF, dioxane, tert-amyl methyl ether (TAME), methyl tert-butyl ether (MTBE), and a chlorinated hydrocarbon.
  18. 18. The method of any one of Claims 1-17, wherein after isolation in step f) the compound of Formula I is purified by crystallization from a solvent comprising a C4-C12 alcohol, an aliphatic hydrocarbon, an aromatic hydrocarbon, or mixtures thereof.
  19. 19. The method of Claim 18, wherein the C4-C12 alcohol comprises 2-ethyl-1-hexanol. 85332884 22
  20. 20. The method of any one of Claims 1-17, wherein after isolation in step f) the compound of Formula I is purified by crystallization from a solvent mixture comprising an aliphatic hydrocarbon that is a hexane or a mixture of hexanes, and an aromatic hydrocarbon that is toluene.

Description

85332884 METHOD OF PREPARING BENZYL 4-AMINO-3-CHLORO-5-FLUORO-6-(4- CHLORO-2-FLUORO-3-METHOXYPHENYL)PICOLINA TE CROSS-REFERENCED TO RELATED APPLICATION This application claims priority to U.S. Provisional Patent Application Serial No. 62/433,415, filed December 12, 2016. BACKGROUND The current methods for preparing florpyrauxifen-benzyl (benzyl 4-amino-3-chloro-5- fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate; I) are described in U.S. 8,609,855 and U.S. 8,871,943. Cl Cl OCH3 I SUMMARY A method for preparing florpyrauxifen-benzyl (i.e., the compound of Formula I) is provided. Specifically, the method involves converting 4,5-difluoro-6-arylpicolinate (the compound of Formula II) to florpyrauxifen-benzyl (Formula I). The method includes the steps of: a) combining a compound of Formula II and anhydrous ammonia; F Cl 1 WO 2018/111639 PCT/0S2017/064833 b) isolating a compound of Formula III from the combination of step a); Cl c) combining the isolated compound of Formula III from step b) with anhydrous HCl to form an HCl salt of Formula IV; Cl OCH3 d) isolating the compound of Formula IV from step c) and combining the isolated compound of Formula IV with a base to reform the compound of Formula III; e) adding a chlorinating agent to the combination of step d); and f) isolating the compound of Formula I. The method may alternatively include reisolating the compound of Formula III after step d) prior to adding the chlorinating agent in step e). DETAILED DESCRIPTION 2 WO 2018/111639 PCT/0S2017/064833 A method for preparing florpyrauxifen-benzyl (Formula I) from a 4,5-difluoro-6- arylpicolinate of Formula II is provided. As illustrated in Scheme 1, the method includes chemical process steps that introduce: (1) the 4-amino group by amination of the compound of Formula II with ammonia and (2) the 3-chloro group by chlorination with an N-chloro compound. Scheme 1: Cl 1. NH3 II 2. N-chloro compound Cl I. Definitions As used herein, the term "aryl," as well as derivative terms such as aryloxy, refers to groups that include a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms. Aryl groups can include a single ring or multiple condensed rings. In some embodiments, aryl groups include C6-C10 aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group can be a phenyl, indanyl or naphthyl group. The term "heteroaryl", as well as derivative terms such as "heteroaryloxy", refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, viz., N, 0 or S; these heteroaromatic rings may be fused to other aromatic systems. In some embodiments, the heteroaryl group can be a pyridyl, pyrimidyl or a triazinyl group. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, amino, halo, hydroxy, nitro, cyano, formyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C10 alkoxycarbonyl, C1-C6 carbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, provided that the 3 WO 2018/111639 PCT/0S2017/064833 substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied. Preferred substituents include halogen, C1-C2 alkyl, C1-C10 alkoxycarbonyl and C1-C2 haloalkyl. As used herein, the term "Bn" as used in a chemical structure drawing (i.e., the compounds of Formula I, II, Ill, Illa, Illb, or IV) refers to a benzyl group, which can also be represented as PhCH2. As described herein, the compound of Formula III is Cl The compound of Formula III may be prepared in different ways. For clarity in the description, the compound formed in different ways may be represented as the compound of Formula Illa or the compound of Formula Illb, depending on how it is prepared. When the compound of Formula III is prepared by amination of the difluoropicolinate compound of Formula II with ammonia, it is referred to as the compound of Formula Illa. When the compound of Formula III is prepared by neutralizing the HCl salt of the compound of Formula IV with a base, it is referred to as compound of Formula Illb. II. Amination of Difluoropicolinate II The first step of the method to prepare the compound of Formula I involves the conversion of the difluoropicolinate of Formula II to the hydrochloride (HCl) salt of Formula IV by amination with ammonia and then treatment with anhydrous HCl (Scheme 3). Scheme 3: 4 WO 2018/111639 PCT/0S2017/064833 F 2. HCI Cl Cl The difluoropicolinate can be first reacted with anhydrous ammonia under pressure to furnish the 4-aminopyridine of Formula Illa and by-product NH4F (Scheme 4). After removal of the NH4F and excess ammonia, the 4-aminopyridine of Formula