Synthesis of 6-aryl-4-aminopicolinates and 2-aryl-6-aminopyrimidine-4-carboxylates by direct Suzuki coupling

Patent metadata

Field	Value
Publication number	US-10087164-B2
Application number	US-201715599716-A
Country	US
Kind code	B2
Filing date	May 19, 2017
Priority date	May 19, 2016
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalkyl and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This invention was expanded to include synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

First claim

We claim:

1. A method for preparing 6-aryl-4-aminopicolinates of the formula:

wherein
Q represents hydrogen or halogen;
R represents hydrogen, alkyl, aryl, or arylalkyl;
W represents H, halogen, C 1-4 alkyl or C 1-3 alkoxy;
X represents H;
Y represents halogen, C 1-4 alkyl, or C 1-3 alkoxy; and
Z represents H, halogen, C 1-4 alkyl, or C 1-3 alkoxy

the method comprising coupling an aminopyridine (AP) and a phenyl boronic acid (PBA) by direct Suzuki coupling in the presence of a catalyst, wherein the concentration of the catalyst is less than or equal to about 3% relative to the limiting reagent and the yield of the 6-aryl-4-aminopicolinate is at least about 60%.

2. A method for preparing 6-aryl-4-aminopicolinates of the formula:

wherein
Q represents hydrogen or halogen;
R represents hydrogen, alkyl, aryl, or arylalkyl;
W represents H, halogen, C 1-4 alkyl, or C 1-3 alkoxy;
X represents F, Cl, C 1-4 alkyl, C 1-3 alkoxy, or −NO 2 ;
Y represents halogen, C 1-4 alkyl, or C 1-3 alkoxy; and
Z represents H, halogen, C 1-4 alkyl, or C 1-3 alkoxy

the method comprising coupling an aminopyridine (AP) and a phenyl boronic acid (PBA) by direct Suzuki coupling in the presence of a catalyst, wherein the concentration of the catalyst is less than or equal to about 3% relative to the limiting reagent and the yield of the 6-aryl-4-aminopicolinate is at least about 60%.

3. The method of claim 1 , wherein the AP is methyl 4-amino-3,6-dichloropyridine-2-carboxylate (AP-Me).

4. The method of claim 2 , wherein the AP is benzyl 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylate (AP-Bz).

5. The method of claim 1 , wherein the AP is crude.

6. The method of claim 3 , wherein the AP is crude.

7. The method of claim 2 , wherein the AP is crude.

8. The method of claim 4 , wherein the AP is crude.

9. The method of claim 6 , wherein the PBA is 4-chloro-2-fluoro-3-methoxy-phenylboronic acid.

10. The method of claim 6 , wherein the PBA is dimethyl (4-chloro-2-fluoro-3-methoxyphenyl)boronate.

11. The method claim 1 , wherein the catalyst is a palladium catalyst.

12. The method of claim 11 , wherein the palladium catalyst is a palladium (II) catalyst.

13. The method of claim 12 , wherein the palladium (II) catalyst is palladium acetate, Pd(OAc) 2 .

14. The method of claim 6 , wherein the PBA is dimethyl (4-chloro-2-fluoro-3-methoxyphenyl)boronate.

15. The method claim 2 , wherein the catalyst is a palladium catalyst.

16. The method of claim 15 , wherein the palladium catalyst is a palladium (II) catalyst.

17. The method of claim 16 , wherein the palladium (II) catalyst is palladium acetate, Pd(OAc) 2 .

18. The method of claim 1 , wherein the concentration of the catalyst is from about 0.2% to about 2.0% relative to the limiting reagent.

19. The method of claim 18 , wherein the concentration of the catalyst is from about 0.4% to about 1.0%.

20. The method of claim 19 , wherein the concentration of the catalyst is about 0.5%.

21. The method of claim 2 , wherein the concentration of the catalyst is from about 0.2% to about 2.0% relative to the limiting reagent.

22. The method of claim 21 , wherein the concentration of the catalyst is from about 0.4% to about 1.0%.

23. The method of claim 22 , wherein the concentration of the catalyst is about 0.5%.

24. The method of claim 1 , wherein the pH of the Suzuki coupling reaction is from about 7 to about 12.

25. The method of claim 24 , wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.

26. The method of claim 25 , wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.

27. The method of claim 24 , wherein the pH is adjusted by the addition of a base and/or CO 2 .

28. The method of claim 27 , wherein the base comprises K 2 CO 3 .

29. The method of claim 27 , wherein the base is added in more than one portion during the direct Suzuki coupling.

30. The method of claim 29 , wherein the portions are added over a period of at least two hours.

31. The method of claim 2 , wherein the pH of the Suzuki coupling reaction is from about 7 to about 12.

32. The method of claim 27 , wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.

33. The method of claim 28 , wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.

34. The method of claim 28 , wherein the pH is adjusted by the addition of a base and/or CO 2 .

35. The method of claim 34 , wherein the base comprises K 2 CO 3 .

36. The method of claim 35 , wherein the base is added in more than one portion during the direct Suzuki coupling.

37. The method of claim 36 , wherein the portions are added over a period of at least two hours.

38. The method of claim 1 , wherein the direct Suzuki coupling is performed in a solvent system comprising a mixture of methyl isobutyl ketone, acetonitrile, and methanol.

39. The method of claim 2 , wherein the direct Suzuki coupling is performed in a solvent system comprising a mixture of methyl isobutyl ketone, acetonitrile, and methanol.

40. The method of claim 1 , wherein the direct Suzuki coupling was performed in a non-aqueous system.

41. The method of claim 2 , wherein the direct Suzuki coupling was performed in a non-aqueous system.

42. The method of claim 1 wherein the compound, 6-aryl-4-aminopicolinate, is produced.

43. The method of claim 42 wherein the yield of said compound is greater than about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.

44. The method of claim 2 wherein the compound, 6-aryl-4-aminopicolinate, is produced.

45. The method of claim 44 wherein the yield of said compound is greater than about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.

Assignees

• Dow Agrosciences Llc

Inventors

• Fisk Jason S
• Li Xiaoyong
• Muehlfeld Mark
• Bauman Robert S
• Oppenheimer Jossian
• Tu Siyu
• Nitz Mark A
• Chakrabarti Reetam
• Feist Shawn D
• Ringer James W
• Leng Ronald B

Classifications

• B01J31/04

  containing carboxylic acids or their salts {(B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226)} · CPC title

• B01J2531/824

  Palladium · CPC title

• B01J31/00

  Catalysts comprising hydrides, coordination complexes or organic compounds (catalyst compositions used only in polymerisation reactions C08 {; catalytic antibodies C12N9/0002}) · CPC title

• C07D239/32

  One oxygen, sulfur or nitrogen atom · CPC title

• C07D213/90

  having more than three double bonds between ring members or between ring members and non-ring members · CPC title