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

Patent metadata

Field	Value
Publication number	US-10544121-B2
Application number	US-201816045896-A
Country	US
Kind code	B2
Filing date	Jul 26, 2018
Priority date	May 19, 2016
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

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 includes 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 H, Cl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyl, or C 2 -C 4 haloalkenyl;
R represents H, alkyl, or arylalkyl;
X represents H, F, Cl, C 1-4 alkyl, C 1-3 alkoxy, or —NO 2 ;
Ar represents a substituted or unsubstituted aryl or heteroaryl group;

the method comprising coupling an aminopyridine (AP) and an aryl boronic acid (ABA) by direct Suzuki coupling in the presence of a catalyst.

2. The method of claim 1 , wherein X is F or Cl.

3. The method of claim 2 , wherein X is F.

4. The method of claim 1 , wherein Ar is:

wherein
W 1 represents H or F;
W 2 represents H, F, C 1 , C 1-4 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy
Y represents halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —CN, or —NO 2 ; and
Z represents H, F, Cl, C 1-4 alkyl, C 1-3 alkoxy, C 1 -C 4 haloalkyl, C 1-3 haloalkoxy, C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl, or —NR 1 R 2 , wherein R 1 and R 2 are independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or
Y and Z or Z and W 2 taken together are a 5-membered aromatic or non-aromatic, carbocyclic or heterocyclic ring.

5. The method of claim 1 , wherein the AP is benzyl 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylate (AP-Bz).

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

7. The method of claim 1 , wherein the AP is methyl 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylate.

8. The method of claim 7 , wherein the AP is methyl 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylate.

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

10. The method of claim 6 , wherein the ABA is 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole.

11. The method of claim 7 , wherein the ABA is 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole.

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

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

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

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

16. The method of claim 15 , wherein the concentration of the catalyst is from about 0.4% to about 1.0%.

17. The method of claim 16 , wherein the concentration of the catalyst is about 0.5%.

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

19. The method of claim 18 , wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.

20. The method of claim 19 , wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.

21. The method of claim 18 , wherein the pH is adjusted by addition of a base and/or CO 2 .

22. The method of claim 21 , wherein the base comprises K 2 CO 3 .

23. The method of claim 21 , wherein the base is added in more than one portion during the direct Suzuki coupling.

24. The method of claim 23 , wherein the portions are added over a period of at least two hours.

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

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

27. The method of claim 1 , wherein a 6-aryl-4-aminopicolinate is produced.

28. The method of claim 27 , wherein the yield 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

• C07D213/79 Primary

  Acids; Esters · CPC title

• C07D239/32

  One oxygen, sulfur or nitrogen atom · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title