IP Library › Granted Patent US 12,291,525

Granted Patent B2

US 12,291,525 · App. 17/781,777 · Granted May 6, 2025

Process for synthesis of a 2-(5-isoxazolyl)-phenol

Inventors: Junbae Hong (Newark, DE); Joerg Bruening (Wilmington, DE)

Assignee: FMC Corporation

C07D413/12 C07D239/38 C07D261/08

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Quick Facts

Patent No.: US 12,291,525
App. No.: 17/781,777
Granted: May 6, 2025
Kind: B2

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Abstract

A method for preparing a compound of Formula (1) and compounds therefrom, comprising treating a compound of Formula (2) to provide a compound of Formula (5) and treating the compound of Formula (5) with a hydroxylamine salt wherein R 1 , R 2 and m are as defined in the specification. The compound of Formula (1), prepared by the above method, can be used to prepare a compound of Formula (8) wherein R 1 , R 2 , R 3 and m are as defined in the specification.

Claims (161)

1. A method for preparing a compound of Formula 1

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3;

the method comprising

treating a compound of Formula 2

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

m is 0, 1, 2 or 3; and

X is halogen;

with a compound of Formula 3

R 2 (C═O)LG 3

wherein

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

LG is chloro, C 1 -C 4 alkoxy or —O(C═O)R 2

in the presence of an alkali metal base to provide a compound of Formula 4 or an alkali metal salt thereof

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

m is 0, 1, 2 or 3; and

X is halogen;

heating the compound of Formula 4 or the alkali metal salt thereof to provide a compound of Formula 5

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3;

treating the compound of Formula 5 with a hydroxylamine salt to provide a compound of Formula 6

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3; and

treating the compound of Formula 6 with acid.

2. The method of claim 1 wherein R 2 is C 1 -C 4 haloalkyl; and m is 0, 1 or 2.

3. The method of claim 2 wherein each R 1 is independently halogen or cyano; and R 2 is C 1 -C 2 fluoroalkyl.

4. The method of claim 3 wherein

R 1 is halogen;

R 2 is C 1 fluoroalkyl;

m is 1; and

R 1 is attached to the remainder of Formula 1 at the 3-position.

5. The method of claim 4 wherein R 1 is chlorine; and R 2 is CHF 2 .

6. The method of claim 1 wherein the compound of Formula 2 is prepared by treating a compound of Formula 9

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

X is halogen; and

m is 0, 1, 2 or 3;

with a methyl magnesium halide followed by treatment with water or aqueous acid.

7. The method of claim 1 further comprising treating the compound of Formula 1 with a compound of Formula 7

wherein

Z is halogen or SO 2 R 4 ;

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

R 4 is C 1 -C 4 alkyl

in the presence of a second base to provide a compound of Formula 8

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3.

8. The method of claim 7 wherein R 3 is chlorine.

9. The method of claim 7 wherein Z is SO 2 R 4 .

10. The method of claim 9 wherein the compound of Formula 7 is prepared by treating a compound of Formula 10

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

Q is Cl or OH

in the presence of a halogenating agent and a compound of Formula 11

wherein

R A and R B are each independently C 1 -C 4 alkyl; or

R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 — to provide an intermediate of Formula 12

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

R A and R B are each independently C 1 -C 4 alkyl; or

R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 —; and

Hal − is chloride or bromide ion;

treating the intermediate of Formula 12 with an acid salt of a compound of Formula 13

wherein R 4 is C 1 -C 4 alkyl

in the presence of a base to provide a compound of Formula 14

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 4 is C 1 -C 4 alkyl; and

treating the compound of Formula 14 with an oxidant.

11. The method of claim 7 wherein the compound of Formula 8 is the compound of Formula 8A

12. A method for preparing a compound of Formula 8

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3;

the method comprising

treating a compound of Formula 2

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

m is 0, 1, 2 or 3; and

X is halogen;

with a compound of Formula 3

R 2 (C═O)LG 3

wherein

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

LG is chloro, C 1 -C 4 alkoxy or —O(C═O)R 2

in the presence of a base to provide a salt of a compound of Formula 4

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

m is 0, 1, 2 or 3; and

X is halogen;

heating the salt of the compound of Formula 4 to provide a compound of Formula 5

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3;

treating the compound of Formula 5 with a hydroxylamine salt to provide a compound of Formula 6

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3;

treating the compound of Formula 6 with acid to provide a compound of Formula 1

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 2 is cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

m is 0, 1, 2 or 3; and

treating the compound of Formula 1 with a compound of Formula 7

wherein

Z is halogen or SO 2 R 4 ;

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 4 is C 1 -C 4 alkyl

in the presence of a second base.

13. The method of claim 12 wherein the compound of Formula 2 is prepared by treating a compound of Formula 9

wherein

each R 1 is independently halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

X is halogen;

and

m is 0, 1, 2 or 3;

with a methyl magnesium halide followed by treatment with water or aqueous acid.

14. The method of claim 12 wherein Z is SO 2 R 4 .

15. The method of claim 14 wherein the compound of Formula 7 is prepared by treating a compound of Formula 10

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

Q is Cl or OH

in the presence of a halogenating agent and a compound of Formula 11

wherein

R A and R B are each independently C 1 -C 4 alkyl; or

R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 — to provide an intermediate of Formula 12

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

R A and R B are each independently C 1 -C 4 alkyl; or

R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 —; and

Hal − is chloride or bromide ion;

treating the intermediate of Formula 12 with an acid salt of a compound of Formula 13

wherein R 4 is C 1 -C 4 alkyl

in the presence of a base to provide a compound of Formula 14

wherein

R 3 is halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 4 is C 1 -C 4 alkyl; and

treating the compound of Formula 14 with an oxidant.

16. The method of claim 12 wherein the compound of Formula 8 is the compound of Formula 8A

17. A compound of Formula 5A

wherein

R 1 is halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

R 2 is C 1 -C 2 haloalkyl; wherein when R 1 is fluoro, R 2 is other than trifluoromethyl.

18. The compound of claim 17 wherein R 2 is C 1 -C 2 fluoroalkyl.

19. The compound of claim 18 wherein R 1 is halogen; and R 2 is C 1 fluoroalkyl.

20. The compound of claim 19 wherein R 1 is chlorine; and R 2 is CF 2 .

Assignments (2)

PATENT SECURITY AGREEMENT Recorded Apr 17, 2026

From: FMC CORPORATION

To: CITIBANK, N.A.

Reel/Frame 075403/0891 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 23, 2022

From: HONG, JUNBAE; BRUENING, JOERG

To: FMC CORPORATION

Reel/Frame 060291/0088 →

Continuity (2)

Provisional Application 62942504 · Dec 2, 2019

Related Publication 20230061554A1 · Mar 2, 2023

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