Process for preparing dihalopyridines
View Patent ↗Processes for manufacturing dihalopyridines without the use of copper salts are described. Additional processes for manufacturing dihalopyridines from niacinamide are described.
1. A process for the manufacture of a compound of formula (A)
wherein
X 1 and X 2 are in each instance independently selected from the group consisting of Cl and Br;
Y represents from 0 to 3 substituents independently selected in each instance from the group consisting of halide, CN, NO 2 , OH, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
wherein the process comprises the step (c) of adding a first liquid mixture comprising a metal nitrite salt to a second liquid mixture comprising a compound of formula (B)
a hydrohalic acid, and an iron compound, wherein the iron compound is an iron(III) compound, or ferrous chloride, or ferrous nitrate, or ferrous sulfate.
2. The process of claim 1 wherein the iron (III) compound is an iron salt.
3. The process of claim 1 further comprising the step (b) of reacting a compound of formula (C)
with a first halogenating agent in the presence a hydrohalic acid to give the compound of formula (B).
4. The process of claim 1 further comprising the step (a) of reacting a compound of formula (D)
with a base and a second halogenating agent to give the compound of formula (C).
5. The process of claim 3 wherein steps (b) and (c) are conducted in the same reaction vessel.
6. The process of claim 4 wherein steps (a), (b), and (c) are conducted in the same reaction vessel.
7. The process of claim 4 wherein the second halogenating agent is selected from the group consisting of group consisting of chlorine, N-chlorosuccinimide, bromine, N-bromosuccinimide, hypochlorous acid, hypobromous acid, alkali metal hypochlorites, alkali metal hypobromites, and benzyltrimethyl ammonium tribromide.
8. The process of claim 3 wherein the first halogenating agent is selected from the group consisting of bromine, N-bromosuccinimide, chlorine, N-chlorosuccinimide, hydrochloric acid and hydrogen peroxide, hypochlorous acid, hypobromous acid, alkali metal hypochlorites, alkali metal hypobromites, and benzyltrimethyl ammonium tribromide.
9. The process of claim 1 wherein Y is not present.
10. The process of claim 1 wherein X 1 is chloro.
11. The process of claim 1 wherein X 2 is chloro.
12. The process of claim 1 wherein Y is absent; and X 1 and X 2 are both chloro.
13. The process of claim 1 wherein the iron compound is selected from the group consisting of ferric chloride, ferric nitrate, ferric sulfate, ferrous chloride, ferrous nitrate, and ferrous sulfate.
14. The process of claim 2 wherein the iron salt is ferric chloride.
15. The process of claim 1 wherein the hydrohalic acid is hydrochloric acid.
16. The process of claim 3 wherein the first halogenating agent is chlorine.
17. The process of claim 4 wherein the second halogenating agent is sodium hypochlorite.
18. The process of claim 1 wherein step (c) conducted at a temperature of about 20° C. to about 80° C.
19. The process of claim 1 wherein step (c) conducted at a temperature of about 55° C. to about 75° C.
20. The process of claim 1 further comprising the step of isolating the compound of formula (A) by co-distillation with water vapor.
21. The process of claim 1 further comprising the step of extracting the compound of formula (A) with a water immiscible solvent.
22. The process of claim 1 wherein the iron (III) compound in step (c) is ferric chloride, the hydrohalic acid is hydrochloric acid, and the ferric chloride is formed by adding ferric oxide to the second liquid mixture.