Homogeneous process for hydrodehalogenating halogenated heteroaryl compounds

• US 10,450,272 B2
• Filed: 11/16/2016
• Issued: 10/22/2019
• Est. Priority Date: 11/19/2015
• Status: Active Grant

• Current Assignee: Johnson Matthey PLC
• Original Assignee: Johnson Matthey PLC
• Inventors: Mortimer, Danny Lee
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US15/776,554
• Publication Number:
  US 20180334433A1
• Time in Patent Office: 1,070 Days
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals

Abstract

The present invention provides a homogeneous process for hydrodehalogenating a halo-substituted C₃-C₂₀ heteroaryl starting material to form a non-halogenated C₃-C₂₀ heteroaryl product and/or a halo-substituted C₃-C₂₀ heteroaryl product, wherein the halo-substituted C₃-C₂₀ heteroaryl product has at least one less halogen substituents than the halo-substituted C₃-C₂₀ heteroaryl starting material, the process comprising the step of hydrogenating the halo-substituted C₃-C₂₀ heteroaryl starting material in the presence of a rhodium or ruthenium complex, molecular hydrogen, a base and a solvent, wherein the process is carried out in a monophasic solvent system and the molar ratio of base to each halogen substituent to be removed is at least 1:1.

Claims

1. A homogeneous process for hydrodehalogenating a halo-substituted C₃-C₂₀ heteroaryl starting material to form a non-halogenated C₃-C₂₀ heteroaryl product and/or a halo-substituted C₃-C₂₀ heteroaryl product, wherein the halo-substituted C₃-C₂₀ heteroaryl product has at least one less halogen substituent than the halo-substituted C₃-C₂₀ heteroaryl starting material, the process comprising the step of:

hydrogenating the halo-substituted C₃-C₂₀ heteroaryl starting material in the presence of a rhodium or ruthenium complex, molecular hydrogen, a base and a solvent, wherein the process is carried out in a monophasic solvent system and the base is present in a molar excess of between 0.1 to 1.0 molar equivalents over an amount required for the stoichiometric reaction to remove each halogen substituent.

2. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl starting material has a number of halogen substituents which is ≥

2 and up to the limitations imposed by the rules of valence.

3. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl starting material is a halo-substituted C₃-C₁₅ heteroaryl starting material.

4. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl starting material is a halo-substituted C₃-C₂₀ nitrogen-containing heteroaryl starting material.

5. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl starting material is a chloro-substituted C₃-C₂₀ heteroaryl starting material.

6. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl starting material is trichloro-pyridine.

7. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl product is a halo-substituted C₃-C₂₀ nitrogen-containing heteroaryl product.

8. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl product is a chloro-substituted C₃-C₂₀ heteroaryl product.

9. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl product is a halo-substituted C₃-C₂₀ nitrogen-containing heteroaryl product.

10. The process of claim 1, wherein the halo-substituted C₃-C₂₀ heteroaryl product is dichloro-pyridine.

11. The process of claim 1, wherein the base is an inorganic base or an organic base.

12. The process of claim 1, wherein the base is present in a molar ratio of about 1.1:

1 to about 2;

1 to each halogen substituent to be removed.

13. The process of claim 12, wherein the base is present in a molar ratio of about 1.5:

1 to about 1.75;

1 to each halogen substituent to be removed.

14. The process of claim 1, wherein the solvent is an alcohol or aromatic solvent.

15. The process of claim 14, wherein the alcohol has a boiling point at atmospheric pressure below 160°

C.

16. The process of claim 14, wherein the aromatic solvent is benzene, toluene or xylene.

17. The process of claim 1, wherein the molecular hydrogen is molecular deuterium or molecular tritium.

18. The process of claim 1, wherein the rhodium complex is a rhodium(I) complex or a rhodium(III) complex.

19. The process of claim 18, wherein the rhodium(I) complex is Rh(monophosphine)₃X, Rh(monophosphine)₂(CO)X, Rh(monophosphine)₃(CO)H, Rh(monophosphine)₄H, [Rh(CO)₂X]₂, [Rh(olefin)_mX]₂, Rh(olefin)_mCp*, [Rh(olefin)_m(phosphine)_n]Y, or a complex generated in situ from [Rh(olefin)_mX]₂ and phosphine, wherein:

Cp* is 1,2,3,4,5-pentamethyl-cyclopentadienyl;

X is a halogen,

Y is a non-coordinated anionic ligand,

the phosphine is a monophosphine or a diphosphine,

m is 1 or 2,

n is 1 or 2, and wherein;

when m=1, the olefin is a diolefin,

when m=2, the olefin is a mono-olefin,

when n=1, the phosphine is a bidentate phosphine, and

when n=2, the phosphine is a monophosphine.

20. The process of claim 18, wherein the rhodium(III) complex is Rh(monophosphine)₂X_pH_q or [Rh(Cp*)X₂]₂, wherein:

X is a halogen,

p is 1 or 2,

q is 2 or 1, and

p+q is 3.

21. The process of claim 1, wherein the ruthenium complex is Ru(monophosphine)₃X₂, Ru(monophosphine)₃HX, Ru(monophosphine)₂(CO)₂X₂, Ru(monophosphine)₃(CO)X_rH_s, [Ru(Cp*)X₂] polymer, Ru(Cp*)(monophosphine)₂X, [Ru(arene)X₂]₂, Ru(monophosphine)(arene)X₂, [Ru(olefin)_tX₂] polymer, Ru(olefin)t(Cp*)X, or a complex generated in situ from [Ru(olefin)_tX₂] polymer and phosphine, wherein:

X is a halogen,

the phosphine is a monophosphine or a diphosphine,

t is 1 or 2,

r is 0 or 1,

s is 2 or 1, and

r+s is 2, and

wherein;

when t=1, the olefin is a diolefin,

when t=2, the olefin is a mono-olefin.

22. The process of claim 19, wherein the mono-olefin is ethylene or cyclooctene.

23. The process of claim 21, wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.

24. The process of claim 19, wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.

25. The process of claim 21, wherein the diolefin is 1,5-hexadiene, cyclooctadiene or norbornadiene.

26. The process of claim 16, wherein Y is [BF₄]⁻

, [CF₃SO₃]⁻

, [PF₆]⁻

or [SbF₆]⁻

.