Processes for the preparation of a diarylthiohydantoin compound

Patent metadata

Field	Value
Publication number	US-10723714-B2
Application number	US-201916427637-A
Country	US
Kind code	B2
Filing date	May 31, 2019
Priority date	Dec 19, 2014
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

Disclosed are processes and intermediates for the preparation of compound (X), which is currently being investigated for the treatment of prostate cancer.

First claim

What is claimed is:

1. A process for preparing compound (X):

the process comprising converting compound (VII) to compound (X)

2. The process of claim 1 , comprising reacting compound (VII) with molybdenum hexacarbonyl in an organic solvent, optionally in presence of one or more of norbornadiene, tetrabutylammonium bromide, triethylamine or DABCO, followed by the addition of methylamine to yield the corresponding compound (X):

3. The process of claim 2 , wherein the solvent is diglyme, dioxane, butyronitrile, or propionitrile.

4. The process of claim 3 , wherein compound (VII) is reacted in the presence of norbornadiene, tetrabutylammonium bromide, and DABCO.

5. The process of claim 1 , comprising reacting compound (VII) with carbon monoxide in a reaction mixture comprising a palladium catalyst, one or more phosphorus ligands, methyl amine, and one or more of DIPEA, potassium carbonate, potassium phosphate, or Cy 2 NMe, or excess methyl amine to yield the corresponding compound (X):

6. The process of claim 5 , wherein the palladium catalyst is added to the reaction mixture as a pre-formed palladium catalyst or is generated in situ.

7. The process of claim 5 , wherein the palladium catalyst is:

8. The process of claim 5 , wherein the palladium catalyst is generated in situ by the reaction of a palladium catalyst or palladium metal compound with one or more of:

9. The process of claim 5 , wherein the palladium catalyst is Pd(P(t-Bu) 3 ) 2 and is generated in situ by the reaction of Pd(OAc) 2 with L10 in the presence of Cy 2 NMe:

10. The process of claim 1 , wherein the process comprises converting compound (VII) to compound (1c), and then converting compound (1c) to compound (X):

11. The process of claim 10 , comprising reacting compound (VII) with an organomagnesium halide in an aprotic solvent, optionally in the presence of a lithium halide, followed by reacting the resulting mixture with carbon dioxide to yield the compound (1c)

12. The process of claim 11 , wherein the organomagnesium halide is a C 1-8 alkylmagnesium halide or a C 5-7 cycloalkylmagnesium halide; wherein the lithium halide is lithium chloride, lithium bromide, or lithium iodide; and the aprotic organic solvent is tetrahydrofuran, 2-methyl-tetrahydrofuran, methyl tert-butylether (MTBE), cyclopentyl methylether (CPME), or toluene.

13. The process of claim 12 , wherein the C 1-8 alkylmagnesium halide is a C 1-8 alkylmagnesium chloride or C 1-8 alkylmagnesium bromide and the C 5-7 cycloalkylmagnesium halide is a C 5-7 cycloalkylmagnesium chloride or a C 5-7 cycloalkylmagnesium bromide.

14. The process of claim 12 wherein the C 1-8 alkylmagnesium halide is isopropylmagnesium chloride, sec-butylmagnesium chloride, n-pentylmagnesium chloride, hexylmagnesium chloride, ethylmagnesium chloride, ethylmagnesium bromide, n-butylmagnesium chloride, or isopropylmagnesium chloride and the C 5-7 cycloalkylmagnesium halide is cyclohexylmagnesium chloride.

15. The process of claim 10 , comprising reacting compound (VII) with carbon monoxide in a mixture comprising a palladium catalyst, with an organic base in alcoholic solvent comprising water to yield the compound (1c)

16. The process of claim 15 , wherein the palladium catalyst is:

17. The process of claim 15 , wherein the palladium catalyst is generated in situ by the reaction of a palladium catalyst or palladium metal compound with one or more of:

18. The process of claim 15 , wherein the palladium catalyst is generated in situ by the reaction of palladium acetate and dppf:

19. The process of claim 10 , wherein compound (1c) is converted to compound (X) by reacting compound (1c) with methylamine in a solvent, in the presence of a coupling agent, to yield compound (X).

20. The method of claim 19 , wherein the coupling agent is 1,1′-carbonyldiimidazole (CDI) and the solvent is tetrahydrofuran or toluene.

21. The process of claim 1 , wherein the process comprises converting compound (VII) to compound (1e), and then converting compound (1e) to compound (X):

22. The process of claim 21 , comprising reacting compound (VII) with an organomagnesium halide in an aprotic solvent, optionally in the presence of a lithium halide, followed by reacting the resulting mixture with a C 1-6 alkyl chloroformate or a C 1-6 alkyl cyanoformate to yield the compound (1e).

23. The process of claim 22 , wherein the organomagnesium halide is a C 1-8 alkylmagnesium halide or a C 5-7 cycloalkylmagnesium halide; wherein the lithium halide is lithium chloride, lithium bromide, or lithium iodide; and the aprotic organic solvent is tetrahydrofuran, 2-methyl-tetrahydrofuran, or toluene.

24. The process of claim 23 , wherein the C 1-8 alkylmagnesium halide is a C 1-8 alkylmagnesium chloride or C 1-8 alkylmagnesium bromide and the C 5-7 cycloalkylmagnesium halide is a C 5-7 cycloalkylmagnesium chloride or a C 5-7 cycloalkylmagnesium bromide.

25. The process of claim 23 , wherein the C 1-8 alkylmagnesium halide is isopropylmagnesium chloride, sec-butylmagnesium chloride, n-pentylmagnesium chloride, hexylmagnesium chloride, ethylmagnesium chloride, ethylmagnesium bromide, n-butylmagnesium chloride, or isopropylmagnesium chloride and the C 5-7 cycloalkylmagnesium halide is cyclohexylmagnesium chloride.

26. The process of claim 23 , wherein the alkylmagnesium halide is n-pentylmagnesium chloride, the aprotic solvent is tetrahydrofuran or 2-methyl-tetrahydrofuran, the lithium halide is absent, and the reaction is conducted at a temperature in a range of from about −50° C. to about 22° C.

27. The process of claim 21 , comprising reacting the compound (V

Assignees

• Aragon Pharmaceuticals Inc

Inventors

• Ben Haim Cyril
• Horvath Andras
• Weerts Johan Erwin Edmond
• Albaneze-Walker Jennifer

Classifications

• C07D401/04 Primary

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

• C07D235/02

  condensed with carbocyclic rings or ring systems · CPC title

• C07D233/86

  Oxygen and sulfur atoms, e.g. thiohydantoin · CPC title

• C07D213/84

  Nitriles · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title