Processes for the preparation of a diarylthiohydantoin compound

Patent metadata

Field	Value
Publication number	US-10316015-B2
Application number	US-201515537859-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 19, 2014
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

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 the preparation of compound (X)

comprising

 reacting compound (V) with cyclobutanone in the presence of sodium cyanide; in acetic acid, or a solvent system comprised of an alcoholic solvent and a protic acid; at a temperature of about 0° C. to about 20° C.; to yield the corresponding compound (VI);

 reacting compound (IV) and compound (VI) in the presence of a thiocarbonylating agent; in an organic solvent; at a temperature of about 0° C. to about 100° C.; to yield the corresponding compound (VII);

 converting compound (VII) to compound (X).

2. The process of claim 1 , wherein step (1a) further comprises

reacting compound (V) with cyclobutanone in the presence of at least one molar equivalent of sodium cyanide; in acetic acid, or a solvent system comprised of at least one molar equivalent of acetic acid or hydrochloric acid and a C 1-4 alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, and butanol; at a temperature of about 0° C. to about 20° C.; to yield the corresponding compound (VI).

3. The process of claim 2 wherein the solvent system is acetic acid.

4. The process of claim 2 wherein the solvent system is 90% acetic acid and 10% ethanol.

5. The process of claim 1 , wherein step (1b) further comprises

reacting compound (IV) and compound (VI) in the presence of a thiocarbonylating agent selected from the group consisting of 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one, 1,1′-thiocarbonyl diimidazole, phenylthionochloroformate, beta-naphthyl thionochloroformate, 1,1′-thiocarbonylbis(pyridin-2(1H)-one), O,O-di(pyridin-2-yl)carbonothioate, 1,1′-thiocarbonylbis (1H-benzotriazole), and thiophosgene; in an organic solvent selected from the group consisting of THF, 2-methyl-THF, acetonitrile, DMA, toluene, DMF, NMP, and DMSO; at a temperature of about 0° C. to about 100° C.; to yield the corresponding compound (VII).

6. The process of claim 5 wherein the thiocarbonylating agent is 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one.

7. The process of claim 6 wherein the organic solvent is DMA.

8. The process of claim 1 , wherein step (1x) further comprises the conversion of compound (VII) to compound (X) via carboxylic acid (1c), by

reacting compound (VII) with an organomagnesium halide; in the presence or absence of a lithium halide; followed by the addition of carbon dioxide gas; in an aprotic organic solvent; at a temperature of about 0° C.; to yield the corresponding carboxylic acid compound (1c).

9. The process of claim 8 , comprising reacting compound (VII) with an organomagnesium halide selected from the group consisting of a C 1-8 alkylmagnesium halide and a C 5-7 cycloalkylmagnesium halide; in the presence or absence of a lithium halide selected from the group consisting of lithium chloride, lithium bromide, and lithium iodide; followed by the addition of carbon dioxide gas; in an aprotic organic solvent selected from the group consisting of THF, 2-MeTHF, MTBE, CPME, and toluene; at a temperature of about 0° C.; to yield the corresponding carboxylic acid compound (1c).

10. The process of claim 9 wherein the C 1-8 alkylmagnesium halide is a C 1-8 alkylmagnesium chloride or C 1-8 alkylmagnesium bromide.

11. The process of claim 10 wherein the C 1-8 alkylmagnesium halide is selected from the group consisting of sec-butylmagnesium chloride, n-pentylmagnesium chloride, hexylmagnesium chloride, ethylmagnesium chloride, ethylmagnesium bromide, n-butylmagnesium chloride, and isopropylmagnesium chloride.

12. The process of claim 11 further comprising reacting compound (VII) with n-pentylmagnesium chloride; in the absence of a lithium halide; followed by the addition of carbon dioxide gas; in THF; at a temperature of about 0° C.; to yield the corresponding carboxylic acid compound (1c).

13. The process of claim 9 wherein the C 5-7 cycloalkylmagnesium halide is a C 5-7 cycloalkylmagnesium chloride or C 5-7 cycloalkylmagnesium bromide.

14. The process of claim 13 wherein the C 5-7 cycloalkylmagnesium halide is cyclohexylmagnesium chloride.

15. The process of claim 1 , wherein step (1x) further comprises the conversion of compound (VII) to compound (X) via carboxylic acid (1c), by

reacting compound (VII) under a carbon monoxide atmosphere; in the presence of a palladium catalyst; in the presence of one or more phosphorus ligands; with an organic base; in a the presence of water; in an organic solvent; at a temperature of about 0° C. to about 100° C.; to yield the corresponding compound (1c).

16. The process of claim 15 wherein the palladium catalyst is comprised of a phosphorus ligand that is dppf and a palladium metal compound that is palladium acetate.

17. The process of claim 1 wherein step (1x) further comprises the conversion of compound (1c) to compound (X) via carboxylic acid (1c), by

reacting compound (1c) with a coupling agent; in an aprotic or protic solvent; at about room temperature; followed by the addition of methylamine; to yield the corresponding compound (X).

18. The process of claim 17 , further comprising reacting compound (1c) with a coupling agent that is CDI; wherein the aprotic or protic solvent is THF or toluene; at about room temperature; followed by the addition of methylamine; to yield the corresponding compound (X).

19. The process of claim 18 wherein methylamine is added as a THF solution.

20. The process of claim 18 wherein methylamine is added in its gaseous state.

21. The process of claim 18 wherein methylamine is added as its methyl ammonium salt.

22. The process of claim 1 , wherein step (1x) further comprises the conversion of compound (VII) to compound (X) via an ester of formula (1e), by

reacting compound (VII) with an organomagnesium halide; in the presence or absence of a lithium halide; in an aprotic organic solvent; at a temperature of about −50° C. to about room temperature; followed by the addition of an C 1-6 alkyl chloroformate or C 1-6 alkyl cyanoformate; to yield the corresponding ester of formula (1e).

23. The process of claim 22 , wherein step (1e) further comprises reacting compound (VII) with an organomagnesium halide selected from the group consisting of a C 1-8 alkylmagnesium halide and a C 5-7 cycloalkylmagnesium halide; in the presence or absence of a lithium halide selected from the group consisting of lithium chloride, lithium bromide, and

Assignees

• Aragon Pharmaceuticals Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/08

  of the prostate · CPC title

• B01J31/24

  Phosphines {, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands} · CPC title

• B01J2531/0205

  Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp · CPC title

• B01J2531/824

  Palladium · CPC title