Process for the preparation of a diarylthiohydantoin compound

Patent metadata

Field	Value
Publication number	US-9688655-B2
Application number	US-201514973089-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 19, 2014
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

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 a compound of formula (XI-c), wherein P is an amino protecting group, with compound (IV); in the presence of an amide coupling reagent; and in the presence of a catalyst; in an organic solvent; at a temperature in the range of from about 0° C. to about 50° C.; to yield the corresponding compound of formula (XII-c); or,

 reacting compound (IV) with phosgene or a phosgene analog; in the presence of an organic base; in an aprotic solvent; then treating a resulting isocyanate intermediate (IVa), optionally without isolation, with a compound of formula (XI-c); in the presence of a non-nucleophilic base; at a temperature in the range of from about −20° C. to about 80° C.; to yield the corresponding compound of formula (XII-c);

 reacting a compound of formula (XII-c) under amino deprotection conditions; in an organic solvent; at a temperature greater than ambient temperature; to yield the corresponding compound (XIII);

 reacting compound (XIII) with a compound of formula (2c-1) wherein X is chloro, bromo, or iodo, and W is C 1-8 alkoxy or methylamino; in the presence of a copper (0) source or a copper salt; in the presence of an inorganic base; in an organic solvent; optionally in the presence of a ligand; optionally in the presence of a reducing agent; at a temperature in the range of from about room temperature to about 140° C.; to yield the corresponding compound of formula (2c-2) wherein W is C 1-8 alkoxy (2c-2B) or methylamino (XVII);

 reacting a compound of formula (2c-2) to form compound (X).

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

reacting a compound of formula (XI-c), wherein P is an amino protecting group, with compound (IV); in the presence of an amide coupling reagent selected from the group consisting of 1,1-carbonyldiimidazole, T3P, EDCI, DMTMM, and EEDQ; in the presence of a catalyst selected from the group consisting of DBU, DBN, DABCO, triethylamine, DIPEA, TBD, TMG, MTBD, NaH, KOtBu, and LiHMDS; in an organic solvent selected from the group consisting of toluene, MeTHF, THF, iPrOAc, DCM, and IPA; at a temperature in the range of from about 0° C. to about 50° C.; to yield the corresponding compound of formula (XII-c).

3. The process of claim 2 wherein the amide coupling agent is 1,1-carbonyldiimidazole and the catalyst is DBU.

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

reacting compound (IV) with phosgene or a phosgene analog selected from the group consisting of triphosgene (bis(trichloromethyl) carbonate) and diphosgene (trichloromethyl chloroformate); in the presence of an organic base selected from the group consisting of triethylamine, ethyl diisopropylamine, and DABCO; in an aprotic solvent that is DCM, toluene, THF, or MeTHF; at a temperature in the range of from about −20° C. to about 50° C.; to form an isocyanate intermediate (IVa); then reacting said isocyanate intermediate (IVa) with a compound of formula (XI-c); in the presence of a non-nucleophilic base selected from the group consisting of DBU, DBN, DABCO, triethylamine, TBD, TMG, and MTBD; at a temperature in the range of from about −20° C. to about 80° C.; to yield the corresponding compound of formula (XII-c).

5. The process of claim 1 wherein step (2c) further comprises

reacting compound (XIII) with a compound of formula (2c-1) wherein X is chloro, bromo, or iodo, and W is C 1-8 alkoxy or methylamino; in the presence of either (1) a copper (0) source that is copper powder or copper sponge, or (2) a copper salt selected from the group consisting of cuprous chloride, cuprous iodide, cuprous bromide, cuprous acetate, and cupric bromide; in the presence of an inorganic base selected from the group consisting of potassium acetate, potassium carbonate, cesium carbonate, and CsF; in an organic solvent that is DMF, DMA, DMSO, acetonitrile, propionitrile, butyronitrile, or amyl alcohol; with or without the addition of a copper (I) salt selected from the group consisting of cuprous chloride, cuprous iodide, cuprous bromide, and cuprous acetate; and, optionally in the presence of a ligand selected from the group consisting of 2-acetylcyclohexanone, TMEDA, and phenanthroline; also, optionally in the presence of a reducing agent that is sodium ascorbate or sodium bisulfite; at a temperature in the range of from about room temperature to about 140° C.; to yield the corresponding compound of formula (2c-2) wherein W is C 1-8 alkoxy (2c-2B) or methylamino (XVII).

6. The process of claim 5 , comprising reacting compound (XIII) with a compound of formula (2c-1) in the presence of cuprous bromide; in the presence of TMEDA; in the presence of potassium acetate; in organic solvent DMA; at a temperature in the range of from about 80° C. to about 140° C.

7. The process of claim 5 , comprising reacting compound (XIII) with a compound of formula (2c-1) in the presence of a copper (0) source that is copper powder or copper sponge; in the presence of potassium acetate or sodium pivalate; in organic solvent DMSO; at a temperature in the range of from about 0° C. to about 80° C.

8. The process of claim 5 , comprising reacting compound (XIII) with a compound of formula (2c-1) in the presence of a copper (0) source that is copper powder or copper sponge; in the presence of potassium acetate; with the addition of a copper (I) salt selected from the group consisting of cuprous chloride, cuprous iodide, cuprous bromide, and cuprous acetate; in organic solvent DMSO; at a temperature in the range of from about 0° C. to about 80° C.

9. The process of claim 1 , wherein step (2d) further comprises the reaction of compound (XVII) to form compound (X) by

reacting compound (XVII) with a thiocarbonyl source; in the presence of an activating agent; in an organic solvent; optionally in the presence of an organic base; at a temperature in the range of from about −20° C. to about 100° C.; to yield the corresponding compound (X).

10. The process of claim 9 , wherein step (2e) further comprises reacting compound (XVII) with a thiocarbonyl source selected from the group consisting of O,O′-di(pyridin-2-yl)carbonothioate, 1,1′-thiocarbonylbis(pyridin-2(1H)-one), di(1H-imidazol-1-yl)methanethione, thiophosgene, phenyl thionochloroformate, O-(2-naphthyl) thionochloroformate, tolyl thionochloroformate, and thiocarbonyl bis(benzotriazole); in the presence of an activating agent selected from the group consisting of DMAP, NaH, and NaOH; in an organic solvent selected from the group consisting of DMA, DMF, toluene, DMSO, ACN, THF, DCM, EtOAc, acetone, MEK, and dioxane; optiona

Assignees

• Aragon Pharmaceuticals Inc
• Janssen Pharmaceutica Nv

Inventors

• Haim Cyril Ben
• Horvath Andras
• Edmond Johan Erwin

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/08

  of the prostate · CPC title

• B01J37/04

  Mixing {(B01J37/0009, B01J37/0018 take precedence)} · CPC title

• C07D213/84 Primary

  Nitriles · CPC title

• C07D213/61 Primary

  Halogen atoms or nitro radicals · CPC title