Method for the preparation of androgen receptor antagonists and intermediates thereof

Patent metadata

Field	Value
Publication number	US-12583840-B2
Application number	US-202117924505-A
Country	US
Kind code	B2
Filing date	May 10, 2021
Priority date	May 11, 2020
Publication date	Mar 24, 2026
Grant date	Mar 24, 2026

Abstract

The present invention relates to an improved process for the preparation of 2-chloro-4-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) which is useful as an intermediate in preparation of carboxamide structured androgen receptor antagonists. The process comprises preparation of compound (III) using heterogeneous palladium catalyst.

First claim

The invention claimed is:

1 . A method for the preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)

comprising reacting a compound of formula (Ia) or (Ib)

wherein R 1 and R 2 are hydrogen, or R 1 and R 2 together form a straight or a branched C 2-6 alkyl chain or a —C(O)—CH 2 —N(CH 3 )—CH 2 —C(O)— chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)

at an elevated temperature in the presence of a heterogeneous palladium catalyst, a solvent comprising dimethyl sulfoxide (DMSO), and a base.

2 . The method according to claim 1 , wherein the heterogeneous palladium catalyst is palladium on carbon, palladium on barium sulfate, palladium on metal oxides, palladium on silicon dioxide or palladium on zeolites.

3 . The method according to claim 2 , wherein the palladium on metal oxides is palladium on alumina.

4 . The method according to claim 1 , wherein the solvent comprises a mixture of dimethyl sulfoxide (DMSO) and water.

5 . The method according to claim 4 , wherein the ratio of water to DMSO is from about 0:100 to about 50:50.

6 . The method according to claim 1 , wherein the base is diisopropylethylamine (DIPEA).

7 . The method according to claim 1 , wherein the reaction is carried out in the presence of a phase transfer catalyst.

8 . The method according to claim 7 , wherein the phase transfer catalyst is a quaternary ammonium salt.

9 . The method according to claim 8 , wherein the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.

10 . The method according to claim 1 , wherein the reaction is conducted in a DMSO-water solvent in the presence of a base and a phase transfer catalyst, wherein the base is diisopropylethylamine (DIPEA), and the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride.

11 . The method according to claim 1 , wherein the reaction temperature is from about 60° C. to about 100° C.

12 . The method according to claim 1 , wherein the amount of palladium catalyst used per amount of compound of formula (II) is from about 0.2 to about 1 mol-%.

13 . The method according to claim 1 , wherein the reaction is carried out under nitrogen atmosphere.

14 . The method according to claim 1 , wherein the reaction time is 1-5 h.

15 . The method according to claim 1 , further comprising the steps of:
(b) removing the catalyst from the reaction mixture; (c) adding water to the cooled reaction mixture; and d) isolating the precipitated compound of formula (III).

16 . The method according to claim 15 , further comprising adding ethanol to the reaction mixture before removing the catalyst from the reaction mixture.

17 . The method according to claim 15 , wherein the isolation of the compound of formula (III) is carried out at 10-30° C.

18 . The method according to claim 1 , wherein the compound of formula (Ia) is selected from the following compounds:

19 . The method according to claim 18 , wherein the compound of formula (Ia) is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3).

20 . A method for the preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V)

comprising the steps of:
(a) reacting a compound of formula (Ia) or (Ib)

wherein R 1 and R 2 are hydrogen, or R 1 and R 2 together form a straight or a branched C 2-6 alkyl chain or a —C(O)—CH 2 —N(CH 3 )—CH 2 —C(O)— chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)

at an elevated temperature in the presence of heterogeneous palladium catalyst, a solvent comprising dimethyl sulfoxide (DMSO), and a base to obtain a compound of formula (III)

(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V).

21 . A method for the preparation of the compound of formula (1A)

comprising the steps of:
(a) reacting a compound of formula (Ia) or (Ib)

wherein R 1 and R 2 are hydrogen, or R 1 and R 2 together form a straight or a branched C 2-6 alkyl chain or a —C(O)—CH 2 —N(CH 3 )—CH 2 —C(O)— chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)

at an elevated temperature in the presence of a heterogeneous palladium catalyst, a solvent comprising dimethyl sulfoxide (DMSO), and a base to obtain a compound of formula (III)

(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V)

(d) reacting a compound of formula (V) with a compound of formula (VI)

to produce a compound of formula (VII)

(e) reacting the compound of formula (VII) with a compound of formula (VIII)

to produce a compound of formula (IX)

and
(f) reducing the compound of formula (IX) to produce the compound of formula (1A).

Assignees

• Orion Corp

Inventors

• Grumann Arne
• Karjalainen Oskari

Classifications

• C07D405/04 Primary

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

• B01J27/24

  Nitrogen compounds · CPC title

• B01J23/44

  Palladium · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title