Process for the preparation of androgen receptor antagonists and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10189789-B2
Application number	US-201615564878-A
Country	US
Kind code	B2
Filing date	Apr 8, 2016
Priority date	Apr 9, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to an improved process for the preparation of carboxamide structured androgen receptor (AR) antagonists such as N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (1A) and key intermediates thereof such as 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (V). AR antagonists are useful in the treatment of cancer, particularly prostate cancer and other diseases where AR antagonism is desired.

First claim

The invention claimed is:

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

comprising the steps of
a) reacting 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole of formula (I)

with 4-bromo-2-chlorobenzonitrile of formula (II)

at an elevated temperature in the presence of Pd(OAc) 2 , triphenylphosphine and a base in an acetonitrile-water solvent to form 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)

b) treating the compound of formula (III) with a catalytic amount of HCl in a methanol solvent;
c) adding a base to neutralize the mixture; and
d) isolating the compound of formula (V).

2. The method according to claim 1 , wherein step a) further comprises
i) isolating the acetonitrile phase;
ii) cooling the acetonitrile phase;
iii) adding water to the cooled acetonitrile phase; and
iv) precipitating 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile of formula (III)

 and
wherein step c) further comprises
i) adding water to the mixture; and
ii) precipitating the compound of formula (V).

3. The method according to claim 1 , wherein the amount of Pd(OAc) 2 used per amount of compound of formula (II) in step a) is from about 0.5 to about 2 mol-%.

4. The method according to claim 3 , wherein the amount of Pd(OAc) 2 used per amount of compound of formula (II) in step a) is from about 0.6 to about 0.8 mol-%.

5. The method according to claim 1 , wherein the molar ratio of the Pd(OAc) 2 to triphenylphosphine is 1:3.

6. The method according to claim 1 , wherein the base is potassium carbonate.

7. The method according to claim 1 , wherein the reaction temperature at step a) is from about 60° C. to about 75° C.

8. The method according to claim 7 , wherein the reaction temperature at step a) is from 67° C. to 73° C.

9. The method according to claim 1 , wherein step a) is carried out under nitrogen flow.

10. The method according to claim 2 , wherein step a) further comprises adding a base to the isolated acetonitrile phase after step ai) and before step aii).

11. The method according to claim 10 , wherein the base is ammonia water.

12. The method according to claim 2 , wherein the temperature of the mixture after step aiii) is 10° C. to 40° C.

13. The method according to claim 12 , wherein the temperature of the mixture after step aiii) is 20° C. to 25° C.

14. The method according to claim 1 , wherein the reaction time at step a) is 1 hour to 8 hours.

15. The method according to claim 14 , wherein the reaction time at step a) is 2 hours to 4 hours.

16. The method according to claim 1 , wherein the amount of HCl used per amount of compound of formula (III) in step b) is from about 0.05 to about 0.2 molar equivalents.

17. The method according to claim 16 , wherein the amount of HCl used per amount of compound of formula (III) in step b) is from about 0.07 to about 0.10 molar equivalents.

18. The method according to claim 1 , wherein the reaction temperature at step b) is 0° C. to 20° C.

19. The method according to claim 18 , wherein the reaction temperature at step b) is 5° C. to 15° C.

20. The method according to claim 1 , wherein the reaction time at step b) is 1 hour to 8 hours.

21. The method according to claim 20 , wherein the reaction time at step b) is 2 hours to 4 hours.

22. The method according to claim 1 , wherein the base used at step c) is ammonia water.

23. The method according to claim 2 , wherein the temperature of the mixture after step ci) is 10° C. to 20° C.

24. The method according to claim 2 , wherein the isolation at step d) is carried out at 0° C. to 5° C.

25. A method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V)

comprising the steps of
a) treating 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (Ill)

with a catalytic amount of HCl in a methanol solvent;
b) adding a base to neutralize the mixture;
c) precipitating the compound of formula (V); and
c) isolating the precipitated compound of formula (V).

26. The method according to claim 25 , wherein step b) further comprises adding water to the mixture after step b) and before step c).

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

comprising the steps of
a) reacting 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4, 5-tetra e hyl-1,3,2- dioxaborolan-2-0-1H-pyrazole of formula (I)

with 4-bromo-2-chlorobenzonitrile of formula (II)

at an elevated temperature in the presence of Pd(OAc) 2 , triphenylphosphine and a base in an acetonitrile-water solvent.

28. The method according to claim 27 , further comprising the steps of
b) isolating the acetonitrile phase;
c) cooling the acetonitrile phase;
d) adding water to the cooled acetonitrile phase;
e) precipitating the compound of formula (III); and
e) isolating the precipitated compound of formula (III).

29. A method for preparing the compound of formula(1A)

comprising the steps of
a) reacting a compound of formula (V)

with a compound of formula (VI)

to produce a compound of formula (VII)

and
b) reacting the compound of formula (VII) with a compound of formula (VIII)

to produce a compound of formula (IX)

and
c) reducing the compound of formula (IX) to produce the compound of formula (1A);
wherein the compound of formula (V) is prepared according to claim 1 .

Assignees

• Orion Corp

Inventors

• Laitinen Ilpo
• Karjalainen Oskari

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/04

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

• C07D231/14 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title