Process of preparing a PD-1/PD-L1 inhibitor

Patent metadata

Field	Value
Publication number	US-11780836-B2
Application number	US-202117520060-A
Country	US
Kind code	B2
Filing date	Nov 5, 2021
Priority date	Nov 6, 2020
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

The present invention relates to processes of preparing PD-1/PD-L1 inhibitor (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or salts thereof, related synthetic intermediates, and salts of the intermediates, where the PD-1/PD-L1 inhibitor is useful in the treatment of various diseases including infectious diseases and cancer.

First claim

What is claimed is:

1. A process of preparing (R)-1-((7-cyano-2-(3′-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, or a salt thereof, comprising:
reacting a compound of formula III-5:

or a salt thereof, with a compound of formula III-6:

or a salt thereof, in the presence of a Suzuki catalyst and a base to form a compound of formula A-1:

or a salt thereof, wherein:
each R 3 is independently selected from H and C 1-6 alkyl; or
each R 3 together form an C 2-3 alkylene linker, which is optionally substituted by 1, 2, 3, or 4 independently selected C 1-4 alkyl groups; and
X 1 is halo.

2. The process of claim 1 , wherein the compound of Formula A-1, or the salt thereof, is a salt of formula A-1a:

3. The process of claim 2 , wherein the salt of Formula A-1a is converted to a compound of Formula A-1 by a process comprising treating the salt of Formula A-1a with a weak acid resin.

4. The process of claim 1 , wherein the process comprises:
reacting a compound of formula III-5b:

with a salt of formula III-6b:

in the presence of a Suzuki catalyst and a base to form a salt of formula A-1a:

5. The process of claim 1 , wherein the compound of Formula III-5, or the salt thereof, is a compound of formula III-5a:

wherein the compound of formula III-5a is prepared by a process comprising:
reacting a compound of formula III-3:

or the salt thereof, with a compound of formula III-4:

or the salt thereof, in the presence of a base to form the compound of formula III-5a, wherein X 3 is halo.

6. The process of claim 5 , wherein the compound of Formula III-5a is prepared by a process comprising:
reacting a salt of formula III-3a:

with a salt of formula III-4a:

in the presence of a base to form the compound of formula III-5a.

7. The process of claim 5 , wherein the compound of Formula III-3, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula III-1:

or a salt thereof, with a compound of formula III-2:

or a salt thereof, in the presence of a reducing agent to form the compound of formula III-3, or the salt thereof, wherein X 3 is halo.

8. The process of claim 7 , wherein the compound of formula III-1, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula XI-6:

or a salt thereof, with a Vilsmeier reagent to form a compound of formula XI-7:

or a salt thereof; and
deprotecting the compound of formula XI-7, or the salt thereof, to form the compound of formula III-1, or the salt thereof, wherein the Vilsmeier reagent formed from dimethylformamide, wherein X 3 is halo.

9. The process of claim 8 , wherein the Vilsmeier reagent, for reacting with the compound of formula XI-6, or the salt thereof, is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

10. The process of claim 8 , wherein the compound of formula XI-6 is prepared by a process comprising:
reacting a compound of formula XI-5:

or a salt thereof, with a methylating agent, and
reacting the product of said reacting of the compound of formula XI-5, or the salt thereof, with a strong base to form the compound of formula XI-6.

11. The process of claim 2 , wherein the compound of formula XI-5, or the salt thereof, is prepared by a process comprising:
hydrolyzing a compound of formula XI-4:

or a salt thereof, to form the compound of formula XI-5, or the salt thereof.

12. The process of claim 11 , wherein the compound of formula XI-4, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula XI-3:

or a salt thereof, with a cyanation reagent to form the compound of formula XI-4, or the salt thereof.

13. The process of claim 12 , wherein the compound of formula XI-3, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula XI-2:

or a salt thereof, with ethylene glycol to form the compound of formula XI-3, or the salt thereof.

14. The process of claim 13 , wherein the compound of formula XI-2, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula XI-1:

or a salt thereof, with a reagent of formula R 11 —Mg—X 11 ; and
reacting the product of said reacting of the compound of XI-1, or the salt thereof, with dimethylformamide to form the compound of formula XI-2, or the salt thereof, wherein:
R 11 is C 1-6 alkyl; and
X 11 is Cl, Br, or I.

15. The process of claim 7 , wherein the compound of formula III-1, or the salt thereof, is prepared by a process comprising:
reducing a compound of formula XII-2:

to form the compound of formula III-1, or the salt thereof, wherein X 3 is halo.

16. The process of claim 15 , wherein the compound of formula XII-2 is prepared by a process comprising:
reacting a compound of formula XII-1:

or a salt thereof, with ethyl 3,3-diethoxypropanoate in the presence of a catalyst, wherein X 3 is halo.

17. The process of claim 15 , wherein the compound of formula XII-2 i

Assignees

• Incyte Corp

Inventors

• Zhou Jiacheng
• Chen Shili
• Jia Zhongjiang
• Li Yi
• Lin Qiyan
• Liu Pingli
• Pan Yongchun
• Martin Timothy
• Shen Bo
• Shi Chongsheng Eric
• Su Naijing
• Wu Yongzhong
• Xia Michael

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07D207/16

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

• C07D405/04

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