Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

Patent metadata

Field	Value
Publication number	US-10577345-B2
Application number	US-201816101251-A
Country	US
Kind code	B2
Filing date	Aug 10, 2018
Priority date	May 12, 2016
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

Abstract

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to herein as Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

First claim

What is claimed is:

1. A compound of formula (2):

wherein each R is —CH(CH 2 R 1 )OR 2 ; and
wherein each R 1 is independently hydrogen or alkyl, and each R 2 is independently alkyl.

2. The compound of claim 1 , wherein each R is independently —CH(CH 3 )—O—CH 2 CH 3 or —CH(CH 2 CH 3 )—O—CH 2 CH 3 .

3. The compound of claim 1 , wherein each R is —CH(CH 3 )—O—CH 2 CH 3 .

4. The compound of claim 1 , wherein each R is —CH(CH 2 CH 3 )—O—CH 2 CH 3 .

5. A method of preparing the compound of formula (2):

wherein each R is —CH(CH 2 R 1 )OR 2 , and
wherein each R 1 is independently hydrogen or alkyl, and each R 2 is independently alkyl; comprising treating a compound of formula (4)

with a formylating agent to provide the compound of formula (2).

6. The method of claim 5 , wherein the formylating agent is n-butyllithium (n-BuLi) and dimethylformamide (DMF).

7. The method of claim 5 , wherein the formylating agent is N-formylmorpholine.

8. The method of claim 5 , further comprising reacting compound (5):

with a vinyl ether of formula CHR 1 ═CHOR 2 in the presence of a weak acid to provide a compound of formula (4);
wherein the compound of formula (4) is treated in situ with the formylating agent to provide the compound of formula (2).

9. The method of claim 8 , wherein the formylating agent is n-butyllithium and dimethylformamide.

10. The method of claim 8 , wherein the formylating agent is N-formylmorpholine.

11. A compound of formula (2a):

12. A method of preparing a compound of formula (2a)

comprising treating a compound of formula (4a)

with a formylating agent to provide the compound of formula (2a).

13. The method of claim 12 , wherein the formylating agent is n-butyllithium and dimethylformamide.

14. The method of claim 12 , wherein the formylating agent is N-formylmorpholine.

15. The method of claim 12 , further comprising reacting compound (5):

with ethyl vinyl ether in the presence of a weak acid to provide a compound of formula (4a);
wherein the compound of formula (4a) is treated in situ with the formylating agent to provide the compound of formula (2a).

16. The method of claim 15 , wherein the formylating agent is n-butyllithium and dimethylformamide.

17. The method of claim 15 , wherein the formylating agent is N-formylmorpholine.

Assignees

• Global Blood Therapeutics Inc

Inventors

• Li Zhe
• Guz Nathan
• Shao Yiyang
• Cocuz Julieana
• Frieser Markus
• Yiannikouros George Petros
• Liao Liang

Classifications

• C07C47/575 Primary

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D401/04 Primary

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

• C07C45/65

  by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups · CPC title

• C07C47/565

  all hydroxy groups bound to the ring · CPC title