IP Library › Granted Patent US 12,612,367
Granted Patent B2
US 12,612,367 · App. 17/783,816 · Granted Apr 28, 2026

Method for producing nitrogen-containing heteroarylcarboxamide acetic acid derivative

Inventors: Kazufumi Ootsuki (Osaka, JP); Muneki Kishida (Osaka, JP); Atsushi Moroda (Osaka, JP); Kohki Fukuhara (Osaka, JP); Hirotoshi Yagishita (Osaka, JP)
Assignee: Akebia Therapeutics, Inc.
C07D213/81C07D213/65C07B2200/13
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Quick Facts
Patent No.
US 12,612,367
App. No.
17/783,816
Granted
Apr 28, 2026
Kind
B2
Abstract

The present invention provides a novel process for preparing the compound I containing the compound [I(A)] (vadadustat) and the compound [I(B)] (roxadustat) which are useful as a medicine in an industrially advantageous manner, and a process for preparing the compound I which comprises reacting the compound (a1) or the compound (b1), the compound (2) or salts of the compound (2), with carbon monoxide in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to prepare the compound I (wherein structure formulae of the compound (a1), the compound (b1) or the compound (2), and the definitions of groups in the formulae are defined in the description.

Claims (175)

1 . A process for preparing a compound of formula (a3):

wherein:

R 2 is a hydrogen atom or an optionally substituted methyl group,

R a3 is a phenyl group, optionally substituted with halogen atom,

R a4 is a hydrogen atom, or alternatively,

R a3 and R a4 bind to each other and combine together with a pyridine group to which they are adjacent to form an isoquinoline group which may be optionally substituted with phenyloxy group, and

Z a2 is a hydroxy group or a substituent represented by formula:

wherein P 1 is a protecting group for hydroxy group;

said process comprising reacting a compound of formula (a1):

wherein

R 2 , R a3 , R a4 , and Z a2 are as defined above; and

Z 1 is a chlorine atom, a bromine atom, or an iodine atom,

with a compound (2) represented by formula:

wherein R 1 is an optionally substituted alkyl group, a hydrogen atom, or a resin residue,

or a salt thereof,

and carbon monoxide,

in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent, to obtain the compound (a3).

2 . The process of claim 1 , wherein the pressure of the carbon monoxide during the reaction is between 0.01 MPa to 1 MPa.

3 . The process of claim 1 , wherein the molar ratio of the compound of formula (a1) used in the reaction to the compound of formula (2) used in the reaction is 2:1 to 1:2.

4 . The process of claim 1 , wherein the reaction is conducted in nitriles as the solvent and between 20 to 150° C. as a reaction temperature.

5 . The process of claim 1 , wherein the compound of formula (a1) is a compound of formula (a1-5-a):

wherein Z 1 is a chlorine atom, a bromine atom or an iodine atom, and

the compound of formula (a3) is a compound of formula (a3-3-a):

wherein R 1 is an optionally substituted alkyl group, a hydrogen atom, or a resin residue.

6 . The process of claim 1 , wherein the compound of formula (a3) is a compound of formula (a3-1):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue,

R 2 is a hydrogen atom or an optionally substituted methyl group,

R a3 is a phenyl group optionally substituted with halogen atom, and

R a4 is a hydrogen atom, or alternatively,

R a3 and R a4 bind to each other and combine together with the pyridine group to which they are adjacent to form an isoquinoline group optionally substituted with phenyloxy group,

Z a2 is a hydroxy group or a substituent represented by formula:

wherein P 1 is a protecting group for hydroxy group,

further comprising converting the compound of formula (a3-1) into the compound of formula (a1):

wherein the symbols are the same as defined above.

7 . The process of claim 1 , wherein:

(i) R 2 is a hydrogen atom,

R a3 is a 3-chlorophenyl group, and

R a4 is a hydrogen atom, or alternatively,

(ii) R 2 is a methyl group, and

R a3 and R a4 bind to each other and combine together with a pyridine group to which they are adjacent to form a 7-phenyloxy-isoquinoline group.

8 . The process of claim 6 , wherein the compound of formula (a3-1) is a compound of formula (a3-2-a):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue, and

the compound of formula (a1) is a compound of formula [I(A)]:

9 . The process according to claim 1 , wherein

the compound of formula (a1) is a compound of formula (a1-1-a):

wherein Z a2 is a hydroxy group or a substituent represented by formula:

wherein P 1 is a protecting group for hydroxy group, and

the compound of formula (a1-1-a) is prepared by reacting a compound of formula (a4):

wherein Z a3 is bromine atom, an iodine atom, or a trifluoromethanesulfoxy group, and Z a2 is the same as defined as above,

with a compound of formula (a5):

wherein X a1 and X a2 each independently is a hydrogen atom or an alkyl group, or alternatively both of them bind to each other to form an alkylene group,

in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in a solvent or in the absence of a solvent.

10 . The process according to claim 9 , wherein

the compound of formula (a1-1-a) is a compound of formula (a1-4-a):

 and

the compound of formula (a4) a compound of formula (a4-2):

wherein Z a3 is a bromine atom or an iodine atom.

11 . A process for preparing a compound of formula [1(A)]:

said process comprising:

(i) reacting a compound of formula (a4):

wherein Z a2 is a hydroxy group or a substituent represented by formula:

wherein P 1 is a protecting group for hydroxy group,

Z a3 is a bromine atom, an iodine atom or a trifluoromethanesulfoxy group, with a compound of formula (a5):

wherein X a1 and X a2 are each independently a hydrogen atom or an alkyl group, or alternatively, both of them bind to each other to form an alkylene group,

in the presence or absence of a base, in the presence or absence of a palladium catalyst, in a solvent or in the absence of a solvent to prepare a compound of formula (a1-1-a):

wherein, Z a2 is the same as defined above:

(ii) reacting the compound of formula (a1-1-a) with a compound of formula (2-1):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue, or

a salt thereof,

and carbon monoxide in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, in a solvent or in the absence of a solvent to obtain a compound of formula (a3-1-a):

wherein R 1-1 and Z a2 are the same defined above;

and

(iii) converting the compound of formula (a3-1-a) into the compound of formula [I(A)]

12 . The process of claim 11 , wherein compound of formula (a4) is a compound of formula (a4-2):

wherein Z a3-1 is a bromine atom or an iodine atom,

the compound of formula (a1-1-a) is a compound of formula (a1-4-a):

and the compound of formula (a3-1-a) is a compound of formula (a3-2-a):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue.

13 . A process for preparing a compound of formula [I(A)]:

said process comprising:

(i) reacting a of compound of formula (a4-1):

wherein Z a2-1 is a substituent represented by formula:

wherein P 1 is a protecting group for a hydroxy group, and

Z a3 is a bromine atom, an iodine atom, or a trifluoromethanesulfoxy group, with a compound of formula (a5):

wherein X a1 and X a2 are each independently a hydrogen atom, or an alkyl group, or alternatively both of them bind to each other to form an alkylene group,

in the presence of absence of a base, in the presence of absence of a palladium catalyst, in a solvent or in the absence of a solvent, to prepare a compound of formula (a1-3-a)

wherein Z a2-1 is the same as defined above;

(ii) converting the compound of formula (a1-3-a) into the compound of formula (a1-4-a):

(iii) reacting the compound of formula (a1-4-a) with a compound of formula (2-1):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue, or a salt thereof,

and carbon monoxide

in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, and in a solvent or in the absence of a solvent to prepare the compound of formula (a3-2-a):

wherein R 1-1 is the same as defined above; and

(iv) converting the compound of formula (a3-2-a) into the compound of formula (I(A)):

14 . A process for preparing a compound of formula (b3-1):

wherein R 1 is an optionally substituted alkyl group, a hydrogen atom, or a resin residue,

R 2 is a hydrogen atom, or an optionally substituted methyl group,

R 3 is a phenyl group which may be optionally substituted with halogen atom, a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfoxy group, and

R 4 is a hydrogen atom, or alternatively,

R 3 and R 4 bind to each other and combine together with the pyridine group to which they are adjacent to form an isoquinoline group which may be optionally substituted with phenyloxy group,

said process comprising:

(i) reacting a compound of formula (b1):

wherein

Z 1 is a chlorine atom, a bromine atom, or an iodine atom,

Z b2 is a chlorine atom, a bromine atom or an iodine atom, and

R 2 , R 3 , and R 4 are the same as defined above,

with a compound of formula (2):

wherein R 1 is an optionally substituted alkyl group, a hydrogen atom, or a resin residue, or a salt thereof,

and carbon monoxide,

in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to obtain a compound of formula (b3):

wherein the symbols are the same as defined above;

and

(ii) reacting the compound of formula (b3) with a compound of formula (b4):

wherein R b5 is an optionally substituted aryl group, or an optionally substituted alkyl group,

in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to prepare a compound of formula (b3-1):

wherein the symbols are the same as defined above.

15 . The process of claim 14 , wherein a pressure of carbon monoxide during a reaction is between 0.01 MPa to 1 MPa.

16 . The process of claim 14 , wherein a molar ratio of the compound of formula (b1) used in the reaction to the compound of formula (2) used in the reaction is between 2:1 to 1:2.

17 . The process of claim 14 , wherein the reaction is conducted in nitriles as a solvent, and between 20° C. to 150° C. as a reaction temperature.

18 . The process of claim 14 , wherein the compound of formula (b3-1) is a compound of formula (b3-2-2):

wherein:

R 1 is an optionally substituted alkyl group, a hydrogen atom, or a resin residue,

R b3 is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfoxy group, and

wherein said process comprises reacting the compound of formula (b-3-2-2) with a compound of formula (b6):

wherein:

X b1 and X b2 are each independently a hydrogen atom or an alkyl group, or alternatively, both of them bind to each other to form an alkylene group,

in the presence or absence of a base, in the presence or absence of a palladium catalyst, in a solvent or in the absence of a solvent to obtain a compound of formula (b3-2-a):

wherein the symbols are the same as defined above.

19 . The process of claim 14 , wherein the compound of formula (b3-1) is a compound of formula (b3-1-1):

wherein:

R 1-1 is an optionally substituted alkyl group or a resin residue,

R 2 is a hydrogen atom or an optionally substituted methyl group,

R 3 is a phenyl group optionally substituted with halogen atom, a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfoxy group, and

R 4 is a hydrogen atom, or alternatively

R 3 and R 4 bind to each other and combine together with the pyridine group to which they are adjacent to form an isoquinoline group optionally substituted with phenyloxy group, and

converting the compound of formula (b3-1-1) into the compound of formula (I):

wherein the symbols are the same as defined above.

20 . The process of claim 14 , wherein:

(i) R 2 is a hydrogen atom,

R 3 is a 3-chlorophenyl group, and

R 4 is a hydrogen atom, or alternatively,

(ii) R 2 is a methyl group, and

R 3 and R 4 bind to each other and combine together with a pyridine group to which they are adjacent to form a 7-phenyloxy-isoquinoline group.

21 . A process for preparing a compound of formula (bI-1):

wherein R 2 is a hydrogen atom or an optionally substituted methyl group,

R b3-3 is a 3-chlorophenyl group, a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfoxy group,

R b4-3 is a hydrogen atom, or alternatively

R b3-3 and R b4-3 bind to each other and combine together with the pyridine group to which they are adjacent to form a 7-phenyloxy-isoquinoline group,

said process comprising:

(i) reacting a compound of formula (b1-2):

wherein:

Z 1 is a chlorine atom, a bromine atom, or an iodine atom,

Z b2 is a chlorine atom, a bromine atom, or an iodine atom, and

R 2 , R b3-3 and R b4-3 are the same as defined above,

or a compound of formula (2-1):

wherein R 1-1 is an optionally substituted alkyl group or a resin residue,

or a salt thereof,

and carbon monoxide,

in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, and in a solvent or in the absence of a solvent to obtain a compound of formula (b3-4):

wherein the symbols are the same as defined above, and

(ii) reacting the compound of formula (b3-4) and a compound of formula (b4):

wherein R b5 is an optionally substituted aryl group or an optionally substituted alkyl group,

in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to obtain a compound of formula (b3-5):

wherein the symbols are the same as defined above; and

(iii) converting the compound of formula (b3-5) into a compound of formula (bI-1):

wherein the symbols are the same as defined above.

22 . A compound of formula (a1-a):

wherein:

Z 1 is a chlorine atom, a bromine atom, or an iodine atom, and

Z a2 is a hydroxy group, or a substituent represented by formula:

wherein P 1 is a protecting group for hydroxy group.

23 . A crystal of the compound of formula (a3-1-A):

which has an X-ray powder diffraction pattern comprising peaks expressed in 20 angles at 7.96, 11.82, 14.14, 15.94, 24.68, or 39.22±0.2° 2θ.

24 . A crystal of the compound of formula (a3-1-A)

which has an X-ray powder diffraction pattern comprising peaks expressed in 20 angles at 8.52, 10.78, 20.16, 22.64, 23.56, or 34.4±0.2° 2θ.

Assignments (3)
SECURITY INTEREST Recorded Jan 29, 2024
From: AKEBIA THERAPEUTICS, INC.; KERYX BIOPHARMACEUTICALS, INC.
To: KREOS CAPITAL VII (UK) LIMITED
Reel/Frame 066377/0654 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: MITSUBISHI TANABE PHARMA CORPORATION
To: AKEBIA THERAPEUTICS, INC.
Reel/Frame 060674/0065 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 13, 2022
From: FUKUHARA, KOHKI; KISHIDA, MUNEKI; MORODA, ATSUSHI; OOTSUKI, KAZUFUMI; YAGISHITA, HIROTOSHI
To: MITSUBISHI TANABE PHARMA CORPORATION
Reel/Frame 060182/0597 →
Priority Claims (1)
JP 2019-222845 · Dec 10, 2019 · national
Continuity (1)
Related Publication 20230159462A1 · May 25, 2023
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