Processes for the preparation of a kinase inhibitor

Patent metadata

Field	Value
Publication number	US-12497367-B2
Application number	US-202117922208-A
Country	US
Kind code	B2
Filing date	Apr 30, 2021
Priority date	Apr 30, 2020
Publication date	Dec 16, 2025
Grant date	Dec 16, 2025

Abstract

The present invention relates to processes for the synthetic preparation of c-Met inhibitors of Formula I, or pharmaceutically acceptable salts thereof. The present invention further relates to processes for the synthetic preparation of the c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to processes for the synthetic preparation of Compound 1·hemifumarate. The invention further relates to large scale processes for the synthetic preparation of the c-Met inhibitor, Compound 1 and Compound 1·hemifumarate.

First claim

What is claimed is:

1 . A process for preparing a compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula II

with a compound of Formula III

in the presence of a solvent and a base, wherein
LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound;
R 1 is selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;
R 2 and R 3 are each independently selected from halo and C 1-6 alkyl;
R 4 is selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, and C 3-6 heteroaryl;
R 5a is selected from H, OH, NH 2 , C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, and C 3-6 heteroaryl, wherein the up to three methylene units of the C 1-8 alkyl are optionally and independently replaced with —O—, NR′—, —C(O)—, —C(O)O—, and —C(O)NR′—, wherein R 5a is optionally substituted with up to three substituents selected from halo, CN, NO 2 , NH 2 , SH, OR′, C(O)OR′, C(O)R′, C(O)NR′ 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and C 3-6 heteroaryl;
R 5b is H or C 1-6 alkyl; or
R 5a and R 5b together with the nitrogen to which they are attached form a C 3-6 heterocycloalkyl optionally substituted with halo, CN, OH, NO 2 , NH 2 , SH, OR′, C(O)OR′, C(O)R′, C(O)NR′ 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, or C 3-6 heteroaryl;
R 5c is H or C 1-6 alkyl optionally substituted with halo, CN, OH, NH 2 , or OR′;
R′ is H or C 1-6 alkyl, and
w, x, y, and z are each independently an integer from 0 to 4;
and wherein the process optionally further comprises contacting the compound of Formula I with an acid to produce a pharmaceutically acceptable salt of the compound of Formula I.

2 . The process of claim 1 , wherein the base is an inorganic base selected from NaOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , and KHCO 3 , and the solvent is a mixture of water and an organic solvent selected from acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene glycol, furfuryl alcohol, glycerol, methanol, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propylene glycol, tetrahydrofuran, and triethylene glycol.

3 . The process of claim 2 , wherein the solvent is a mixture of water and tetrahydrofuran which is from approximately 2:1 tetrahydrofuran:water to approximately 3:1 tetrahydrofuran:water.

4 . The process of claim 1 , wherein contacting a compound of Formula II with a compound of Formula III comprises adding a solution of the compound of Formula III dissolved in a first solvent to a solution of the compound of Formula II dissolved in a second solvent to create a reaction mixture, wherein the first solvent is tetrahydrofuran and the second solvent is approximately 2:1 tetrahydrofuran:water.

5 . The process of claim/0, wherein the reaction mixture is maintained at a temperature at approximately 20 to 25° C., and then heated to 35-40° C. and let stand to separate to an organic phase and an aqueous phase, followed by discarding the aqueous phase, heating the organic phase to 55-60° C., and then filtering the organic phase at 55-60° C.

6 . The process of claim 1 , further comprising reacting a compound of Formula IV

with a reagent selected from thionyl chloride and oxalyl chloride to produce the compound of Formula III

wherein LG is Cl.

7 . The process of claim 6 , wherein the reagent is oxalyl chloride and reacting the compound of Formula IV with the reagent is performed in the presence of a catalytic amount of dimethylformamide and tetrahydrofuran at a temperature between 5° C. and 15° C.

8 . The process of claim 1 , further comprising reacting a compound of Formula V

with a compound of Formula VI

to provide the compound of Formula II

wherein LG′ is selected from F, Cl, Br, I,

and —N 2 + .

9 . The process of claim 8 , wherein reacting a compound of Formula V with a compound of Formula VI is performed in the presence of a solvent and a base, wherein the solvent is an organic solvent selected from acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamde (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane, and the base is selected from n-BuLi, lithium diisopropyl amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydroxide, sodium methoxide, sodium t-butoxide, sodium t-pentoxide, lithium hydroxide, lithium methoxide, lithium t-butoxide, lithium t-pentoxide, potassium hydroxide, potassium methoxide, potassium t-butoxide, potassium t-pentoxide, cesium hydroxide, cesium methoxide, cesium t-butoxide, and cesium t-pentoxide.

10 . The process of claim 8 , wherein LG′ is selected from F, Cl, Br, and

w is 0;
x is 0;
y is 0;
z is 0;
R 5a is methyl;
R 5b is H; and
R 5c is methyl.

11 . A process for preparing Compound 1

or a pharmaceutically acceptable salt thereof, comprising contacting Compound 4

with a compound of Formula III′

in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound, and wherein the process optionally further comprises contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt of Compound 1.

12 . The process of claim 11 , wherein the base is an inorganic base selected from NaOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , and KHCO 3 , and the solvent is a mixture of water and an organic solvent selected from acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene glycol, furfuryl alcohol, glycerol, methanol, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propylene glycol, tetrahydrofuran, and triethylene glycol.

13 . The process of claim 11 , wherein the solvent is a mixture of water and tetrahydrofuran which is from approximately 2:1 tetrahydrofuran:water to approxima

Assignees

• Exelixis Inc

Inventors

• Demorin Frenel
• Shah Khalid
• Shakya Sagar
• Wang Yong
• Xu Wei

Classifications

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07D215/48 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D215/20 Primary

  Oxygen atoms · CPC title