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US 2025/0304556 A1Published application
Processes for preparation of prmt5 inhibitors and intermediates for making the same
AssigneeMirati Therapeutics, Inc.
InventorsMICHAL ACHMATOWICZ, JOSEPH LIZZA, GUIHUI CHEN, HONGLIANG CHEN
Life of this patent
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Abstract
Disclosed are processes for preparation of Protein Arginine N-Methyl Transferase 5 (PRMT5) Inhibitors and intermediates for making the same.
Claims118
A process for preparing a compound of Formula (I)
- wherein:
- R1 is halogen, an aryl group, or a heteroaryl group;
- each of R2 and R3 is independently halogen;
- and
- R4 is halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo C1-C6 alkyl, or OR5, wherein R5 is C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl,
- the process comprising treating a compound of Formula (IA)
- with an electrophile which is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound,
- wherein:
- M represents a divalent metal of a divalent metal base;
- and
- X1 represents a counterion of the divalent metal base.
8 more elements
A process for preparing a compound of Formula (II)
- wherein:
- each of R2, R3, and R11 is independently halogen;
- R4 is halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo C1-C6 alkyl, or OR5, wherein R5 is C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;
- R9 is C1-C6 alkyl, C3-C6 cycloalkyl, or halo C1-C6 alkyl;
- and
- R10 is hydrogen,
- the process comprising:
- (a) reacting a compound of Formula (I)
- with an amine to provide a compound of Formula (IIA)
- wherein R1 is halogen, an aryl group, or a heteroaryl group;
- (b) dehydrating the compound of Formula (IIA) to provide a compound of Formula (IIB)
- (c) coupling the compound of Formula (IIB) with an organoboron compound or an organozinc compound to provide a compound of Formula (IIC)
- and
- (d) halogenating the compound of Formula (IIC) to provide the compound of Formula (II).
11 more elements
A process for preparing a compound of Formula (III)
- the process comprising:
- (a) treating 4-chloro-2,5-difluorobenzoic acid with a divalent metal base to provide a mixture;
- (b) treating the mixture with iodine to provide 4-chloro-3,6-difluoro-2-iodobenzoic acid;
- (c) reacting the 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to provide 4-chloro-3,6-difluoro-2-iodobenzamide;
- (d) dehydrating the 4-chloro-3,6-difluoro-2-iodobenzamide to provide 4-chloro-3,6-difluoro-2-iodobenzonitrile;
- (e) coupling the 4-chloro-3,6-difluoro-2-iodobenzonitrile with an organoboron compound or an organozinc compound to provide 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile;
- (f) iodinating the 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile to provide 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile;
- and
- (g) reacting the 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile with cyclopropanol to provide 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile.
6 more elements
A compound of Formula (IV)
- wherein:
- R1 is iodo, an aryl group, or a heteroaryl group;
- R3 is bromo or chloro;
- and
- R12 is-OR13 or —NR14R15, wherein each of R13, R14, and R15 is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.
2 more elements
A composition comprising a mixture of 4-chloro-2,5-difluorobenzoic acid and 4-chloro-3,6-difluoro-2-iodobenzoic acid.
Dependencies are inferred from the claim text.