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US 9,174,943 B2Granted
Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds
AssigneeMedivation Prostate Therapeutics, Inc.
InventorsRajendra Parasmal Jain, Remy Angelaud, Andrew Thompson, Carol Lamberson, Scott Greenfield
Life of this patent
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Abstract
Processes are provided for the synthesis of diarylthiohydantoin and diarylhydantoin compounds. Medicinal products containing the same find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.
Claims20
A process for preparing a compound of formula (I,2-I):
- wherein:
- X is S or O;
- Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
- R1 is L1-C(═O)—NR4R5, or L1-CN;
- where L1 is a single bond or C1-C8 alkylene;
- R4 is H or C1-C8 alkyl;
- R5 is C1-C8 alkyl;
- and
- R2 is fluoro;
- said process comprising reacting the compound of formula D:
- wherein R6 is C1-C8 alkyl;
- with the compound of formula (F,2-F):
- where X is S or O,
- to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-I):
11 more elements
A process for preparing a compound of formula (I,2-I):
- wherein:
- X is S or O;
- Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
- R1 is L1-C(═O)—NR4R5, or L1-CN;
- where L1 is a single bond or C1-C8 alkylene;
- R4 and R5 are independently selected from H and C1-C8 alkyl;
- and
- R2 is hydrogen or fluoro;
- said process comprising reacting the compound of formula A:
- wherein LG is a leaving group, Br, or I;
- with the compound of formula B:
- to yield a compound of formula C:
- reacting the compound of formula C with a compound of formula R6-LG under alkylating conditions or with a compound of formula R6—OH under esterification conditions to form the compound of formula D:
- wherein R6 is C1-C8 alkyl;
- and
- reacting the compound of formula D with the compound of formula (F,2-F):
- where X is S or O,
- to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-I):
15 more elements
A process for preparing a compound of formula (I, 2-Ia):
- wherein:
- X is S or O;
- Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
- R7 is C—COOH, where L1 is a single bond or C1-C8 alkylene and
- R2 is hydrogen or fluoro;
- said process comprising reacting the compound of formula Aa:
- with the compound of formula B:
- to yield a compound of formula Ca:
- reacting the compound of formula Ca with a compound of formula R6-LG under alkylating conditions or with a compound of formula R6—OH under esterification conditions to form the compound of formula Da:
- wherein R6 is C1-C8 alkyl;
- and reacting the compound of formula Da with the compound of formula (F,2-F):
- where X is S or O, to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-Ia):
9 more elements
The process of 9, wherein Y1 and Y2 are both methyl, R7 is —C(═O)—OH, and R2 is F.
Dependencies are inferred from the claim text.