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US 12,729,191 B2Granted
Production method for synthetic intermediate of monocyclic pyridine derivative
AssigneeEisai R&D Management Co., Ltd.
InventorsMitsuo Nagai, Takashi Fukuyama, Yasuaki Kamada, Jun Niijima, Hirofumi Kuroda, Yuki Karoji, Keiichi Murakami, Masayuki Omori, Yusuke Miyashita, Atsushi Kamada, Masaaki Matsuda
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Abstract
The invention provides a production process allowing more high-yield and efficient synthesis of key intermediates (compound (2i) or a salt thereof, and compound (1g)) for production of E7090, which is useful as an FGFR inhibitor.
Claims7
A process for producing compound (2i):
- or a salt thereof, wherein the process comprises:
- 2-a) step 2-a) in which a protecting group is introduced into compound (1g):
- to produce compound (2a):
- (where PG1 represents a nitrogen protecting group),
- 2-b) step 2-b) in which compound (2a) obtained in step 2-a) and compound (2b):
- (where X1 represents a leaving group),
- are reacted in the presence of a base to produce compound (2c):
- (where PG1 represents the same group as specified above),
- 2-c) step 2-c) in which compound (2c) obtained in step 2-b) and compound (2d):
- R1—NH2 (2d)
- (where R1 represents a tert-pentyl, tert-butyl, tert-octyl or cumyl group),
- are reacted in the presence of an activating agent to produce compound (2e):
- (where PG1 and R1 represent the same groups as specified above),
- 2-d) step 2-d) in which PG1 in compound (2e) obtained in step 2-c) is removed to produce compound (2f):
- (where R1 represents the same group as specified above),
- 2-e) step 2-e) in which compound (2f) obtained in step 2-d) and compound (2g-1) or compound (2g-2):
- (where R2 of formula (2g-1) is a C1-6 alkyl group or C6-10 aryl group, the C1-6 alkyl group optionally having 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and methoxy groups, and the C6-10 aryl group optionally having 1 to 3 identical or different substituents selected from halogen atoms and methyl, methoxy and nitro groups, and X2 of formula (2g-2) represents a halogen atom),
- are reacted in the presence of a base to produce compound (2h):
- (where R1 represents the same group as specified above), and
- 2-f) step 2-f) in which R1 of compound (2h) obtained in step 2-e) is removed to produce compound (2i):
- and if necessary step 2-g) in which compound (2i) obtained in step 2-f) is converted to a salt.
18 more elements
A process for producing compound (1g):
- wherein the process comprises:
- 1-a) step 1-a) in which 1,2-(methylenedioxy)-4-nitrobenzene and 4-bromobenzyl alcohol are reacted in the presence of a base to produce compound (1c):
- 1-b) step 1-b) in which compound (1c) obtained in step 1-a) and a methoxyethylating agent are reacted in the presence of a base to produce compound (1d):
- 1-c) step 1-c) in which compound (1d) obtained in step 1-b) and a cyanomethylating agent are reacted in the presence of a base to produce compound (1f):
- and
- 1-d) step 1-d) in which compound (1g):
- is produced by conversion of the nitro group of compound (11) obtained in step 1-c) to an amino group, removal of the 4-bromobenzyl group, and ring closure with an acid catalyst.
4 more elements
Dependencies are inferred from the claim text.