Stereoselective process for preparing substituted polycyclic pyridone
Inventors
Okamoto, Kazuya • Ueno, Tatsuhiko • Hato, Yoshio • Hakogi, Toshikazu • MAJIMA, Shohei
Assignees
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Publication Number
US-12612415-B2
Publication Date
2026-04-28
Expiration Date
Abstract
The present invention provides industrially suitable processes for preparing intermediates in the production of substituted polycyclic pyridone derivatives having a cap-dependent endonuclease inhibitory activity. In the process as shown below, wherein each symbol is as defined in the specification, an optically active substituted tricyclic pyridone derivative of the formula (VII) is obtained in high yield and high enantioselectivity by subjecting a compound of the formula (III) or (VI) to intramolecular cyclization with controlling stereochemistry to obtain a compound of the formula (IV) having a removable functional group on an asymmetric carbon, and then removing the functional group thereof;
Core Innovation
The patent provides a stereoselective, industrially suitable synthetic strategy to prepare optically active substituted polycyclic pyridone derivatives. It describes intramolecular cyclization of a compound of formula (III) or (VI) with stereochemical control, using stereochemical and structural definitions for a removable functional group on an asymmetric carbon and defined substituent groups and protecting groups.
The strategy forms a compound of formula (IV) bearing a removable functional group on an asymmetric carbon, and the removable functional group is removed to obtain the optically active compound of formula (VII). The disclosure also relates to compounds of formula (III) or pharmaceutically acceptable salts thereof and to a process for preparing the compounds by reacting a compound of formula (Ia) with a compound of formula (II).
The disclosed subject matter concerns cap-dependent endonuclease inhibitory substituted polycyclic pyridone derivatives and intermediates. The structural selection of R1, R2, R7, RA1/RA2/RA3, X, RA, R8, and R4 is defined by specific restrictions, including conditional relationships among RA1, RA2, and RA3 and allowed values of X.
Claims Coverage
The independent claim set covers a process for preparing a compound of formula (III) or a salt thereof and the compound of formula (III) or a salt itself. The inventive features are defined by constrained substituent patterns, conditional relationships among RA1, RA2, and RA3, allowed values of X, and defined R8 and R4 substituents; additional claim language also refers to intramolecular cyclization and stereochemical control.
Reacting Ia with II to form formula (III)
A process prepares a compound of formula (III) or a salt thereof by reacting a compound of formula (Ia) with a compound of formula (II).
Restricted substituents on Ia and II
On (Ia), R1 is hydrogen or a protecting group for hydroxyl group, R7 is NH2 or NHR2, and R2 is a protecting group for amino group; on (II), RA1, RA2, and RA3 are each hydrogen or RA, with X being O, CH2, or CHRA.
Conditional RA assignment and X restriction
One of RA1, RA2, and RA3 is RA and the other two are hydrogen, with X being O or CH2; alternatively RA1, RA2, and RA3 are hydrogen and X is CHRA.
Formyl and ketal-related R8 and acid-deprotectable R4
R8 is —CHO or —CH(OR4)(OR4), and each R4 is hydrogen or a protecting group deprotectable by an acid, with two R4 optionally taken together to form a ring.
Compound of formula (III) with constrained substituents
A compound of formula (III) or a salt thereof is defined by the same substituent restrictions, including the conditional RA1/RA2/RA3 patterns, the allowed values of X, and the specified forms of R8 and R4.
The claims center on a constrained formula (III) structure and a corresponding preparation process. The main inventive features are the reaction of specific intermediates, conditional selection among RA1/RA2/RA3, the permitted X values tied to that condition, and the defined R8 and acid-deprotectable or ring-forming R4 substituents.
Stated Advantages
Efficient, selective production with high optical purity is mentioned.
The strategy is presented as stereoselective and industrially suitable.
The described scheme is presented as an alternative to existing routes.
Prior art routes are stated to form racemic/enantiomer mixtures and may involve resolution inefficiencies.
Optically active products with high diastereoselectivity.
Documented Applications
Production of polycyclic pyridone derivatives via intramolecular cyclization.
Preparation of compounds of formula (III) or salts through reacting compounds of formula (Ia) and formula (II).
Preparation of an optically active tricyclic pyridone derivative (VII) associated with cap-dependent endonuclease inhibitory activity.
Cap-dependent endonuclease inhibitory substituted polycyclic pyridone derivatives and intermediates.
Doltegravir synthetic routes are discussed in the background.
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