Substituted heterocycle fused gamma-carbolines synthesis
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Publication Number
US-12297200-B2
Publication Date
2025-05-13
Expiration Date
Abstract
The present invention provides improved methods for the preparation of substituted heterocycle fused gamma-carbolines, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines.
Core Innovation
The document describes a method for preparing a compound of Formula 1J in free or salt form, where R is H and Q is 3-(4-fluorophenoxy) propyl, from a compound of Formula 1E′ in free or salt form with a protecting group B of the formula P-Z. The method reacts Formula 1E′ with an alkyl haloacetate of the formula XCH2C(O)OR′ in the presence of a base, and optionally an alkali metal or ammonium iodide or bromide, to form Formula 1F.
The piperidine nitrogen of Formula 1F is deprotected to yield Formula 1I, and Formula 1I is then alkylated with an alkylating agent of general formula Q-X to yield Formula 1J. The document further states that Formula 1J can be converted to an acid addition salt form, and refers to substituted heterocycle-fused gamma-carbolines, stereochemical definitions, and free form versus acid addition salt form.
The document also describes impurity control and purification aspects, including copper contamination, telescoping of steps without isolation or purification, and enantiomeric enrichment for intermediates such as 1B/2B. It further mentions impurity profiling, residual solvent impurity limits, and characterization support including HPLC, MS/NMR, XRPD, and NMR.
Claims Coverage
The provided content includes two independent claims: a method claim for preparing Formula 1J and an active pharmaceutical composition claim. The inventive features center on a defined stepwise preparation sequence from Formula 1E′ to Formula 1J and on a composition of Formula 1J with explicit purity and impurity limits.
Stepwise preparation of Formula 1J through Formula 1F and Formula 1I
A method for preparing a compound of Formula 1J in free or salt form, wherein R is H and Q is 3-(4-fluorophenoxy)propyl, comprising reacting Formula 1E′ with an alkyl haloacetate of the formula XCH2C(O)OR′ in the presence of a base and optionally an alkali metal or ammonium iodide or bromide to form Formula 1F, deprotecting the piperidine nitrogen to yield Formula 1I, and alkylating the piperidine nitrogen of Formula 1I with an alkylating agent of general formula Q-X, optionally converting the free form to an acid addition salt form.
High-purity Formula 1J active pharmaceutical composition with impurity limits
An active pharmaceutical composition comprising Formula 1J in free or salt form, wherein R is H and Q is 3-(4-fluorophenoxy)propyl, having at least 97% purity, not more than 50 ppm of copper, and not more than 0.08% w/w of 1-(3-chloropropoxy)-4-fluorobenzene.
Claim coverage centers on a defined sequence for preparing Formula 1J and on an active pharmaceutical composition containing Formula 1J with explicit purity, copper, and impurity thresholds.
Stated Advantages
Controls copper content to not more than 50 ppm.
Provides a method to prepare a compound of Formula 1J in free or salt form using defined intermediates.
Provides an active pharmaceutical composition with at least 97% purity.
Controls 1-(3-chloropropoxy)-4-fluorobenzene to not more than 0.08% w/w.
Documented Applications
Production of a compound of Formula 1J in free or acid addition salt form.
An active pharmaceutical composition comprising the compound of Formula 1J in free or salt form, where R is H and Q is 3-(4-fluorophenoxy) propyl.
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