Process for Preparing Heterocyclic Methanone Compounds and AZA-Bicyclo Intermediates Thereof
AssigneeActinogen Medical Limited
InventorChristian GRUGEL
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Abstract
The present disclosure relates to a process for synthesis of heterocyclic methanone compounds, and in particular 3′-substituted, 3-hydroxyl-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds, and aza-bicyclo intermediates thereof. In particular, the present disclosure also relates to a process for the synthesis of Xanamem. The present disclosure also relates to a process for the synthesis of optionally protected aza-bicyclo intermediate compounds. The present disclosure also relates to 3′-substituted, 3-hydroxyl-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds and aza-bicyclo intermediate compounds thereof.
Claims28
A process for preparing an aza-bicyclic compound of Formula 4:
- comprising a Grignard reaction of a nortropinone compound of Formula 5:
- with a halogenated compound of Formula 6:
- X—R1 Formula 6;
- wherein
- R1 is selected from a carbocyclyl or heterocyclyl, wherein each carbocyclyl and heterocyclyl is a monocyclic or bicyclic group each unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OH, —C1-6alkyl, —O—C1-6alkyl, —C1-6haloalkyl, —O—C1-6haloalkyl, —CN, —NR3R4, —COR3, —CO2R3, and each R3 and R4 are independently selected from the group consisting of hydrogen and —C1-6alkyl;
- R2 is an amine protecting group;
- and
- X is a halogen.
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A process for preparing a heterocyclic methanone compound of Formula 1:
- comprising reacting a carboxylic acid compound of Formula 2 or a salt thereof:
- with an amine bicyclic compound of Formula 3 or a salt thereof, in the presence of at least one coupling reagent selected from an oxime coupling reagent and a carbodiimide coupling reagent:
- wherein
- R1 is selected from a carbocyclyl or heterocyclyl, wherein each carbocyclyl and heterocyclyl is a monocyclic or bicyclic group each unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OH, —C1-6alkyl, —O—C1-6alkyl, C1-6haloalkyl, —O—C1-6haloalkyl, —CN, —NR3R4, —COR3, —CO2R3, and each R3 and R4 are independently selected from the group consisting of hydrogen and C1-6alkyl;
- R5 is hydrogen or an amine protecting group.
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A composition comprising a compound of Formula 1a:
- wherein any impurities, if present, are in an amount (by weight % of the total composition) of less than about 1 wt %.
Dependencies are inferred from the claim text.