5,6-dihydro-4H-benzo[b]thieno-[2,3-d]azepine derivative
Inventors
Hunt, Simon Fraser • Onions, Stuart Thomas • Sherbukhin, Vladimir • FORDYCE, EUAN ALEXANDER FRASER • Murray, Peter John • BROOKES, Daniel William • Ito, Kazuhiro • Strong, Peter • COATES, Matthew Stephen
Assignees
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Publication Number
US-10472375-B2
Publication Date
2019-11-12
Expiration Date
Abstract
There is provided a 5,6-dihydro-4H-benzo[b]thieno-[2,3-d]azepine derivative which is useful in the treatment of respiratory syncytial virus (RSV) infection and for the prevention of disease associated with RSV infection. (Formula (I)).
Core Innovation
The disclosure relates to processes for the preparation of substituted benzo[b]thieno[2,3-d]azepine derivatives, including a compound of formula (IV) or a salt thereof and related intermediates. A compound of formula (VII) or a salt thereof is reacted with 2-fluoro-6-methylaniline or a salt thereof, followed by reduction of the nitro group. The sequences link formation of an aminobenzoyl intermediate from a nitrobenzoyl-containing precursor with subsequent conversion of the nitro group to an amine.
In the described synthetic sequence, a 6-(4-nitrobenzoyl)-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxylic acid is converted to the corresponding acid chloride and coupled with 2-fluoro-6-methylaniline using pyridine to give 6-(4-nitrobenzoyl)-N-(2-fluoro-6-methylphenyl)-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide. The nitro group is then reduced to an aminobenzoyl intermediate, and further acylation is carried out to higher analogs within the overall series.
The disclosure further describes formation of a spirocyclic nicotinamide-containing Compound (I) by reacting with 7-oxa-2-azaspiro[3.5]nonane hemi oxalate in the presence of potassium carbonate in NMP. The document presents multiple upstream routes for reaching key intermediates, including chlorination/condensation steps that use acid chlorides and amide coupling intermediates, and includes scale-up preparation and analytical characterization using RP-HPLC and NMR.
Claims Coverage
The provided independent claims cover two process families. Across these independent claims, there are three inventive features: the core substrate-to-substrate reaction pairing for formula (IV), the reduction of the nitro group, and the separate preparation of formula (X) from formula (IX) and formula (V).
Preparing a formula (IV) compound by reacting formula (VII) with 2-fluoro-6-methylaniline then reducing a nitro group
A process for the preparation of a compound of formula (IV) or a salt thereof, comprising reacting a compound of formula (VII) or a salt thereof with 2-fluoro-6-methylaniline or a salt thereof, followed by reduction of the nitro group.
Dissolving metal reduction of the nitro group
The process where the reduction of the nitro group is performed as a dissolving metal reduction.
Catalytic hydrogenation reduction of the nitro group
The process where the reduction of the nitro group is carried out as a catalytic hydrogenation reaction.
Reacting formula (IX) with formula (V) to prepare formula (X)
A process for the preparation of a compound of formula (X) or a salt thereof by reacting a compound of formula (IX) where Ra is lower alkyl or a salt thereof with a compound of formula (V) or a salt thereof.
Across the independent claims, the document’s claim coverage centers on preparing formula (IV) by reacting formula (VII) with 2-fluoro-6-methylaniline followed by nitro-group reduction, with the reduction specified as dissolving metal reduction or catalytic hydrogenation, and on preparing formula (X) by reacting formula (IX) with formula (V).
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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