Process for preparing spiro derivatives
Inventors
Giblin, Gerard M. • MacPherson, David T. • Suleiman, Osama • Williams, Michael • Witty, David R. • Bonnaud, Thierry • Edwards, Richard
Assignees
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Publication Number
US-11149039-B2
Publication Date
2021-10-19
Expiration Date
Abstract
The invention relates to a novel process for preparing Spiro derivatives, in particular 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one, and to novel intermediates for use in said process along with processes for preparing said intermediates.
Core Innovation
The invention concerns a synthetic sequence converting 1-methylpyrrolidin-2-one through intermediates D2, D3, D4, D5, D6, D7, D9, and D10 to compound(s) of formula (I). The sequence is described in terms of defined intermediates and intermediate sequences that connect starting materials to the final compound of formula I, including a spirocyclic diazaspiro[4.4]nonan-6-one bearing a substituted pyrimidine/aryl system.
A key intermediate is compound D6, identified as (S)-1-methyl-2-oxo-3-(prop-2-yn-1-yl)pyrrolidine-3-carboxylic acid. D6 is prepared from D5, identified as the (S)-phenylglycinol salt, by eluting a solution comprising D5 through a resin. The document also describes D6 and related intermediates as precursors to a key carbamate intermediate used toward formula I.
The patent further states that formula (I) is present as various salts, including hydrochloride, sulfuric acid salt, sulfuric acid salt hydrate, citric acid salt, and methanesulfonic acid (mesylate). Embodiments are also described for forming downstream intermediates and for later coupling, reduction, and formulation stages.
Claims Coverage
The provided claims include two independent claims. Across the independent claims, there are two core inventive features: resin elution preparation of D6 from D5 and direct claiming of the chemical identity of D6.
Resin elution preparation of D6 from D5
A process of preparing the compound of D6 from a compound which is (S)-1-methyl-2-oxo-3-(prop-2-yn-1-yl)pyrrolidine-3-carboxylic acid (S)-phenylglycinol salt (D5), comprising eluting a solution comprising the compound of D5 through a resin.
Compound D6 identity
A compound which is (S)-1-methyl-2-oxo-3-(prop-2-yn-1-yl)pyrrolidine-3-carboxylic acid (D6).
The claim coverage focuses on obtaining D6 from D5 by resin elution and on claiming D6 as a specific compound.
Stated Advantages
Fewer stages than prior routes.
Cheaper starting materials.
Avoidance of burdensome chromatography.
Increased purity via recrystallization.
High chiral purity/purity metrics are reported.
Documented Applications
Precursor utility: D6/D5/D7 are described as precursors to a key carbamate intermediate used toward formula I.
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