The development of two efficient strategies for the synthesis of AZD4407 is reported, both of which are considered suitable for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2-methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivatives. Reprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2-methyltetrahydropyran-4-one provides AZD4407 after acid-catalysed deprotection and epimerisation.

Routes to (2S)-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of (S)-5-hydroxyhex-1-en-3-one, derived either from an alkyl (S)-3-hydroxybutyrate or (S)-propylene oxide. Formation of the tetrahydropyran ring directly via an intramolecular oxy-Michael reaction under acid-catalysed conditions resulted in loss of optical purity, whereas proceeding through the intermediate (2S)-2-methyl-2,3-dihydropyran-4-one, via an oxidative Pd-catalysed ring closure, followed by hydrogenation of the alkenyl bond, preserved the optical purity. An alternative approach to (2S)-2-methyl-2,3-dihydropyran-4-one is also reported, again starting from an alkyl (S)-3-hydroxybutyrate by elaboration to a carbonyl-protected (6S)-6-methyl-5,6-dihydropyran-2,4-dione derivative, followed by partial reduction and dehydration. Alternatively, the carbonyl group can be reduced out completely in one step to furnish (2S)-2-methyltetrahydropyran-4-one directly after deprotection.

A process for commercial manufacture of the dual D2-β2 receptor agonist sibenadet hydrochloride has been developed. The process relies upon introduction of operationally simple chemistry at the final stages where two key intermediates are reacted to assemble the final molecule, isolated by crystallization. A nine-stage sequence for synthesis of the key amine hydrochloride intermediate was developed, and modifications to the original process are described. Major strategic improvements were made in definition of the final route to the “side chain” precursor molecule, the second key intermediate, hinging around a thiyl radical addition and subsequent high-yielding telescoped processes for synthesis of this highly crystalline benzoate ester. Development of these chemistries is discussed, together with some issues surrounding definition of the final validated commercial processes.