Processes for preparing a pan-JAK inhibitor and related intermediate compounds
Inventors
Kraut, Norbert • Conza, Matteo • Huste, Anja • Lellek, Vit • Gielen, Bjorn • Pater, Christian • Filipov, Dimitar • Huang, Xiaojun • Roseblade, Stephen
Assignees
Theravance Biopharma R&d Lp LLC • Theravance Biopharma R&D IP LLC
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Publication Number
US-11739103-B2
Publication Date
2023-08-29
Expiration Date
Abstract
The present disclosure provides processes for preparing a crystalline form of 3-((1R,3s,5S)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile and related intermediate compounds.
Core Innovation
The invention provides an industrially scalable multistep process for preparing crystalline Form I of compound Formula (VIII), identified as a gut-selective pan-JAK inhibitor, wherein n is 0 or 0.5. The process converts starting compound Formula (I-B) through intermediate compounds Formula (III-B), (V-B), (VI-B), and (VII-B), followed by recrystallization. XRPD diffractograms, thermogravimetric profiles, and thermal analysis traces characterize the resulting crystalline materials. Stepwise operational details are [procedural detail omitted for safety].
The route addresses scalable synthesis requirements by avoiding chromatography and solvate-mediated recrystallization sequences. It provides intermediate yields of 88–99% and crystalline Form I yields of 89–92% with 99.9% UHPLC purity while reducing costs, byproducts, and chemical waste under sustainable conditions. Furthermore, the resulting crystalline material exhibits uniform particle size, narrow particle-size distribution, and consistent prism-to-rod morphology.
Claims Coverage
The claims define an integrated preparation process for a crystalline form of compound Formula (VIII), comprising three inventive features.
Conversion through intermediate compounds
The process converts starting compounds of Formula (I-B), Formula (II-B), and Formula (IV) through intermediate compounds of Formula (III-B), Formula (V-B), and Formula (VI-B) to prepare Formula (VII-B). Stepwise operational details are [procedural detail omitted for safety].
Recrystallization to crystalline compound Formula (VIII)
The process recrystallizes compound Formula (VII-B) to provide a crystalline form of compound Formula (VIII), wherein n is 0 or 0.5. Stepwise operational details are [procedural detail omitted for safety].
XRPD characteristics of the crystalline form
A claim specifies an XRPD diffractogram with characteristic peaks at 7.82, 12.82, 15.76, and 20.51 degrees-2-theta, each within ±0.20.
The claims cover an integrated multistep process converting starting materials through designated intermediates to yield a crystalline form of Formula (VIII) via recrystallization, alongside specific XRPD peak characteristics.
Stated Advantages
The disclosed route enables direct, scalable crystallization without chromatography or a solvate-mediated recrystallization sequence.
The route reduces cost, byproducts, and chemical waste while employing fewer steps and more sustainable conditions.
The route provides higher yields.
The resulting crystals exhibit uniform particle size, narrow particle-size distribution, and consistent prism-to-rod morphology.
Documented Applications
Preparation of a crystalline form of compound Formula (VIII), including crystalline Form I.
Drug-product manufacturing utilizing crystalline Form I.
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