US 11,739,103 B2
Processes for preparing a pan-JAK inhibitor and related intermediate compounds
Norbert Kraut, Singen (DE); Matteo Conza, Thayngen (CH); Anja Huste, Büsingen (DE); Vit Lellek, Eglisau (CH); Bjorn Gielen, Limgburg (BE); Christian Pater, Mühlhausen-Ehingen (DE); Dimitar Filipov, San Francisco, CA (US); Xiaojun Huang, San Jose, CA (US); and Stephen Roseblade, Cambridge (GB)
Assigned to Theravance Biopharma R&D LP, LLC, South San Francisco, CA (US)
Filed by THERAVANCE BIOPHARMA R&D IP, LLC, South San Francisco, CA (US)
Filed on Oct. 7, 2021, as Appl. No. 17/450,199.
Claims priority of provisional application 63/089,919, filed on Oct. 9, 2020.
Prior Publication US 2022/0112219 A1, Apr. 14, 2022
Int. Cl. C07D 519/00 (2006.01); B01J 31/18 (2006.01); B01J 31/22 (2006.01)
CPC C07D 519/00 (2013.01) [B01J 31/1805 (2013.01); B01J 31/1845 (2013.01); B01J 31/2226 (2013.01); B01J 31/2252 (2013.01); B01J 31/2295 (2013.01); B01J 2531/824 (2013.01)] 13 Claims
 
1. A process of preparing a crystalline form of a compound of Formula (VIII):

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comprising:
(A) combining a compound of Formula (I-B):

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with a compound of Formula (II-B):

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and a first non-nucleophilic base in a first solvent to provide a compound of Formula (III-B):

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(B) combining the compound of Formula (III-B) with a compound of Formula (IV):

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a second non-nucleophilic base, and a palladium catalyst in 1-propanol to provide a compound of Formula (V-B):

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(C) combining the compound of Formula (V-B) with hydrochloric acid and a palladium scavenger in a second solvent comprising water to provide a compound of Formula (VI-B):

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(D) combining the compound of Formula (VI-B) with 3-bromopropionitrile and a third non-nucleophilic base in 1-butanol to provide a compound of Formula (VII-B):

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and (E) recrystallizing the compound of Formula (VII-B) in a third solvent and acetonitrile to provide the crystalline form of the compound of Formula (VIII);
wherein n is 0 or 0.5.