Acerta Pharma B.v.

Kingchem Llc.

Angang Wang

Katie Grace Cooper

Lucinda Victoria Jackson

Andrew John Phillips

Qiu Junying

Rustam Ferdinand Garrey

David Allen Short

Michael Joseph Lawler

Zheqing Wang

Kirsty Jane Millard

Alexander James Telford

Robert John Cox

Shaun Alan Hughes

Michael David Golden

Paul Allen Bethel

Lai Chun Chan

Jerry B Evarts

Remy E J N Litjens

Peter Johannes Servaas Savio Van Eijk

Mathilda Maria Henrica Verstappen

Eric Jurriën Zijp

Frank L M Vos

Zhenwei Li

Yongcan Wang

The present disclosure relates, in general, to improved processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)-benzamide, particularly large-scale processes for manufacturing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide and intermediates used in such processes.

Processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)-pyrrolidin-2-yljimidazo[1,5-a]-pyrazin-1-yl}n-(pyridin-2-yl)-benzamide

Processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}N-(pyridin-2-yl)-benzamide

The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-caboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using NaCOand/or KCOto promote the ring-closure reaction to produce the alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoromethyl-2-methyl-1H-pyrazole-4-caboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

Process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate and its analogs

The present disclosure provides a novel and economically advantageous process for preparation of compounds of Formula I, such as alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester. The process includes acidification of the sodium enolate of alkyl difluoroacetoacetate by carbonic acid generated in situ by reacting carbon dioxide with water. The disclosure also includes promoting the ring closure reaction in which alkyl 2-alkomethylene-4,4-difluoro-3-oxobutyrate is reacted with methylhydrazine in two phase system with a weak base such as NaCOor KCO.

Preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester

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Dalian, China

Angang Wang