Array Biopharma Inc.

Astrazeneca Ab

Loxo Oncology, Inc.

Astrazeneca Sb

Bruno P Hache

John A DeMattei

Sagar Raj Shakya

James Gair Ford

John Leonard

Matthew Charles Evans

Anthony D Piscopio

Simon Mark Pointon

Koen Peeters

Timothy John Lilley

Stacey Spencer

Derrick Juengst

Steven Wade Andrews

Yutong Jiang

Julia Haas

Mark A Reynolds

Peter J Stengel

Charles Todd Eary

Paul Nichols

Daniel John Watson

C Todd Eary

Bradley R Barnett

Simon Mark Astrazeneca Ab Pointon

Matthew Charles Pdlsw2 PR&D Office Um2 Astrazeneca Evans

John Astrazeneca Ab Leonard

James Gair Astrazeneca Ab Ford

Timothy John Astrazeneca Ab Lilley

Stacey Renee Spencer

Todd C Eary

Matthew Charles Astrazeneca Ab Evans

John Demattei

Paul J Nichols

Process for preparing (S)&#x2014;N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3-ol (formula 14). Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formula 12). Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R)-2-hydroxysuccinate (formula 10) by treating (R)&#x2014;N&#x2014;((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (formula 19) with an acid and a reducing agent. (S)&#x2014;N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing e.g. cancer. 

Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof

Provided herein are novel processes for preparing a compound of Formula (I) to the use of said compound as an intermediate in novel processes for the synthesis of indazole derivatives, and to indazole intermediates and derivatives prepared by the processes described herein. 

Intermediates for use in the preparation of indazole derivatives and processes for the preparation thereof

Provided are processes for the preparation of benzimidazole structures having Formula VIIIb-1: and salts and solvates thereof, wherein Z, X, R, Rand Rare as defined herein. Compounds of Formula VIIIb-1 are useful for the preparation of benzimidazole derivatives.

Processes for preparing benzimidazole compounds

Provided are compounds having Formula VIIIa-1: wherein Z, X, R, Rand Rare as defined herein. Compounds of Formula VIIIa-1 can be used to prepare heterocyclic derivatives such as benzimidazole derivatives.

Benzimidazole compounds

Provided are methods for the synthesis of heterocyclic compounds such as benzimidazole carboxylic acid core structures having Formula Ib-1: wherein Z, X, X, X, Rand Rare as defined herein. Compounds of Formula Ib-1 can be used to prepare heterocyclic derivatives such as benzimidazole derivatives.

Process for preparing benzimidazole compounds

Provided are methods for the synthesis of heterocyclic compounds such as benzimidazole carboxylic acid core structures having Formula Ia-2 and their synthetic intermediates: wherein X, X, X, R, Rand Rare as defined herein. Compounds of Formula Ia-2 and their synthetic intermediates can be used to prepare heterocyclic derivatives such as benzimidazole derivatives. 

SNAR process for preparing benzimidazole compounds

Provided are methods for the synthesis of heterocyclic compounds such as benzimidazole carboxylic acid core structures having Formula Ia-1 and their synthetic intermediates: wherein Z, X, X, X, Rand Rare as defined herein. Compounds of Formula Ia-1 and their synthetic intermediates can be used to prepare heterocyclic derivatives such as benzimidazole derivatives. 

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Boulder, CO, United States of America

Bruno P Hache