Hoffmann-la Roche Inc.

Genentech, Inc.

F. Hoffmann-la Roche Ag

Stephan Bachmann

Francis Gosselin

Haiming Zhang

Ngiap-Kie Lim

Stefan Hildbrand

Alec Fettes

Sushant Malhotra

Qingping Tian

Serena Maria Fantasia

Stefan Koenig

Theresa Cravillion

Danial Beaudry

Chong Han

Rene Trussardi

Christophe Pfleger

Xin Linghu

Roland Meier

Michael Jansen

Jie Xu

Andreas Zogg

Nicholas Andrew White

Kyle Bradley Pascual Clagg

Bernd Kuhn

Juergen Wichmann

Thomas Johannes Woltering

Yimin Qian

Patrick Schnider

Jens-Uwe Peters

Michelangelo Scalone

Alexander Flohr

Katrin Groebke Zbinden

Shawn David Erickson

Markus Rudolph

Matthias Koerner

Matthias Beller

Kurt Puentener

Alexander Gmehling

Jacob C Timmerman

Nathaniel L Segraves

Sebastian Rieth

Etienne Trachsel

Jeff Shen

Lauren Elizabeth Sirois

Ugo Jonathan Orcel

James Jappy

Dinesh Maganbhai Patel

Robert John Ernest Tidswell

Paul Spurr

Scott J Savage

Ursula Hoffmann

Jason Yang

Pingsheng Zhang

Andrew McClory

Amit Srivastava

Sean M Kelly

Miall Cedilote

Kathrin Junge

Sebastian Herold

Pankaj Rege

Michael Dalziel

Andreas Stumpf

Zhiming Dong

Doreen Miller

Johannes Adrian Burkhard

Theresa Humphries

Christian Moessner

Jodie Brice

Yonghui Ge

Antonio Giovanni Dipasquale

Rene Lebl

Joerg Sedelmeier

Thomas Michael Bass

Dainis Kaldre

Christian Oliver Kappe

Christian Leitner

Ngiap Kie Lim

Eduardo V Mercado-marin

Daniel Zell

Diane E Carrera

Raphael Bigler

Laure Elizabeth Simone Finet

Regis Jean Georges Mondiere

Lukas Chytil

Yuki Nakagawa

Jie Zhang

Christian Jenny

Daniel Bailey

Marcel Garbe

Dramane Ibrahim Laine

Jason Douglas Williams

Paolo Tosatti

Provided herein are methods of synthesizing quinazoline compounds comprising at least one atropisomeric center.

Synthesis of quinazoline compounds

Methods for preparing the Bruton's Tyrosine Kinase ('BTK') inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided.

Process for preparing BTK inhibitors

Provided herein are methods to synthesize compounds useful in the treatment of cancer where such compounds comprise a quinazolinyl core moiety and at least one stereoisomeric or atropisomeric moiety.

Process for synthesis of quinazoline compounds

A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N',N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Synthesis of a bis-mesylate salt of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and intermediates thereto

Methods for preparing the Bruton's Tyrosine Kinase ('BTK') inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4&#x2032;]bipyridinyl-2&#x2032;-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided. Methods for preparing tricyclic lactam compounds are also provided.

The invention comprises novel chiral metal complex compounds of the formula  wherein M, PR, Rand Rare outlined in the description, its stereoisomers, in the form as a neutral complex or a complex cation with a suitable counter ion. The chiral metal complex compounds can be used in asymmetric reactions, particularly in asymmetric reductions of ketones, imines or oximes.

Chiral metal complex compounds

Processes are described for the preparation of F-benzoxazinorifamycin I: and intermediates for conjugation with an antibody.

Process for the preparation of an antibody-rifamycin conjugate

Processes are described for the preparation of estrogen receptor modulating compound, (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid I: 

Process for the preparation of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid

The present invention provides methods for preparing 5-[2-[7-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]ethynyl]-2-pyridinamine (compound A), which is useful for the treatment of depression and other CNS disorders. The present methods are useful for preparing compound A on large scale in manufacturing facilities. 

Methods for the preparation of 5-[2-[7 (trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo [1,5-A]pyrimidin-3-yl[ethynyl]-2-pyridinamine

The invention is concerned with a compound of formula (I) wherein R1, R2, R2', R3, R3&#x2032; are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Imidazopyridine derivatives

The present invention relates to compounds of formula (I) wherein R, R, R, R, W, X, X, Y, Y, Z and Zare as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit PDE10A and can be used in the treatment of CNS disorders such as schizophrenia, Alzheimer's disease, and Parkinson's disease.

PDE10 modulators

The present invention comprises a process for the preparation of 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid of the formula or of a salt thereof 3-Chloro-2-fluoro-5-trifluoromethyl benzoic acid or salts thereof are versatile intermediates for the preparation of active pharmaceutical or agrochemical agents.

Process for the preparation of halogenated benzoic acid derivatives

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Basel, Switzerland

Stephan Bachmann