Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy

View Author Information
Technical Sciences—Chemical Synthesis, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States
Cite this: Org. Process Res. Dev. 2014, 18, 1, 228–238
Publication Date (Web):August 27, 2013
Copyright © 2013 American Chemical Society

    Article Views





    Other access options
    Supporting Info (2)»


    Abstract Image

    A scalable and convergent synthesis of a BTK (Bruton’s tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, mediated by AlCl3. Improved routes to key building blocks were demonstrated by expedient multikilogram productions. The target compound was assembled through a Pd-catalyzed amidation reaction followed by a Suzuki–Miyaura cross-coupling reaction.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    Reaction conditions of the Suzuki–Miyaura coupling of aryl chloride 38 with boronate 33; and 1H and 13C NMR spectra for compounds 5, 21, 22, 24, 25, 32b, 33, 36, 37, and 1. This material is available free of charge via the Internet at

    Terms & Conditions

    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at

    Cited By

    This article is cited by 17 publications.

    1. Emily E. Freeman, Randy Jackson, Jessica Luo, Rajen Somwaru, Alex A. Sons, Andrew Bean, Ronald N. Buckle, R. Jason Herr. A Three-Step Method for the Preparation of N-Substituted 3,4-Dihydroisoquinolin-1(2H)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1H)-ones from 2-Bromobenzoate Precursors. The Journal of Organic Chemistry 2023, 88 (4) , 2589-2598.
    2. Ruili Feng, Sushil Ramchandani, Noorulameen Mohammad Salih, Xiu Yan Eleen Lim, Song Wei Benjamin Tan, Lai Yeng Lee, Soo Khean Teoh, Paul Sharratt, Kamelia Boodhoo. Process Intensification Strategies and Sustainability Analysis for Amidation Processing in the Pharmaceutical Industry. Industrial & Engineering Chemistry Research 2019, 58 (11) , 4656-4666.
    3. Feng Hu, Pradeep Nareddy, Roger Lalancette, Frank Jordan, and Michal Szostak . σ N–C Bond Difunctionalization in Bridged Twisted Amides: Sew-and-Cut Activation Approach to Functionalized Isoquinolines. Organic Letters 2017, 19 (9) , 2386-2389.
    4. Paula Ruiz-Castillo and Stephen L. Buchwald . Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chemical Reviews 2016, 116 (19) , 12564-12649.
    5. Joshua R. Dunetz, Javier Magano, and Gerald A. Weisenburger . Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Organic Process Research & Development 2016, 20 (2) , 140-177.
    6. Paul C. Lobben, Rasidul Amin, Bang-Chi Chen, Wenge Cui, Min Hu, Matthew Isherwood, Shuang Liu, Kassoum Nacro, Brandon Miles, Bingidimi Mobele, Richard E. Olson, Bei Wang, Yuh-Lin Yang, and Rulin Zhao . Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836, a Potential Therapeutic Agent for the Treatment of Depression. Organic Process Research & Development 2016, 20 (1) , 44-50.
    7. Paula Ruiz-Castillo, Donna G. Blackmond, and Stephen L. Buchwald . Rational Ligand Design for the Arylation of Hindered Primary Amines Guided by Reaction Progress Kinetic Analysis. Journal of the American Chemical Society 2015, 137 (8) , 3085-3092.
    8. Ngiap-Kie Lim, Haiming Zhang, C. Gregory Sowell, Francis Gosselin. A fit for purpose synthesis of Bruton’s tyrosine kinase inhibitor GDC-0852. Tetrahedron Letters 2020, 61 (44) , 152447.
    9. Mahesh R. Kulkarni, Nitin D. Gaikwad. Recent Advances in Synthesis of 3,4‐Dihydroisoquinolin‐1(2 H )‐one. ChemistrySelect 2020, 5 (27) , 8157-8184.
    10. Hammed Olawale Oloyede, Joseph Anthony Orighomisan Woods, Helmar Görls, Winfried Plass, Abiodun Omokehinde Eseola. N-donor-stabilized Pd(II) species supported by sulphonamide-azo ligands: Ligand architecture, solvent co-ligands, C–C coupling. Journal of Molecular Structure 2020, 1199 , 127030.
    11. S. Mikhailov, A. Sulman, V. Matveeva, V. Doluda. The Process of Catalytic Hydrocondensation of Sugars and Amines. Bulletin of Science and Practice 2019, 5 (11) , 45-49.
    12. John F. Hartwig, Kevin H. Shaughnessy, Shashank Shekhar, Rebecca A. Green. Palladium‐Catalyzed Amination of Aryl Halides. 2019, 853-958.
    13. Neha Kathewad, Anagha M. C., Nasrina Parvin, Sneha Parambath, Pattiyil Parameswaran, Shabana Khan. Facile Buchwald–Hartwig coupling of sterically encumbered substrates effected by PNP ligands. Dalton Transactions 2019, 48 (8) , 2730-2734.
    14. . Catalytic Cross‐Coupling Reactions – Nobel Prize Catalysis. 2018, 175-257.
    15. Dan Zhao, Shanshan Huang, Menghua Qu, Changyuan Wang, Zhihao Liu, Zhen Li, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma, Xiaohong Shu. Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines. European Journal of Medicinal Chemistry 2017, 126 , 444-455.
    16. . Reaction Workup. 2016, 607-768.
    17. Yan Lou, Zachary K. Sweeney, Andreas Kuglstatter, Dana Davis, David M. Goldstein, Xiaochun Han, Junbae Hong, Buelent Kocer, Rama K. Kondru, Renee Litman, Joel McIntosh, Keshab Sarma, Judy Suh, Joshua Taygerly, Timothy D. Owens. Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s Tyrosine Kinase (BTK) inhibitor scaffold. Bioorganic & Medicinal Chemistry Letters 2015, 25 (2) , 367-371.