Sahar Roshandel

Mirati Therapeutics (United States)

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G. K. Surya Prakash

Saveetha University

S. C. SURI

University of Southern California

Golam Rasul

University of Southern California

David R. Snead

Mirati Therapeutics (United States)

Cheng‐yi Chen

Mirati Therapeutics (United States)

Jacob C. Marcischak

Edwards Air Force Base

Thomas Mathew

St. John's College of Nursing

Thomas Scattolin

Mirati Therapeutics (United States)

Philip Cherian

Dasman Diabetes Institute

Charles E. McKenna

University of Southern California

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University of Southern California

Southern California University for Professional Studies

Mirati Therapeutics (United States)

BioVinc (United States)

Los Angeles City College

California State University, Long Beach

University of Rochester

Pasadena City College

University of Oxford

Edwards Air Force Base

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Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex

Organic Process Research & Development (2023)

Michał Achmatowicz Thomas Scattolin David R. Snead Dinesh J. Paymode Sahar Roshandel

MRTX1719 was identified as a potent inhibitor of the PRMT5/MTA complex, designed to selectively target MTAP-deleted cancers. A scalable synthesis of this atropisomeric compound and an efficient isolation of the desired isomer were required to support Phase 1 clinical trials, and this was established through further development of the racemic medicinal chemistry route. In the key step, the desired (M)-atropisomer of MRTX1719 was amplified from racemic API by combining crystallization (20 °C) and racemization (160 °C, 4 min). Concurrent execution of these, ostensibly incompatible, operations was enabled by a continuous flow setup (SPACE = Simultaneous Processing of Antagonistic Chemical Events) providing 98.4% e.e. of (M)-atropisomer in 75% yield from racemic API on 12 kg scale. Process development targeting earlier steps of the API synthesis led to several impactful revisions including desymmetrization of 4-chlorobenzamide to access the 6-substituted-4-(aminomethyl)phthalazin-1(2H)-one ring system, improved borylation conditions (Suzuki–Miyaura or photocatalytic), and demonstration of an economically viable route to the challenging pentasubstituted benzene from 1,4-difluorobenzene and cyclopropyl methyl ketone.

Atropisomer

Racemization

Desymmetrization

10.1021/acs.oprd.3c00072

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Calixarene‐Mediated Liquid Membrane Transport of Choline Conjugates 2: Transport of Drug‐Choline Conjugates and Neurotransmitters

European Journal of Organic Chemistry (2015)

Birendra Babu Adhikari Sahar Roshandel Ayu Fujii Michael P. Schramm

Abstract Lower rim carboxylic acid calix[ n ]arenes and upper rim phosphonic acid functionalized calix[4]arenes effect selective transport of distinct molecular payloads through a liquid membrane. The secret to this success lies in the attachment of a receptor‐complementary handle. We find that the trimethylammonium ethylene group present in choline is a general handle for the transport of drug and drug‐like species. Furthermore, neurotransmitters possessing ionizable amine termini are also transported. Some limitations to this strategy have been uncovered as payloads become increasingly lipophilic. These developments reveal new approaches to synthetic receptor‐mediated selective small molecule transport in vesicular and cellular systems.

Calixarene

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Choline

10.1002/ejoc.201403519

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Halotrimethylsilane-Nitrite/Nitrate Salts: Efficient and Versatile Reagent System for Diverse Organic Synthetic Transformations

Synlett (2019)

Thomas Mathew Laxman Gurung Sahar Roshandel Sócrates B. Munoz G. K. Surya Prakash

The reagent system comprised of halotrimethylsilane and nitrite or nitrate salts has now been successfully used as an efficient system for a series of versatile synthetic transformations. In recent years, the significance and efficacy of this system for reactions such as nitration of aromatics and olefins, oxidation of thiols to sulfonyl chlorides, ipso-nitrosation/nitration of arylboronic acids, ipso-nitration of α,β-unsaturated carboxylic acids to nitro olefins, etc. have been disclosed. Though the reagent system has not been exploited to its full potential, the reported reactions reveal its advantages as a very safe and convenient system that works under mild conditions. This brief Account reveals various synthetic applications of halotrimethylsilane-nitrite/nitrate salts in organic synthesis hitherto reported. 1 Introduction 2 Reactions Using a Halotrimethylsilane-Nitrate Salt System 2.1 Nitration of Olefins and Aromatics 2.2 One-Pot Preparation of gem-Chloronitroso, gem-Chloronitro, and vic-Dichloro Compounds 2.3 One-Step Conversion of Anilines into Haloarenes 2.4 Deoximation of Aldoximes to Aldehydes and Ketoximes to Ketones 2.5 One-Pot Synthesis of Cyclic/Noncyclic α-Nitroketones from Cyclic/Noncyclic Olefins 2.6 ipso-Nitration of Arylboronic Acids 2.7 ipso-Nitrosation of Arylboronic Acids 2.8 Oxidation of Sulfides and Sulfoxides to Sulfones 2.9 Oxidative Chlorination of Thiols and Disulfides to Sulfonyl Chlorides 2.10 α-Halogenation of Carbonyl Compounds 2.11 Decarboxylative ipso-Nitration and Dibromination of Cinnamic Acid 3 Conclusion

Nitrosation

Organic Synthesis

Sulfonyl

10.1055/s-0037-1612105

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Citations (7)