RISDIPLAM , リスジプラム « New Drug Approvals

RISDIPLAM , リスジプラム « New Drug Approvals

Taselisib

TASELISIB

SYNTHESIS........https://newdrugapprovals.org/2018/06/15/rg-7604taselisib/

CLIP

Manufacture of the PI3K β-Sparing Inhibitor Taselisib. Part 2: Development of a Highly Efficient and Regioselective Late-Stage Process

Frédéric St-Jean*† , Travis Remarchuk†, Rémy Angelaud*†, Diane E. Carrera†, Danial Beaudry†, Sushant Malhotra†, Andrew McClory†, Archana Kumar†, Gerd Ohlenbusch‡, Andreas M. Schuster‡, and Francis Gosselin†

† Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States

‡ Small Molecules Technical Development PTDC-C, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.9b00050

*E-mail: stjean.frederic@gene.com. (F.St.-J.), *E-mail: angelaud.remy@gene.com. (R.A.)

A highly efficient and regioselective manufacturing route for the phosphoinositide 3-kinase β-sparing inhibitor taselisib was developed. Highlights of the synthesis include: (1) magnesium-mediated formation of a challenging cyclic amidine; (2) regioselective imidazole construction via alkylation/condensation with bromopyruvic acid; and (3) triazole formation with 2-isopropyl acetamidrazone to generate the key bromobenzoxazepine core intermediate. Subsequent highly efficient one-pot palladium-catalyzed Miyaura borylation/Suzuki cross-coupling/saponification, followed by a 1,1′-carbonyldiimidazole-mediated coupling with ammonia, led to the pentacyclic taselisib. This new synthetic approach provides a more efficient route to taselisib with a significant decrease in process mass intensity compared to the previous early development routes to the bromobenzoxazepine core. Finally, implementation of a controlled crystallization provided the active pharmaceutical ingredient with the desired polymorphic form.

Taselisib was obtained in 90% yield (16.2 kg) as a white to off-white solid (>99.9 wt %; >99.9 A%) as Form B crystal.

mp (DSC): 257–258 °C.

HRMS (ESI-CID) m/z Calcd for [M + H]+ C24H29N8O2: 461.2408; found: 461.2409.

 1H NMR (600 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 8.37 (d, J = 8.4, 1H), 8.02 (s, 1H), 7.88 (m, 1H), 7.45 (dd, J = 8.4, 1.7 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.20 (br s, 1H), 6.84 (br s, 1 H), 5.83 (sept, J = 6.6 Hz, 1H), 4.53–4.51 (m, 2H), 4.52 (m, 2H), 2.26 (s, 3H), 1.75 (s, 6H), 1.47 (d, J = 6.7 Hz, 6H).

 13C NMR (DMSO-d6, 151 MHz) δ = 173.8, 158.3, 155.9, 147.3, 144.0, 136.6, 134.6, 130.3, 129.9, 126.4, 123.6, 120.4, 119.3, 116.2, 115.3, 68.3, 64.5, 49.9, 49.7, 25.5, 25.5, 22.3, 22.3, 13.8.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00050

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.9b00050/suppl_file/op9b00050_si_001.pdf

Ultraviolet/Visible Spectroscopy

Apparatus: Perkin Elmer, UV-6190, Lambda 25

Solvent: Acetonitrile/Water 1:1 (v/v)

  

////////////////

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

READ

ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Anthony Melvin Crasto Dr. | ResearchGate

 amcrasto@gmail.com

CALL +919323115463  INDIA

//////////////

1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic pivalic anhydride

 

1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic pivalic anhydride (10): tan solid,

mp (DSC): onset = 172.4 °C, peak temperature = 173.0 °C;

1H NMR (400 MHz, CD3CN) δ 8.23 (d, J = 7.6 Hz, 1 H), 7.35–7.25 (m, 4 H), 6.36 (d, J = 8.0 Hz, 1 H), 2.02 (s, 3 H), 1.25 (s, 9 H);

13C NMR (100 MHz, CD3CN) 175.9 (1 C), 163.6 (d, 1 C, JCF = 245.4 Hz), 162.9 (1 C ), 161.1 (1 C), 158.2 (1 C), 148.6 (1 C), 135.7 (1 C), 131.0 (d, JCF = 8.7 Hz, 2 C), 117.7 (d, JCF = 23.2 Hz, 2 C), 116.0 (1 C), 107.1 (1 C), 40.4 (1 C), 27.0 (3 C), 22.8 (1 C);

19F NMR (376 MHz, CD3CN) δ -114.2 (m, 1 F);

IR (ATR, cm-1 ) 2966 (w), 2939 (w), 2876 (w), 1789 (vs), 1697 (s), 1682 (vs), 1554 (s), 1509 (vs);

HRMS calcd for C18H18O4NFNa (M+Na+ ) = 354.1112; found 354.1113, δ = 0.3 ppm.

//////////////https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00441

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

READ

ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Anthony Melvin Crasto Dr. | ResearchGate

 amcrasto@gmail.com

CALL +919323115463  INDIA

//////////////

A multistep sequential flow synthesis of isopropyl phenol is demonstrated, involving 4-step exothermic, endothermic, and temperature sensitive reactions such as nitration, reduction, diazotization, and high temperature hydrolysis. Nitration of cumene with fuming nitric acid produces 2- and 4-nitrocumene which are converted into respective cumidines by the hydrogenation using Pd/Ni catalyst in H-cube with gravity separation. Hydrolysis of in situ generated diazonium salts in the boiling acidic conditions is carried out using integration of flow and microwave-assisted synthesis. 58% of 4-isopropyl phenol was obtained. The sequential flow synthesis can be applied to synthesize other organic compounds involving this specific sequence of reactions.

Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

Yachita Sharma, Arun V. Nikam, and Amol A. Kulkarni* 

Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00008

Yachita Sharma

 

*Phone: +91-20-25902153, E-mail: aa.kulkarni@ncl.res.in.

 

 

Amol A. Kulkarni

Dr.Amol A. Kulkarni
Chemical Engineering & Process Development
CSIR-National Chemical Laboratory

Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Yachita Sharma

CSIR - National Chemical Laboratory, Pune

Location Pune, India

Department, Chemical Engineering and Process Development Division (NCL)

Yachita Sharma is a PhD student at CSIR-National Chemical Laboratory, Pune (India). She received her MSc in Applied Organic Chemistry in 2010. Her work focuses on exploring the continuous flow synthesis involving exothermic reactions and their integration.

 

Arun Nikam

CSIR - National Chemical Laboratory, Pune

Location, Pune, India

Department, Chemical Engineering and Process Development Division (NCL)

Email: arun11nikam@gmail.com
Arun was born and raised in Koregaon, Maharashtra, India. He completed his bachelors and masters in chemical sciences from Shivaji Unversity, Kolhapur, India. Currently, He is pursuing his Ph. D. under the supervision of Dr. Amol A. Kulkarni and Dr. B. L. V. Prasad. His work mainly focuses on flow synthesis of nanoparticles, drug formulation, and polymers. He develops new synthesis procedures and translates into flow chemistry to increase productivity with excellent control over the quality of the product. He is also exploring the application of nanoparticles in catalysis, electronics and pharmaceutical fields. He specializes in microwave-assisted continuous flow synthesis of nanomaterial and organic intermediate. Apart from his research, he actively pursues Yoga and spirituality. He also likes to play volleyball and has competed in inter CSIR tournaments.

/////////isopropyl phenol, flow chem,

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

READ

ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Anthony Melvin Crasto Dr. | ResearchGate

 amcrasto@gmail.com

CALL +919323115463  INDIA

//////////////

Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

Org. Chem. Front., 2019, Advance Article
DOI: 10.1039/C8QO01274A, Research Article

Ze-lin Li, Kang-kang Sun, Chun Cai
Nickel-catalyzed regioselective C–H oxygenation reactions of chelating arenes using iodobenzene diacetate, alcohols, and benzoic acids respectively as attacking reagents have been developed for the first time.
To cite this article before page numbers are assigned, use the DOI form of citation above.

Abstract

Nickel-catalyzed regioselective C–H oxygenation reactions of chelating arenes using iodobenzene diacetate, alcohols, and benzoic acids respectively as attacking reagents have been developed for the first time. Simplicity of operation, broad range of functional group tolerance, use of cheap transition metal nickel, and avoiding extraneous directing groups are the key features, thus providing an important complement to C–H oxygenation reactions and expanding the field of nickel-catalyzed C–H functionalizations. Explorations of mechanistic details are also described.

Nickel-catalyzed regioselective C–H oxygenation: new routes for versatile C–O bond formation

Ze-lin Li,a  Kang-kang Suna  and  Chun Cai*a 

 Author affiliations

*Corresponding authors

aCollege of Chemical Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing, China
E-mail:c.cai@njust.edu.cn

https://pubs.rsc.org/en/Content/ArticleLanding/2019/QO/C8QO01274A#!divAbstract

2-(pyridin-2-yl)phenyl acetate (2a)

Formula: C13H11NO2 Mass: 213

To a mixture of 2-phenylpyridine (77.5 mg, 0.5 mmol) 1a, Ni(acac)2 (25.7 mg, 0.1 mmol, 20 mol %), ligand MePh2P (20.0 mg, 0.1 mmol, 20 mol %), and PhI(OAc)2 (483.2 mg, 0.75 mmol, 1.5 equiv) in a reaction tube was added solvent (CH3CN=2.0 mL). The reaction mixture was stirred at 115 °C for 24 h in air. Following the general procedure, 2a was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1) as a white solid (80.9 mg, 76%).

1H NMR (500 MHz, Chloroform-d) δ 8.8 – 8.7 (m, 1H), 7.8 – 7.7 (m, 2H), 7.6 (dd, J = 7.9, 1.1 Hz, 1H), 7.5 (td, J = 7.7, 1.7 Hz, 1H), 7.4 (td, J = 7.5, 1.2 Hz, 1H), 7.3 – 7.3 (m, 1H), 7.2 (dd, J = 8.0, 1.2 Hz, 1H), 2.2 (s, 3H).

13C NMR (126 MHz, Chloroform-d) δ 168.4, 154.9, 148.6, 147.1, 135.3, 132.2, 129.8, 128.7, 125.4, 122.6, 122.3, 121.2, 20.0. GC-MS (EI) m/z: 213

 

//////////