A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities

Synthesis of 2-Trifluoromethyl-4-fluorophenylboronic acid (2a)
2a: 2-Trifluoromethyl-4-fluorophenylboronic acid After reaching steady-state, the outcoming stream was quenched for 25 min (765 mmol) on 797 mL citric acid (10% in water) at 0 °C. After full addition, the mixture was stirred for 30 min at 0 °C and then warmed up to r.t. and stirred for another hour. The phases were separated and the water phase was extracted twice with 1.8 L isopropyl acetate. The organic phases were combined, washed with 20% NaClsolution (1.8 L) and dried in vacuum to yield the final product. The product was obtained as a slightly yellow solid. 146.1 g (HPLC purity at 210 nm = 97.4%). Yield = 89%.

1H NMR (400 MHz, DMSO-d6): δ = 8.00 (dd, J = 8.3, 6.6 Hz, 1H, Ar-H), 7.52 (dd, J = 9.9, 2.5 Hz, 1H, Ar-H), 7.55−7.45 (m, 1H, Ar-H) ppm.

13C NMR (100 MHz, DMSO-d6): δ = 162.6 (d, J = 247.0 Hz, CF), 138.1 (d, J = 7.9 Hz), 134.8 (dq, J = 31.6, 7.7 Hz), 133.8, 124.5 (dq, J = 274.8, 3.00 Hz, CF3), 118.4 (d, J = 19.2 Hz), 113.3 (dq, J = 24.2, 6.1 Hz) ppm.

 19F NMR (376 MHz, DMSO-d6): δ = −57.8 (s, 3F, CF3), −111.2 (s, 1F, CF) ppm. 11B-NMR (128 MHz, DMSO-d6): δ = 13.8 ppm. Analytical data is identical with the literature.1 [1] A. Hafner, M. Meisenbach, J. Sedelmeier, Org. Lett. 2016, 18, 3630-3633.

A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities Andreas Hafner, Paolo Filipponi, Lorenzo Piccioni, Mark Meisenbach, Berthold Schenkel, Francesco Venturoni and Joerg Sedelmeier* Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland Joerg.Sedelmeier@novartis.com  

N-(5-amino-2-tert-butyl)-11-fluorbenzol[f]thiazol-[4,5-h]-quinazolin-10-yl)-2,6-difluorbenzolsulfonamide = Dabrafenib_photo (2)

C23H18F3N5O2S2 (Mr = 517.09)

Solution of 5 mg (9.6 μmol) dabrafenib in 2 ml THF was irradiated at 365 nm with 5.4 W for 2 min. This procedure was repeated 18 times at room temperature. The reaction batches were combined. The total initial weight of dabrafenib was 101 mg (190 μmol). The solvent was removed under reduced pressure and the residue was purified by the flash chromatography (SiO2 reversed phase, MeOH/water gradient 50:50 to 100:0) to give compound 2 as a yellowish solid (36.2 mg, 70.0 μmol, yield: 37%).

1H-NMR (DMSO-d6 , 300 MHz): δ = 1.52 (s, 9 H, H-8), 7.28 (m, 2 H, NH2), 7.28 (ddd, 5 J = 0.4 Hz, 4 J = 1.7 Hz, 3 J = 8.5 Hz, 3 J = 8.9 Hz, 2 H, H-18), 7.59 (dd, 3 J = 7.4 Hz, 3 J = 7.8 Hz, 1 H, H-13), 7.71 (tt, 4 J = 6.1 Hz, 3 J = 8.5 Hz, 1 H, H-19), 8.56 (dd, 4 J = 0.9 Hz, 3 J = 9.3 Hz, 1 H, H-14), 9.79 (s, 1 H, H-2), 11.01 (s, 1 H, NH) ppm.

13C-NMR (DMSO-d6 , 300 MHz): δ = 30.4 (s, C-8), 38.3 (s, C-7), 110.9 (d, 4 JCF = 1.6 Hz, C-3), 113.4 (dd, 2 JCF = 22.7 Hz, 2 JCH = 3.5 Hz, C-18), 114.6 (d, 3 JCF = 10.3 Hz, C-9), 117.4 (d, 2 JCF = 16.1 Hz, C-16), 117.6 (dd, 4 JCF = 0.54 Hz, 2 JCH = 4.4 Hz, C-13), 120.8 (d, 2 JCF = 12.3 Hz, C-10), 125.4 (s, C-13), 129.3 (d, 3 JCF = 3.9 Hz, C-15), 130.6 (s, C-5), 135.9 (tt, 3 JCF = 10.9 Hz, 2 JCH = 3.3 Hz, C-19), 148.8 (dd, 2 JCF = 0.54 Hz, 2 JCH = 7.2 Hz, C-12), 149.2 (s, C-4), 150.1 (s, C-11), 157.1 160.5 (dd, 3 JFF = 257.3 Hz, 2 JCF = 3.61 Hz, C-4), 157.9 (s, C-2), 162.1 (s, C-1), 184.0 (s, C-6) ppm.

15N-HMBC (DMSO-d6 , 300 MHz): δ = 9.79/-119.60, 11.01/-268.37 ppm. 19F-NMR (DMSO-d6 , 300 MHz): δ = -121.03 (s, 1 F, F-11), -107.18 (m, 2 F, F-17) ppm.

HRMS (EI, 205 °C, THF): m/z = 517.0849 [M]+ .

LC-MS (ESI, 70 eV, MeOH): tR = 9.3 min; m/z (%) = 518.1 (100) [M+H]+

IR (ATR):  ̃ = 3490 (N-H), 3176 (arom. C-H), 2926 (C-H3), 1696 (N=N), 1613 (N-H), 1587, 1522, 1488, 1469 (arom. C=C), 1342 (sulfonamide), 1277, 1240, 1174 (C-F) cm-1 .

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Boris Pinchuk, Thorsten von Drathen, Viktoria Opel, and Christian Peifer*

Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00340

Publication Date (Web): September 20, 2016

Copyright © 2016 American Chemical Society

*E-mail: cpeifer@pharmazie.uni-kiel.de. Tel: +49-431-880-1137.

ACS Editors' Choice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00340

Abstract

Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/K mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that 2 is still a potent BRAFV600E inhibitor. The intracellular formation of 2 from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications.

////////Photoinduced Conversion, Antimelanoma Agent,  Dabrafenib, Novel Fluorescent BRAFV600E Inhibitor, BRAFV600E; Dabrafenib, fluorescent probe,  kinase inhibitor,  photoinduced conversion

Mutianyu

Great Wall of China at Mutianyu.

Mutianyu

Mutianyu is a section of the Great Wall of China located in Huairou County 70 km northeast of central Beijing. The Mutianyu section of the Great Wall is connected with Jiankou in the west and Lianhuachi in the east. Wikipedia

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Olmesartan dimer

olmesartan dimer

Olmesartan Dimer Ester 

CAS No.

:

1040250-19-8

Molecular Weight

:

874.99

Molecular Formula

:

C48H50N12O5

A dimeric degradation product in stressed tablets of Olmesartan .;Impurity in commercial preparations of Olmesartan 

Synonyms

4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2�-(2H-tetrazol-5-yl)[1,1�-biphenyl]-4-yl]methyl]-1H-imidazoleopyl-1-[[2�-(2H-tetrazol-5-yl) [1,1�-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]-1-methylethyl Ester; DP-1; 

References

Murakami, T., et al.: J. Pharma. Biomed. Anal., 47, 553 (2008), 

CN 104650046 



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A high-yielding method for the preparation of isoxazolopyridin-3-amine derivatives

A highly efficient and green method has been developed for the rapid preparation of highly functionalized isoxazolopyridin-3-amine derivatives in excellent yields. This process has a broad substrate scope, is operationally simple, and generally requires no chromatographic purification. In addition, the process is scalable and significantly greener than current alternatives with a PMI of 18 and water as the reaction solvent.

A rapid preparation of highly functionalized isoxazolopyridin-3-amine and other heterocyclic fused aminoisoxazole derivatives

A high-yielding method for the preparation of isoxazolopyridin-3-amine derivatives

Wensheng Yu,*^a   Paul G. Bulger^b and   Kevin M. Maloney*^b  

*

Corresponding authors

^a

Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, USA
E-mail: wensheng.yu@merck.com

^b

Process Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, USA

Green Chem., 2016,18, 4941-4946

DOI: 10.1039/C6GC01125J

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01125J?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Wensheng Yu

Associate Principal Scientist at Merck

Paul G. Bulger was born in London, England, in 1978. He received his undergraduate M.Chem degree in 2000 from the University of Oxford, completing his Part II project under the supervision of Dr. Mark G. Moloney. He remained at Oxford for his graduate studies, obtaining his D. Phil. in chemistry in 2003 for research conducted under the supervision of Professor Sir Jack E. Baldwin. After an enjoyable three-year stint as a postdoctoral researcher in Professor K. C. Nicolaou's group at The Scripps Research Institute, he joined the Process Research Department of Merck & Co., Inc. in the fall of 2006.






pic not available

Kevin Maloney

Sr Research Chemist at Merck Sharp & Dohme

Experience

Sr Research Chemist

Merck Sharp & Dohme

Sr Research Chemist

Merck

2007 – Present (9 years)

Education

Massachusetts Institute of Technology

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Chopda

Chopda is a city and a municipal council in Jalgaon district in the state of Maharashtra, India.

Chopda

City in India

Chopda is a city and a municipal council in Jalgaon district in the state of Maharashtra, India. Wikipedia

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