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Friday, 30 September 2016

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  

Wednesday, 28 September 2016

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

Abstract Image
str1
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

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.

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, BRAFV600EDabrafenib, 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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Monday, 26 September 2016

Olmesartan dimer

Figure CN104650046AD00041
olmesartan dimer



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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 
Google's 18th Birthday


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Sunday, 25 September 2016

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

Image result for 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.



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


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

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



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. Bulgerb 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


Wensheng Yu

Associate Principal Scientist at Merck



Image result for Paul G. Bulger 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
 – Present (9 years)

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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
Map of Chopda India



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Image result for Chopda City in Maharashtra, India


Image result for Chopda City in Maharashtra, India



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Saturday, 24 September 2016

Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors





Based on reported pharmacophores as topoisomerase inhibitors, 2,5-dimethylthiophene/furan based N-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors. The target compounds were synthesized and tested in vitro against human topoisomerases in decatenation, relaxation, cleavage complex and DNA intercalation assays. Out of 29 compounds, three (1011 and 29) showed potent and selective topoisomerase II inhibitory activity with no intercalation with DNA. Further, molecular docking studies also endorsed them as ATP dependent topoisomerase II catalytic inhibitors. These compounds exerted potential anticancer effects on breast, colon, lung and prostate cancer cell lines at a low micromolar level, as compared to etoposide, and low toxicity to normal cells. Apart from the topoisomerase II inhibition, these compounds also induced a reactive oxygen species (ROS) level in cancer cells. The cell cycle analyses showed their apoptotic effect at the G1 phase.


Graphical abstract: Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors







Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors

*
Corresponding authors
a
Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
E-mail: raj.khunger@gmail.comrajcps@cup.ac.in
Fax: +91-1636-236564
Tel: +91-0164-2864215
b
Indo-Soviet Friendship College of Pharmacy, Moga, India
c
Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Mohali, S. A. S. Nagar, Sec 67, India
d
Centre for Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
RSC Adv., 2016,6, 14880-14892

DOI: 10.1039/C5RA25705K


























































































Image result for Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors



Image result for Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors

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Scheme 1 Reagents and conditions: (a) 5% NaOH, ethanol, rt, 4–5 h, 65–82% (b) NH2NH2·H2O, CH3COOH, reflux, 4–6 h, 75–90%.






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