TSRI Chemists Devise Powerful New Method for Modifying Drug Molecules

Chemists from The Scripps Research Institute illustrate their powerful new technique to make and modify medicines, published recently in the journal Science. Professor Phil Baran (center) holds a flask representing amines to cleave strained C–C bonds, which are depicted by a tug-of-war between co-first authors Ryan Gianatassio (left center) and Justin Lopchuk (right center) with co-authors Chung-Mao Pan (left) and Jie Wang.

 

Bicyclo[1.1.1]pentan-1-amine

177287-49-9 [RN]

22287-35-0 [RN]

Bicyclo[1.1.1]pentan-1-amine hydrochloride

 http://www.scripps.edu/news/press/2016/20160114baran.html

TSRI Chemists Devise Powerful New Method for Modifying Drug Molecules

‘Strain-release amination’ technique emerged from efforts to help Pfizer synthesize promising cancer drug candidate
LA JOLLA, CA—January 14, 2016—Chemists at The Scripps Research Institute (TSRI) have developed a versatile new technique for making modifications—especially one type of extremely difficult, but much-sought-after modification—to complex drug molecules.
The feat, reported in the January 15 issue of the journal Science, has already enabled pharma giant Pfizer to proceed with the evaluation of a promising cancer drug candidate that otherwise could not have been made in sufficient quantities.
“People from other pharma companies who have seen early drafts of this paper can’t get their hands on the supporting information fast enough,” said senior investigator Phil S. Baran, the Darlene Shiley Professor of Chemistry at TSRI. “I expect that every company in the business of making drugs will be using this chemistry soon.”
The technique, known as “strain-release amination,” also should enable the easier construction of a variety of molecules besides pharmaceuticals, including molecular probes for basic biology studies, plastics, and other materials made from organic compounds.
Pfizer’s Bottleneck
The project began with Pfizer’s request for help in synthesizing a molecule known as bicyclo[1.1.1]pentan-1-amine, which it needed to make the cancer drug candidate. The Baran laboratory frequently collaborates with Pfizer and other pharma companies to solve tough problems in medicinal and process chemistry.
Traditional methods of synthesizing bicyclo[1.1.1]pentan-1-amine left much to be desired. “Most of the previously published synthetic routes require three to five steps with toxic reagents and yield only tens of milligrams,” said Ryan Gianatassio, a PhD student at TSRI who was co-first author of the study.
Pfizer needed kilograms of bicyclo[1.1.1]pentan-1-amine for preclinical studies of its cancer drug candidate, and the company had had to shelve the drug’s development until it could make that much of it.
“We built a team of expert synthetic chemists to solve this challenging problem, including chemists from Phil Baran’s lab and Pfizer’s synthetic and process chemistry groups,” said Michael R. Collins, a senior principal scientist at the drug company’s La Jolla Laboratories.
Baran and his team, including Gianatassio and co-first author TSRI Research Associate Justin M. Lopchuk, were able to solve the supply problem for this building block, enabling a relatively quick and easy synthesis from a readily available starting compound. “Using our procedure, Pfizer easily produced over 100 grams, and they are now in a position to scale that up further and re-start that delayed drug development program,” said Gianatassio.
Adding Strained-Ring Structures
Baran realized that the new method could have much broader applications.
Bicyclo[1.1.1]pentan-1-amine is a “spring-loaded” or “strained ring” molecule, in which carbon atoms are arranged in rings at odd angles, with relatively large bond energies. Pharmaceutical chemists know that adding such a structure to a drug molecule sometimes greatly improves the drug’s properties: making it more absorbable by the gut, for example, or enabling it to resist breakdown by enzymes in the body so that it works therapeutically for longer periods.
The problem has been that, using traditional methods, the insertion of these small structures into larger drug molecules is tricky—so much so that chemists often have had to redesign the entire synthesis around the small added structure.
“The way they’ve been doing it is like decorating a Christmas tree by putting the ornaments in place first and then growing the tree around it,” said Baran. “In many cases they just won’t pursue that because of the time and labor it would take.”
Baran and his team showed that they could use their new method to directly append a strained-ring molecule favored by pharmaceutical chemists—propellane, so-called because its structure resembles a propeller—to existing larger drug molecules. “We can make that five-carbon ring structure of propellane click onto a wide range of drug molecules of a type known as secondary amines—we call that a propellerization reaction,” said Lopchuck.
“In fact, starting with a stock solution of the propellane, we can use high-throughput techniques to quickly elaborate a matrix of amine-containing compounds with the bicyclopentyl moiety, instead of painstakingly synthesizing the compounds one at a time,” Collins said.
The team went on to demonstrate similar direct modifications using two other strained-ring structures, azetidine and cyclobutane.
The TSRI researchers also found that they could use the new method to attach molecules very precisely and selectively to specific amino acids on proteins, thus in principle enabling the creation of new biologic drugs as well as new reagents that would be useful in basic biology research. “This technique opens up a world of chemistry that academic and commercial laboratories have really wanted to look into but couldn’t, due to the technical obstacles,” said Baran.
The supporting, publicly available information on strain-release amination is meant to enable chemists to start using the technique right away. A behind-the-scenes account and high-definition photos of the new reaction setup can be found on the Baran Lab Blog, Open Flask.
“This can be considered rapid bench-to-bedside chemistry because it is fundamental science that will have a positive impact on human medicine in a short period of time,” Baran said.
Other co-authors of the paper, “Strain Release Amination,” were Jie Wang, Chung-Mao Pan, Lara R. Malins and Liher Prieto of TSRI; and Thomas A. Brandt, Gary M. Gallego, Neal W. Sach, Jillian E. Spangler, Huichun Zhu and Jinjiang Zhu, of Pfizer.
The research was funded in part by Pfizer and the National Institutes of Health’s National Institute of General Medical Sciences.
About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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Org Lett. 2014 Apr 4;16(7):1884-7. doi: 10.1021/ol500635p. Epub 2014 Mar 14.

A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane.

Goh YL¹, Tam EK, Bernardo PH, Cheong CB, Johannes CW, William AD, Adsool VA.

¹Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology, and Research (A*STAR), 11 Biopolis Way, Helios Block, #03-08, Singapore 138667, Singapore.

 http://pubs.acs.org/doi/abs/10.1021/ol500635p

Abstract

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.

Scalable Synthesis of 1-Bicyclo[1.1.1]pentylamine via a Hydrohydrazination Reaction

Kevin D. Bunker, Neal W. Sach, Qinhua Huang, and Paul F. Richardson

Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, United States

Org. Lett., 2011, 13 (17), pp 4746–4748

DOI: 10.1021/ol201883z

Publication Date (Web): August 11, 2011

Copyright © 2011 American Chemical Society

kevin.bunker@pfizer.com

 http://pubs.acs.org/doi/abs/10.1021/ol201883z

Abstract

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)₃ to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.

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Design, Synthesis, Antimicrobial and Anti-inflammatory Activity of N-Pyrazolyl Benzamide Derivatives

.

Synthesis of 5-amino-3-t-butyl-1-(2', 4'-dinitro)phenyl-1Hpyrazole (3)

A mixture of 4, 4-dimethyl-3-oxo-pentanenitrile (1, 34 mM), 2, 4-dinitrophenyl hydrazine hydrochloride (2, 35 mM) and 50 mL absolute ethanol along with few drops of AcOH were heated at the reflux temperature for overnight and cooled to room temperature. The mixture was evaporated under vacuum and the residue thus obtained was washed with ether, suspended in EtOAc, and treated with 1 M NaOH solution. The organic layer then separated, washed with brine, dried over anhydrous magnesium sulphate and concentrated. The solid which separated was collected, then washed with a mixture of ether and hexane to give 5-amino-3-t-butyl-1-(2', 4'-dinitro)phenyl-1H-pyrazole (3) [22].

General procedure for N-[3'-t-butyl-1'-(2", 4"-dinitro) phenylpyrazol-5'-yl] benzamide (5a-l)

To a solution of 5-amino-3-t-butyl-1-(2', 4'-dinitro)phenyl-1Hpyrazole (3, 9.3 mM) in dichloromethane (5 mL), triethyl amine (23 mM) was added drop wise. The appropriate benzoylchlorides (4a-k, 12 mM) in dichloromethane were added to the above reaction mixture drop wise and stirred for 3 hours at room temperature. The mixture was further diluted with dichloromethane and washed with water, brine followed by once again with water. Sodium sulfate was used to dry the organic layer; solvent was removed under vacuum to get the final derivatives (5a-l). All the compounds were purified over silica to get pure N-(3-tert-butyl-2, 4-dinitro-1-phenyl-1H-pyrazol-5-yl) benzamides (5a-l).

Compound characterization

N-[3'-t-butyl-1'-(2", 4"-dinitro)phenylpyrazol-5'-yl] benzamide 5a: Yield: 85%, m.p.: 190-192°C,  IR (KBr) ν cm-1: 3362 cm-1 (NH str.), 3020 cm-1 (CH str. aromatic), 2950 cm-1 (CH str. methyl), 1643 cm-1 (NH bnd)   1H NMR (CDCl3) δ (ppm): 1.23 (s, 9H, t-butyl), 6.18 (s, 1H, C4, pyrazole), 7.15-7.55 (m, 3H, C3', C4', C5' aromatic), 7.7-7.8 (m, 2H, C5, C6, aromatic), 7.9-8.1 (d, 2H, C2', C6', aromatic), 8.2 (s, 1H, C3, aromatic), 9.61 (bs, 1H, NH amide).  ESI-MS (m/z): 410, 100% [M+H]+. The intermediate compound 5-amino-3-t-butyl-1-(2', 4'-dinitro)phenyl-1H-pyrazole 3 was prepared in good yields by refluxing 4, 4-dimethyl-3-oxo-pentanenitrile 1 and 2, 4-dinitrophenyl hydrazine hydrochloride 2. The FT IR spectrum of 3 showed the presence of bands characteristic for primary amine at 3423.42 cm-1 and 3264.21 cm-1 which are attributed to the asymmetric and symmetric stretching respectively and aromatic hydrogen stretching band located at 3056.75 cm-1. The CH3 groups of t-butyl vibrations were observed at 2961.33 cm-1 and 2828.42 cm-1 and peak assigned for bending vibration of NH group was observed at 1625.94 cm-1. The1H NMR of 3 revealed a broad singlet at δ 3.77 ppm characteristic for primary amine group, multiplet at delta value of 8.05, 7.35 and 7.63 for C3, C5 and C6 aromatic protons and a pyrazolyl-C4-H as a singlet at 6.1 ppm. The nine t-butyl protons were found as singlet at δ 1.23 ppm. The EI Mass spectrum of 3 showed molecular ion peak at m/z 215. When 5-amino-3-t-butyl-1-(2', 4'-dinitro)phenyl-1H-pyrazole 3 was stirred with substituted benzoylchlorides 4a-k in dichloromethane and triethylamine, pyrazolylbenzamides 5a-l were obtained in moderate to good yields (5j was reduced with stannous chloride to form 5l). The structures of the isolated compounds were determined by spectral methods. The FT IR spectrum of 5a revealed characteristic NH band at 3362 cm-1, the aromatic hydrogen stretching was found at 3020 cm-1 and stretching vibrations of CH3 group of t-butyl band was noticed at 2950 cm-1. A band at 1595 cm-1 was assigned for the C=C stretching. The 1H NMR spectra displayed a broad absorption peak at δ 9.61 which was due to resonance of NH proton of amide while the pyrazol-C4-H and nine t-butyl protons appears as singlet’s at δ 6.18 and 1.23 ppm respectively. The aromatic protons appeared as doublet at δ 7.9-8.1 which indicated the resonance of C2', C6' protons. Three aromatic protons C3', C4', C5' resonated as multiplet at δ 7.15-7.55 and another multiplet at δ 7.7-7.8 integrated for two protons C5 and C6. C3 proton was observed as singlet at δ 8.2. Design, Synthesis, Antimicrobial and Anti-inflammatory Activity of N-Pyrazolyl Benzamide Derivatives Aneesa Fatima1*, Ravindra Kulkarni2 and Bhagavanraju Mantipragada3 1Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad, Telangana, India 2SVERI College of Pharmacy, Gopalpur Ranjini Road, Gopalpur, Pandharpur, Maharashtra, India 3Sri Venkateswara College of Pharmacy, HITEC City, Madhapur, Telangana, India Corresponding Author : Aneesa Fatima Malla Reddy College of Pharmacy Maisammaguda, Secunderabad Telangana, India Tel: +918125343156 E-mail: aneesafatima.16@gmail.com Received: November 17, 2015; Accepted: December 07, 2015; Published: December 10, 2015 Citation: Fatima A, Kulkarni R, Mantipragada B (2015) Design, Synthesis, Antimicrobial and Anti-inflammatory Activity of N-Pyrazolyl Benzamide Derivatives. Med chem 5:521-527. doi:10.4172/2161-0444.1000311 http://www.omicsonline.org/open-access/design-synthesis-antimicrobial-and-antiinflammatory-activity-ofnpyrazolyl-benzamide-derivatives-2161-0444-1000311.php?aid=64851 Figure 1: Structure of VHw along with antibacterial activity against Bacillus subtilis (MTCC 619). //////////////////

Cyclopropanes in water: a diastereoselective synthesis of substituted 2H-chromen-2-one and quinolin-2(1H)-one linked cyclopropanes

Green Chem., 2016, Advance Article
DOI: 10.1039/C5GC02443A, Paper

Ashish Anand, Jayashree Yenagi, J. Tonannavar, Manohar V. Kulkarni
A one-pot three component reaction has been developed for the synthesis of substituted cyclopropanes employing 4-bromomethyl-2H-chromen-2-one/quinolin-2(1H)-ones, aromatic aldehydes and activated nitriles.

A one-pot three component reaction has been developed for the synthesis of substituted cyclopropanes employing 4-bromomethyl-2H-chromen-2-one/quinolin-2(1H)-ones, aromatic aldehydes and activated nitriles. The room temperature reaction in aqueous medium has been found to be diastereoselective and high yielding.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C5GC02443A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

2-(6-Methyl-2-oxo-2H-chromen-4-yl)-3-phenyl-cyclopropane-1,1-dicarbonitrile (4a)
4a, (R= -H, R’= 6-CH3, R”= -CN, X=O)

For a typical compound 4a, (R= -H, R’= 6-CH3, R”= -CN, X=O) IR spectrum showed band at 2246 cm-1 (cyanide) and 1720 cm-1 (lactone). Further, the formation of cyclopropane ring was confirmed by the 1H-NMR wherein the C5-H of coumarin ring resonated at 7.83 ppm as a doublet with 5JC5-H = 1.2 Hz showing a 5-bond coupling with the C4-CH of coumarin ring. C4- CH of coumarin ring appeared at 4.83 ppm as doublet of doublets with Jvic(CH) = 8.8 Hz, Cou-CH 5JC5-H = 1.2 Hz. CH attached to aryl group resonated at 4.61 ppm as a doublet with Jvic(CH) = 8.8 Hz. C6-CH3 protons appeared at 2.45 as a singlet. C3-H was observed as a singlet at 6.82 ppm. Other aromatic protons resonated between 7.68-7.41 ppm. In 13C-NMR, the carbon attached to two cyano group resonated at 15.08 ppm, the methyl carbon appeared at 20.55 ppm. Cyclopropane ring carbon attached to aryl group resonated at 32.81 ppm whereas the one attached to coumarin appeared at 36.78 ppm. Carbon of two cyano group resonated at 112.68 and 112.91 ppm. The lactone carbon of the coumarin ring appeared at 159.35 ppm. Aromatic carbons resonated in the range of 112-159 ppm. Formation of the product was further confirmed by EI-MS where the molecular ion peak was observed at 326 m/z

 

 2-(6-Methyl-2-oxo-2H-chromen-4-yl)-3-phenyl-cyclopropane-1,1-dicarbonitrile (4a) White; Yield 85%; 

m.p: 268-270°C; 

IR (KBr) cm-1 1720 (C=O lactone), 2246 (CN); 

 1H-NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.83(d, 1H, 5JC5-H = 1.2 Hz, C5-H), 7.68-7.41(m, 7H, ArH), 6.82(s, 1H, C3-H), 4.83(dd, 1H, Jvic(CH) = 8.8Hz, Cou-CH, 5JC5-H = 1.2 Hz), 4.61(d, 1H, Jvic(CH) = 8.8Hz, Ar-CH), 2.45(s, 3H, -CH3); 

 

 

  13C-NMR (100 MHz, DMSO-d6) δ (ppm): 8.57, 15.08, 20.55, 32.81, 36.78, 45.73, 112.68, 112.91, 115.95, 116.69, 117.64, 124.60, 128.62, 129.00,129.12, 130.90, 133.63, 134.23, 146.64, 151.12, 159.35; 

      

MS m/z 326(100%); 

 

 

Anal Calcd. for C21H14N2O2 (%), Calcd: C, 77.29; H, 4.32; N, 8.58; found: C, 77.26; H, 4.29; N, 8.55

   Cyclopropanes in water: a diastereoselective synthesis of substituted 2H-chromen-2-one and quinolin-2(1H)-one linked cyclopropanes

Cyclopropanes in water: a diastereoselective synthesis of substituted 2H-chromen-2-one and quinolin-2(1H)-one linked cyclopropanes

Ashish Anand,^a   Jayashree Yenagi,^b   J. Tonannavar^b and  Manohar V. Kulkarni*^a  

*

Corresponding authors

^a

Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad 580003, India 
E-mail: manohar274@gmail.com

^b

Department of Studies in Physics, Karnatak University, Pavate Nagar, Dharwad 580003, India

Green Chem., 2016, Advance Article

DOI: 10.1039/C5GC02443A http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C5GC02443A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract   http://www.rsc.org/suppdata/c5/gc/c5gc02443a/c5gc02443a1.pdf /////////////////////////  c1(ccc4c(c1C2[C@@H](C2(C#N)C#N)c3ccccc3)\C=C/C(O4)=O)C 

Palladium(II) porphyrin – anthracene dyad bridged via short and conformationally rigid bicyclo[2.2.2]octadiene spacer

.





The synthesis and photophysical characterization of a palladium(II) porphyrin – anthracene dyad bridged via short and conformationally rigid bicyclo[2.2.2]octadiene spacer were achieved. A spectroscopic investigation of the prepared molecule in solution has been undertaken to study electronic energy transfer in excited singlet and triplet states between the anthracene and porphyrin units. By using steady-state and time-resolved photoluminescence spectroscopy it was shown that excitation of the singlet excited state of the anthracene leads to energy transfer to the lower-lying singlet state of porphyrin. Alternatively, excitation of the porphyrin followed by intersystem crossing to the triplet state leads to very fast energy transfer to the triplet state of anthracene. The rate of this energy transfer has been determined by transient absorption spectroscopy. Comparative studies of the dynamics of triplet excited states of the dyad and reference palladium octaethylporphyrin (PdOEP) have been performed.

 



SEE..................

 http://pubs.rsc.org/en/content/articlelanding/2015/dt/c5dt03784k#!divAbstract

http://www.rsc.org/suppdata/c5/dt/c5dt03784k/c5dt03784k1.pdf

Paper

Interplay between singlet and triplet excited states in a conformationally locked donor–acceptor dyad

Mikhail A. Filatov,*^ab   Fabian Etzold,^a   Dominik Gehrig,^a   Frédéric Laquai,^ac   Dmitri Busko,^a   Katharina Landfester^a and   Stanislav Baluschev^ade  

*

Corresponding authors

^a

Max Planck Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany
E-mail: filatovm@tcd.ie

^b

Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., block 103-A, BG – 1113 Sofia, Bulgaria

^c

Physical Sciences and Engineering Division (PSE), Material Science and Engineering (MSE), Solar and Photovoltaics Engineering Research Center (SPERC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia

^d

Optics and Spectroscopy Department, Faculty of Physics, Sofia University “St. Kliment Ochridski”, 5 James Bourchier, 1164 Sofia, Bulgaria

^e

Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Albertstraße 19, D-79104 Freiburg, Germany

Dalton Trans., 2015,44, 19207-19217

DOI: 10.1039/C5DT03784K




 

Mikhail A Filatov

Dr.

Marie Curie Postdoctoral Research Fellow

Trinity College Dublin, Dublin · School of Chemistry

Research Experience

• Sep 2015–
  present

  Marie Curie Postdoctoral Research Fellow

  Trinity College Dublin · School of Chemistry
  Ireland · Dublin
• Mar 2014–
  Sep 2015

  Research Associate

  Institute of Polymers, Bulgarian Academy of Sciences
  Bulgaria · Sofia, Sofia-Capital
• Feb 2010–
  Mar 2014

  Postdoctoral researcher

  Max Planck Insitute for Polymer Research
  Germany · Mainz
• Dec 2008–
  Dec 2009

  Postdoctoral researcher

  Institut de Chimie Moléculaire de l'Université de Bourgogne, CNRS
  France · Dijon

Education

• Sep 2000–
  Oct 2008

  Lomonosov Moscow State University

  Chemistry · MS and PhD
  Russia · Moscow

Awards & achievements

• Feb 2015
  Award: Marie Skłodowska-Curie Individual Fellowship
• Oct 2007
  Scholarship: • Scholarship of the President of Russian Federation for outstanding PhD students
• Sep 2005
  Grant: • Grant from the Russian Foundation for Assistance to Small Innovative Enterprises (FASIE) for establishing a start-up company with the innovative project “Development of Technology of 24-Epibrassinolide Production”

Other

• Languages
  Bulgarian, English, German, Russian
• Journal
  Referee
  The Journal of Organic Chemistry
• Other Interests
  Reading, hiking, diving, traveling

/////////

Fluoxastrobin

Fluoxastrobin

Fluoxastrobin
Fluoxastrobin; Disarm; Fluoxastrobin [ISO]; UNII-XQ43WY091Y; HEC 480 SC;
(E)-1-[2-[6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl]oxyphenyl]-1-(5,6-dihydro-1,4,2-dioxazin-3-yl)-N-methoxymethanimine

• (1E)-(2-((6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime
• 361377-29-9
• 193740-76-0

Molecular Formula:	C21H16ClFN4O5
Molecular Weight:	458.826943 g/mol

103-108 deg C

MacBean C, ed; e-Pesticide Manual. 15th ed., ver. 5.1, Alton, UK; British Crop Protection Council. Fluoxastrobin (361377-29-9) (2008-2010)


 http://fluoridealert.org/wp-content/pesticides/fluoxastrobin.2004.article.pdf

 PAPER

 
 http://pubs.rsc.org/en/content/articlehtml/2015/gc/c5gc00402k



PATENT


US-9193698-B2 / 2015-11-24

Process for preparing fluoxastrobin

 

(E)-(2-((6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime [Fluoxastrobin]

To a solution of (E)-(2-((6-chloro-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14)(100 g, 0.564 mol) in toluene was added 2-chlorophenol (54 g, 0.846 mol), K₂CO₃ (50 g, 0.733 mol), and DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 50-60° C. for 3-4 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, aqueous NaOH (10%) (200 mL) was charged followed by water (300 mL). The mixture was stirred and the toluene layer was separated. The toluene layer was washed with a solution of brine (600 mL). The final toluene layer was recovered completely to get the crude product. To the above crude product, methanol was charged and heated to 60° C. until the clear solution is formed. The solution was stirred at room temperature to get the pure product precipitated. The pure fluoxastrobin product was filtered and washed with methanol. The product was further dried to obtain the pure fluoxastrobin product meeting the desired specifications. Yield—75-88%.

IR (cm⁻¹, KBr) 3072.99w, 2981.58w, 2936.76s, 2819.79w, 2502.01w, 1601.14s, 1572.37s, 1447.88s, 1305.43m, 1268.11m, 1217.15m, 1191.21m, 1092.60m, 1049.05m, 1001.26w, 910.25w, 762.81w. 

¹H NMR (CDCl₃, 400 MHz) δ 3.846 (s, 3H), 4.170-4.160 (t, J=4 Hz, 2H), 4.464-4.484 (t, J=4 Hz, 2H), 7.261-7.295 (m, 2H), 7.322-7.409 (2, 4H), 8.069 (s, 1H).

 ¹³C NMR (CDCl₃, 400 MHz) δ 63.103, 64.153, 64.550, 122.659, 123.259, 123.823, 125.712, 127.150, 127.397, 128.094, 130.511, 130.679, 130.776, 131.473, 134.138, 146.004, 148.166, 148.943, 150.354, 150.478, 151.819, 157.395, 157.466, 157.783, 157.854.

MS (EI) m/z 459.1 (M+1); MS2 (EI) m/z 427.1, 383.0, 366.9, 342.1, 306.2, 246.0, 231.1, 188.0. 

HPLC (Area %): 99.40%. M.P. 108-112° C.

(Z)-(2-((6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime[(Z)-fluoxastrobin]

Isomerisation of (Z)-Fluoxastrobin to (E)-Fluoxastrobin using methane sulphonic acid. To a stirred solution of (Z)-Fluoxastrobin (0.3 g; 0.65 mmole) in acetonitrile (3 ml) was dropwise added methane sulphonic acid (0.04 ml, 0.65 mmole) at an ambient temperature. The reaction mixture was stirred for 2-3 hr at the same temperature. The progress of reaction was monitored by thin layer chromatography (TLC). Dichloromethane (5 ml) and DM water (5 ml) was added to reaction mass at an ambient temperature. After vigorous stirring, the layers were separated. The aqueous layer was back extracted with dichloromethane (5 ml) and the combined dichloromethane layer was washed with 10% aqueous sodium bicarbonate solution (20 ml) followed by washing with 10% brine solution (20 ml). Dichloromethane was distilled off at reduced pressure at 35-45° C. to obtain (E)-Fluoxastrobin as crude product (0.25 g, 83% of theoretical yield). Crude fluoxastrobin on purification in ethanol affords pure (E)-Fluoxastrobin. Isolated product HPLC purity (% area): (Z)-fluoxastrobin: 1.02% and (E)-fluoxastrobin: 95.92%.

Isomerisation of (Z)-Fluoxastrobin to (E)-Fluoxastrobin using phosphoric acid. To a stirred solution of (Z)-Fluoxastrobin (0.25 g; 0.54 mmole) in acetonitrile (4 ml) was dropwise added phosphoric acid (0.03 g, 0.54 mmole) at an ambient temperature. The reaction mixture was stirred for 2-3 hr at the same temperature. Progress of reaction was monitored by thin layer chromatography/HPLC. Dichloromethane (5 ml) and DM water (5 ml) was added to reaction mass at an ambient temperature. After vigorous stirring, layers were separated. The aqueous layer was back extracted with dichloromethane (5 ml). The combined dichloromethane layers were washed with 10% aq. Sodium bicarbonate solution (20 ml) followed by washing with 10% brine solution (20 ml). Dichloromethane was distilled off at reduced pressure at 40-45° C. to obtained (E)-Fluoxastrobin (0.22 g, 88% of Theoretical yield). Reaction monitoring by HPLC (% area): (Z)-Fluoxastrobin: 6.79% and (E)-Fluoxastrobin: 88.84%. Isolated product HPLC purity (% area): (Z)-Fluoxastrobin: 6.94% and (E)-Fluoxastrobin: 84.43%.

IR (cm⁻¹, KBr) 3066.28w, 2981.58w, 2939.36s, 2825.71w, 2500.61w, 1602.36s, 1572.76s, 1441.05s, 1297.05m, 1218.17m, 1116.52s, 1046.15m 1000.86w, 904.73s, 764.71w. ¹H NMR (CDCl₃, 400 MHz) δ 3.983 (s, 3H), 4.163-4.218 (t, 2H), 4.432-4.440 (t, J=3.2 Hz, 2H), 7.217-7.352 (m, 4H), 7.371-7.390 (m, 2H), 7.483-7.516 (m, 2H), 7.702-7.722 (d, J=8 Hz, 1H), 8.016 (s, 1H). MS (EI) m/z 459.1 (M+1); MS2 (EI) m/z 427.0, 382.9, 366.7, 340.0, 305.8, 246.1, 188.0. HPLC (Area %): 99.11%. M.P. 150-152° C.

 

Title: Fluoxastrobin

CAS Registry Number: 361377-29-9

CAS Name: (1E)-[2-[[6-(2-Chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime

Manufacturers' Codes: HEC-5725

Trademarks: Fandango (Bayer CropSci.)

Molecular Formula: C21H16ClFN4O5

Molecular Weight: 458.83

Percent Composition: C 54.97%, H 3.51%, Cl 7.73%, F 4.14%, N 12.21%, O 17.43%

Literature References: Leaf-systemic broad-spectrum fungicide for use in cereal and food crops; member of methoxyimiodihydro-dioxazines. Prepn (stereochem. unspecified): U. Heinemann et al., DE 19602095; eidem, US 6103717 (1997, 2000 both to Bayer). Comprehensive description: S. Dutzmann et al., BCPC Conf. - Pests Dis. 2002, 365. Field trial in winter wheat seeds: I. Haeuser-Hahn et al., BCPC Int. Cong. - Crop Sci. Tech. 2003, 801. Series of articles on chemistry, biology, determn, and environmental fate: Pflanzenschutz-Nachr. Bayer (Engl. Ed.) 57, 299-449 (2004). Ecotoxicology: P. Breuer, ibid. 319.

Properties: White crystals with slight characteristic odor, mp 103-108°. bp 497° (est.). d420 1.422. Log P (octanol/water): 2.86 (20°). Vapor pressure at 20° (extrapolated): 6 ´ 10-10 Pa. Soly at 20° (g/l): n-heptane 0.04; 2-propanol 6.7; xylene 38.1; dichloromethane >250; in water (mg/l): 2.56 (unbuffered); 2.43 (pH 4); 2.29 (pH 7); 2.27 (pH 9). LD50 in rats, bobwhite quail (mg/kg): >2500, >2000 orally; LC50 (96 hr) rainbow trout, bluegill sunfish, carp (mg/l): 0.44, 0.97, 0.57 (Breuer).

Melting point: mp 103-108°

Boiling point: bp 497° (est.)

Log P: Log P (octanol/water): 2.86 (20°)

Density: d420 1.422

Toxicity data: LD50 in rats, bobwhite quail (mg/kg): >2500, >2000 orally; LC50 (96 hr) rainbow trout, bluegill sunfish, carp (mg/l): 0.44, 0.97, 0.57 (Breuer)

Use: Agricultural fungicide.