DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow

organic chemistry, PROCESS Comments Off

Apr 262019

A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon–carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer’s drug.

Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow

Benjamin Laroche^†, Yuki Saito^†, Haruro Ishitani^‡, and Shu̅ Kobayashi*^†^‡

^†Department of Chemistry, School of Science, and ^‡Green & Sustainable Chemistry Social Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.9b00048

*E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00048

////////donepezil

Design, synthesis and antimicrobial activity of usnic acid derivatives

Uncategorized Comments Off

Feb 012019

Design, synthesis and antimicrobial activity of usnic acid derivatives

Victor Kartsev,^a Boris Lichitsky,^b Athina Geronikaki,*^c Anthi Petrou,^c Marija Smiljkovic,^d Marina Kostic,^d Oliver Radanovic^e and Marina Soković^d

Author affiliations

*Corresponding authors

^aInterBioscreen, Moscow, Russia

^bZelinsky Institute of Organic Chemistry, Leninsky Prospect, Moscow, Russia
E-mail: blich2006@mail.ru

^cSchool of Health, Department of Pharmacy, Aristotle University of Thessaloniki, Greece

^dMycological Laboratory, Department of Plant Physiology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Bulevar Despota Stefana 142, Belgrade, Serbia

^eScientific Institute of Veterinary Medicine of Serbia, ul. Vojvode Toze 14, 11000 Belgrade, Serbia

Abstract

Usnic acid, a dibenzofuran, was originally isolated from lichens producing secondary metabolites, and is well known as an antibiotic, but is also endowed with several other interesting properties. Thus, the goal of this paper is the design of new usnic acid derivatives and evaluation of their antimicrobial activity. All newly synthesized compounds possess good antibacterial activity with MIC ranging from 1.02–50.93 × 10⁻² mmol mL⁻¹ and MBC from 2.05–70.57 × 10⁻² mmol mL⁻¹. The most sensitive bacterial species was Staphylococcus aureus, while Pseudomonas aeruginosa and Escherichia coli were the most resistant among the ATCC strains, and MRSA was the most resistant among all tested bacteria (ATCC and clinical isolates). Their antifungal activity was very strong (MIC = 0.35–7.53 × 10⁻² mmol mL⁻¹ and MFC = 0.70–15.05 × 10⁻² mmol mL⁻¹) – better than those of reference compounds and usnic acid itself. The most sensitive fungal species was Trichoderma viride, while Penicillium versicolor var. cyclopium appeared to be the most resistant. It should be mentioned that in general most of the compounds showed weaker antibacterial activity, but better antifungal properties than usnic acid itself. The results allow us to conclude that the title compounds are good lead compounds for novel more active antibacterial drugs. On the other hand, these compounds are very promising as antifungals.

https://pubs.rsc.org/en/content/articlelanding/2018/md/c8md00076j#!divAbstract

////////////Usnic acid, dibenzofuran

Structural evolution of carbon in an Fe@C catalyst during the Fischer–Tropsch synthesis reaction

ANTHONY CRASTO, organic chemistry, SYNTHESIS Comments Off

Feb 012019

Structural evolution of carbon in an Fe@C catalyst during the Fischer–Tropsch synthesis reaction

Shuai Lyu,^a^b Chengchao Liu,^b Guanghui Wang,*^a Yuhua Zhang,^b Jinlin Li^b and Li Wang*^b

Author affiliations

*Corresponding authors

^aHubei Key Laboratory of Coal Conversion and New Carbon Material, School of Chemical Engineering and Technology, Wuhan University of Science and Technology, Wuhan 430081, China
E-mail: wghwang@263.net

^bKey Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission & Ministry of Education, South-Central University for Nationalities, Wuhan 430074, China
E-mail: li.wang@mail.scuec.edu.cn

Abstract

A pseudo-in situ research method was applied to provide insight into the structural evolution of carbon in an Fe@C catalyst at different stages of the Fischer–Tropsch reaction. Five typical stages of the catalyst were selected for in-depth structural investigation; these were: the fresh catalyst, reduced catalyst, and catalyst in the stable conversion period, in an increased-conversion period and at the inactivation stage. The results indicated that the integral structure of Fe@C constantly changed in the Fischer–Tropsch reaction. Iron carbide transformed from the Fe phase that was easily oxidized under high temperature Fischer–Tropsch conditions, and the carbon framework was completely destroyed in the reaction process, leading to a drastic decrease in the specific surface area of the material. This destruction could have two opposing effects: on the one hand, the loss of carbon could re-expose the active sites that have been covered by carbon at a reaction temperature of 320 °C and favor the reaction; on the other hand, the deposition of carbon could block the active sites and lead to inactivation when the reaction temperature is over 340 °C.

https://pubs.rsc.org/en/Content/ArticleLanding/2019/CY/C8CY02420K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

////////Fischer–Tropsch

Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

FLOW CHEMISTRY, flow synthesis Comments Off

Jan 312019

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

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ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

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

spectroscopy, SYNTHESIS Comments Off

Jan 302019

Graphical abstract: Nickel-catalyzed regioselective CâH oxygenation: new routes for versatile CâO 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 Sun^a 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

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“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

amcrasto@gmail.com

CALL +919323115463 INDIA

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

A solvent-free catalytic protocol for the Achmatowicz rearrangement

green chemistry, spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: A solvent-free catalytic protocol for the Achmatowicz rearrangement

Abstract

Reported here is the development of an environmentally friendly catalytic (KBr/oxone) and solvent-free protocol for the Achmatowicz rearrangement (AchR). Different from all previous methods is that the use of chromatographic alumina (Al₂O₃) allows AchR to proceed smoothly in the absence of any organic solvent and therefore considerably facilitates the subsequent workup and purification with minimal environmental impacts. Importantly, this protocol allows for scaling up (from milligram to gram), recycling of the Al₂O₃, and integrating with other reactions in a one-pot sequential manner.

A solvent-free catalytic protocol for the

Achmatowicz rearrangement

Guodong Zhao^a and Rongbiao Tong*^a^b

Author affiliations

*Corresponding authors

^aDepartment of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, China
E-mail: rtong@ust.hk
Fax: +(852)23581594
Tel: +(852) 23587357

^bHKUST Shenzhen Research Institute, Shenzhen 518057, China

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03030H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

1n: colorless oil, 0.33 g, 73% yield for 2 steps.

1H-NMR (400 MHz, DMSO) δ: 7.59–7.58 (m, 1H), 7.45 (s, 2H), 6.40 (dd, J = 3.2, 1.8 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H), 5.49 (s, 1H), 4.74–4.60 (m, 1H), 4.18–4.07 (m, 2H), 2.09–2.04 (m, 2H).

13C-NMR (100 MHz, DMSO) δ: 157.6, 142.4, 110.7, 106.1, 66.5, 62.8, 35.2. IR (KBr) 3282.9, 2928.7, 1627.4, 1562.5, 1353.8, 1174.6, 1074.0, 999.7, 918.4, 742.8 cm-1 ;

HRMS (CI+ ) (m/z) calcd. for C7H11NO5S [M]+ 221.0352; found 221.0354.

2n (EtOAc/hexane = 3:1):colorless oil (dr 7:3), 46 mg, 97%.

1H-NMR (400 MHz, DMSO) δ: 7.48–7.47 (m, 2H), 7.34–7.02 (m, 2H), 6.12–6.03 (m, 1H), 5.61–5.48 (m, 1H), 4.60 (dd, J = 8.3, 4.1 Hz, 0.7H), 4.28 (ddd, J = 8.8, 4.0, 1.3 Hz, 0.3H), 4.20–4.11 (m, 2H), 2.27–2.20 (m, 1H), 1.97–1.86 (m, 1H).

13C-NMR (100 MHz, DMSO) δ: 196.7, 196.5, 151.9, 148.3, 127.7, 126.0, 90.9, 87.2, 74.6, 70.1, 65.8, 65.8, 30.3, 29.6. IR (KBr) 3370.4, 2987.0, 1689.5, 1364.3, 1268.0, 1178.4, 1023.3, 928.3, 755.1 cm-1 ;

HRMS (CI+ ) (m/z) calcd. for C7H11NO6S [M]+ 237.0302; found 237.0315.

////////////////Achmatowicz rearrangement

Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

Abstract

An environmentally benign decarboxylative cyclization in water has been developed to synthesize 4-quinolones from readily available isatoic anhydrides and 1,3-dicarbonyl compounds. Isatins are also compatible for the reaction to generate 4-quinolones in the presence of TBHP in DMSO. This protocol provides excellent yields under mild conditions for a broad scope of 4-quinolones, and has good functional group tolerance. Only un-harmful carbon dioxide and water are released in this procedure. Moreover, the newly synthesized products have also been selected for anti-malarial examination against the chloroquine drug-sensitive Plasmodium falciparum 3D7 strain. 3u is found to display excellent anti-malarial activity with an IC₅₀ value of 33 nM.

Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

Yue Ma,^a Yongping Zhu,^a Dong Zhang,^a Yuqing Meng,^a Tian Tang,^a Kun Wang,^a Ji Ma,^a Jigang Wang^a and Peng Sun*^a

Author affiliations

*Corresponding authors

^aArtermisinin Research Center and Institute of Chinese Meteria Medica, Academy of Chinese Medical Sciences, Beijing, P. R. China
E-mail:psun@icmm.ac.cn

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03570A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

ethyl 2-(4-(benzyloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (3u) White solid, m.p. 288-289 oC;

1H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.72 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (td, J = 8.5, 1.7 Hz, 1H), 7.43 – 7.35 (m, 4H), 7.29 – 7.21 (m, 4H), 7.10 (td, J = 7.5, 0.5 Hz, 1H), 5.17 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 2.00 (s, 1H), 0.83 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (150 MHz, DMSO-d6) δ 174.1, 166.2, 156.2, 148.0, 139.8, 137.2, 132.8, 132.0, 130.5, 129.4, 128.7, 128.2, 127.6, 125.5, 125.2, 124.3, 123.6, 120.9, 118.9, 116.4, 115.8, 113.5, 70.2, 60.2, 14.0 ppm;

HRMS (ESI) calcd for [C25H21NO4+H]+ 400.1471, found 400.1463.

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Photo-organocatalytic synthesis of acetals from aldehydes

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Jan 292019

Graphical abstract: Photo-organocatalytic synthesis of acetals from aldehydes

Abstract

A mild and green photo-organocatalytic protocol for the highly efficient acetalization of aldehydes has been developed. Utilizing thioxanthenone as the photocatalyst and inexpensive household lamps as the light source, a variety of aromatic and aliphatic aldehydes have been converted into acyclic and cyclic acetals in high yields. The reaction mechanism was extensively studied

Photo-organocatalytic synthesis of acetals from aldehydes

Nikolaos F. Nikitas,^a Ierasia Triandafillidi^a and Christoforos G. Kokotos*^a

Author affiliations

*Corresponding authors

^aLaboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
E-mail:ckokotos@chem.uoa.gr

https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03605E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

(3,3-Dimethoxypropyl)benzene (2a)6

Colorless oil; 95% yield; 1H NMR (200 MHz, CDCl3) δ: 7.33-7.18 (5H, m, ArH), 4.37 (1H, t, J = 5.8 Hz, OCH), 3.33 (6H, s, 2 x OCH3), 2.68 (2H, t, J = 7.6 Hz, CH2), 1.98- 1.87 (2H, m, CH2); 13C NMR (50 MHz, CDCl3) δ: 141.8, 128.4, 125.9, 103.7, 52.8, 34.0, 30.8; MS (ESI) m/z 181 [M+H]+ .

6. Q. Zhou, T. Jia. X.-X. Li, L. Zhou, C.-J. Li, Y. S. Feng, Synth. Commun., 2018, 48, 1068.

.////////////////

Large scale synthesis of chiral (3Z,5Z)-2,7-dihydro-1H-azepine-derived Hamari ligand for general asymmetric synthesis of tailor-made amino acids.

spectroscopy, SYNTHESIS Comments Off

Jan 292019

(R)-2,2′-bis(bromomethyl)-1,1′-binaphthalene ((R)-17) was prepared in the identical manner and had identical analytical properties to those given here.

¹H NMR (400 MHz, CDCl₃): δ 4.25 (4H, s, 2 × CH₂), 7.07 (2H, dd, J = 8.4, 0.8 Hz, ArH), 7.27 (2H, ddd, J = 8.4, 6.8, 1.2 Hz, ArH), 7.48 (2H, ddd, J = 8.2, 6.8, 1.2 Hz, ArH), 7.74 (2H, d, J = 8.6 Hz, ArH), 7.92 (2H, d, J = 8.2 Hz, ArH), 8.02 (2H, d, J = 8.6 Hz, ArH).

¹³C NMR (100.6 MHz, CDCl₃): δ 32.6 (CH₂), 126.80 (ArCH), 126.82 (ArCH), 126.84 (ArCH), 127.7 (ArCH), 128.0 (ArCH), 129.4 (ArCH), 132.5 (quaternary ArC), 133.3 (quaternary ArC), 134.1 (quaternary ArC), 134.2 (quaternary ArC).

[α]²⁰_D = +173.8° (c = 1.0, CHCl₃).

An advanced process for large scale (500 g) preparation of a (3Z,5Z)-2,7-dihydro-1H-azepine-derived chiral tridentate ligand (Hamari ligand), widely used for asymmetric synthesis of tailor-made α-amino acids via the corresponding glycine Schiff base Ni(II) complex, is disclosed. The process includes amidation, bis-alkylation, and precipitation/purification of the target compound by TFA as a counterion.

Large Scale Synthesis of Chiral (3Z,5Z)-2,7-Dihydro-1H-azepine-Derived Hamari Ligand for General Asymmetric Synthesis of Tailor-Made Amino Acids

Motohiro Takahashi*^†

, Hiroki Moriwaki^†, Toshio Miwa^†, Brittanie Hoang^‡, Peng Wang^‡, and Vadim A. Soloshonok*^§^∥

^† Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan

^‡ Hamari Chemicals USA, San Diego Research Center, 11494 Sorrento Valley Road, San Diego, California 92121, United States

^§ Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain

^∥ IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00406

Publication Date (Web): January 18, 2019

*E-mail: motohiro-takahashi@hamari.co.jp., *E-mail: vadym.soloshonok@ehu.es.

This article is part of the Japanese Society for Process Chemistry special issue.

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Kalyan Kumar Pasunooti, Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Uncategorized Comments Off

Jan 052019

Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC₅₀ of 73 nM without a significant effect on CYP3A4 (EC₅₀ > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Yingjun Li^†^§, Kalyan Kumar Pasunooti^†^§, Ruo-Jing Li^†, Wukun Liu^†, Sarah A. Head^†, Wei Q. Shi^†

, and Jun O. Liu*^†^‡

^†Department of Pharmacology and Molecular Sciences and ^‡Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States

J. Med. Chem., 2018, 61 (24), pp 11158–11168

DOI: 10.1021/acs.jmedchem.8b01252

Publication Date (Web): November 27, 2018

*E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955-4520.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01252

■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01252. Molecular formula strings (CSV) Detail of synthesis procedures; kinetic curve of CYP3A4 enzyme activities; philipin staining of compound 15c, 15g; competition assay of itraconazole photoaffinity probe; and NMR and HPLC chart of representative compounds (PDF)

■ AUTHOR INFORMATION Corresponding Author *E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955- 4520. ORCID Wei Q. Shi: 0000-0001-5453-1753 Jun O. Liu: 0000-0003-3842-9841 Author Contributions § Y.L. and K.K.P. contributed equally to this work. Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Cancer Institutes (grant R01CA184103) and the Flight Attendant Medical Research Institute

4-(4-(4-(4-(((2S,4R)-2-((1H-Tetrazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)- 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (15n).

1 H NMR (500 MHz, CDCl3, δH): 8.46 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.36 (d, J = 14.0 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 1H), 4.31−4.27 (m, 1H), 3.95 (dd, J = 8.5, 6.5 Hz, 1H), 3.88−3.83 (m, 2H), 3.53 (dd, J = 9.5, 6.5 Hz, 1H), 3.38 (br s, 4H), 3.26 (br s, 4H), 1.89−1.83 (m, 1H), 1.74−1.69 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).

13C NMR (125 MHz, CDCl3, δC): 162.5, 152.8, 152.7, 152.0, 136.3, 133.9, 133.3, 131.5, 130.1, 129.6, 127.2, 123.6, 116.8, 115.4, 107.4, 74.8, 67.9, 67.6, 56.6, 52.7, 36.5, 31.0, 28.5, 19.2, 10.8.

HRMS (ESI) calcd for C34H37Cl2N9O4, 706.2424; found, 706.2425.

HPLC purity: 95.9%, tR = 10.5 min

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical Society, Org. Lett., ACS Chem Bio, J Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.

Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.

He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.