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

 

(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

Copyright © 2019 American Chemical Society

*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.

 

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

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.

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

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.
 

////////

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*^ab 

 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

Guest of honour at Selectbio Drug discovery india 2019 international conference at Orchid Mumbai India 17 Jan 2019 Breakthrough in medicinal chemistry

Guest of honour at
Attending Selectbio Drug discovery india 2019 international conference at Orchid Mumbai India 17 Jan 2019 Breakthrough in medicinal chemistry
Thanks

Omecamtiv mecarbil オメカムティブメカビル « New Drug Approvals

Omecamtiv mecarbil オメカムティブメカビル « New Drug Approvals

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

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

Copyright © 2018 American Chemical Society

*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.

Experience

Research Scientist

Company NameSingapore-MIT Alliance for Research & Technology Centre

Dates EmployedJul 2017 – Present

Employment Duration1 yr 4 mos

LocationSingapore

Medicinal Chemistry and Drug Discovery

Research Fellow

Company NameNanyang Technological University, Singapore

Dates EmployedOct 2013 – Jun 2017

Employment Duration3 yrs 9 mos

LocationSingapore

Peptide & Protein Chemistry and Medicinal Chemistry

Postdoctoral Fellow

Company NameJohns Hopkins Medicine

Dates EmployedMay 2012 – Sep 2013

Employment Duration1 yr 5 mos

LocationBaltimore, Maryland Area

Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology

Postdoctoral Associate

Company NameNanyang Technological University

Dates EmployedJul 2011 – Mar 2012

Employment Duration9 mos

LocationSingapore

Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.

Senior Research Associate in Medicinal Chemistry

Company NameGVK Biosciences

Dates EmployedJan 2007 – Jul 2007

Employment Duration7 mos

LocationHyderabad Area, India

Synthesis of bioactive molecules for medicinal chemistry applications.

Junior Scientist in Medicinal Chemistry (Anti-Infective group)

Company NameDr. Reddy’s Laboratories

Dates EmployedAug 2003 – Dec 2006

Employment Duration3 yrs 5 mos

LocationHyderabad Area, India

Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more

Education

• 

  Nanyang Technological University

  Degree NamePhD

  Field Of StudyOrganic and Bioorganic chemistry

  Dates attended or expected graduation2007 – 2011
• 

  Osmania University

  Degree NameM. Sc

  Field Of StudyPhysical Organic Chemistry

  Dates attended or expected graduation2000 – 2002
• 

  Kakatiya University

  Degree NameB. Sc,

  Field Of StudyMathematics Physics Chemistry

  Dates attended or expected graduation1996 – 1999

 

 

 Research Scientist at Singapore-MIT Alliance for Research and Technology

• 
  

  Research Fellow at Nanyang Technological University, Singapore
• 
  

  Former Post-Doctoral Fellow at Johns Hopkins School of Medicine
• 
  

  Studied Physical organic chemistry at PG College of Science, Saifabad/Osmania University
• 
  

  Studied M.P.C at Government Junior College, Hanamkonda
• 
  

  Studied B.Sc. at Kakatiya Government Degree College
• 
  

  Went to Z. P. S. S. Geesugonda

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

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