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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc 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 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Altiratinib


Altiratinib
DCC-2701; DP-5164
CAS :1345847-93-9
N-[4-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Mechanism of Action:MET/TIE2/VEGFR2/TRK (A,B,C) kinase inhibitor
Indication:invasive solid tumors. The FDA has granted altiratinib Orphan Drug Designation for glioblastoma multiforme (GBM)
Development Stage:Phase I
Developer:Deciphera Pharmaceuticals, Llc

Altiratinib, also known as DCC-270, DP-5164, is an oral, selective and  highly potent inhibitor of MET, TIE2, VEGFR2 and TRK kinases with potential anticancer activity. DCC-2701 effectively reduces tumor burden in vivo and blocks c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701’s anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF. DCC-2701 may be superior to HGF antagonists that are in clinical trials and that pTyr(1349) levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment.  Inhibition of MET kinase blocks a key mechanism in tumor cells that causes cancer invasiveness and metastasis. (Oncogene. 2015 Jan 8;34(2):144-53.)

DCC-2701 is an angiogenesis inhibitor acting on Tie2 receptor, HGF receptor and VEGFR-2. The product is being evaluated in phase I clinical studies at Deciphera for the oral treatment of solid tumors.

Altiratinib(DCC-2701) is a novel c-MET/TIE-2/VEGFR inhibitor; effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro.

Altiratinib

SYNTHESIS

CLICK ON IMAGE TO ENLARGE

OR SEE

http://apisynthesisint.blogspot.in/2015/10/altiratinib-dcc-2701-dp-5164.html

IM5

IM3

IM2

IM4

PATENT

https://www.google.co.in/patents/WO2011137342A1?cl=en

Figure imgf000025_0001

Scheme 1

Figure imgf000030_0002
BEAWARE THIS IS NOT THE COMPD

Scheme 11

INTERMEDIATES

Scheme 9

[00108] A non-limiting example of Scheme 9 is illustrated below for the synthesis of 36, a specific example of 26 wherein X is F, Y is CI, and Zl , Z2, and Z3 are CH (Scheme 10). Addition of l ,2,4-trifluoro-5-nitrobenzene (33) to a solution of 2-chloropyridin-4-ol (34) and sodium hydride in DMF at 0 °C yields the nitro intermediate 35. The nitro moiety of 35 is subsequently reduced at RT in the presence of zinc dust and ammonium chloride in solution of me hanol and THF to yield amine 36.

Scheme 10

[00109] A non-limiting example of Scheme 7 is illustrated in Scheme 11, beginning with intermediate 36, prepared in Scheme 10. Thus, 36 readily reacts with acid chloride 13 (see Scheme 3) in the presence of triethylamine to yield chloro-pyridine 37. Chloro-pyridine 37 is then converted to 38, a specific example of 1 wherein Rl is F, X is F, Zl , Z2, and Z3 are CH and R3 is -C(0)CH3, upon treatment with acetamide (an example of R3-NH2 27 where R3 is acetyl) and cesium carbonate in the presence of a catalytic amount of palladium acetate and xantphos.

 NOTE 38 IS NOT THE FINAL PRODUCT

REFERENCES

Kwon Y, Smith BD, Zhou Y, Kaufman MD, Godwin AK. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015 Jan 8;34(2):144-53. doi: 10.1038/onc.2013.539. Epub 2013 Dec 23. PubMed PMID: 24362531; PubMed Central PMCID: PMC4067476.

////Altiratinib, DCC-2701, DP-5164, Phase I, Deciphera Pharmaceuticals

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