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ChemSpider 2D Image | Diquafosol | C18H26N4O23P4

Diquafosol

  • Molecular FormulaC18H26N4O23P4
  • Average mass790.307 Da
{Oxybis[(hydroxyphosphoryl)oxy]}bis[hydrogéno(phosphonate)] de bis{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxytétrahydro-2-furanyl]méthyle}
59985-21-6 [RN]
7828VC80FJ
8326
Bis{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxytetrahydro-2-furanyl]methyl} {oxybis[(hydroxyphosphoryl)oxy]}bis[hydrogen (phosphonate)]
ChemSpider 2D Image | Diquafosol tetrasodium | C18H22N4Na4O23P4
Diquafosol Tetrasodium | CAS#:211427-08-6 | Chemsrc

Diquafosol tetrasodium

  • Molecular FormulaC18H22N4Na4O23P4
  • Average mass878.234 Da
1) uridine, 5′-(pentahydrogen tetraphosphate), P”’->5′-ester with uridine, tetrasodium salt
211427-08-6[RN]
Diquafosol tetrasodium[USAN]
uridine(5′)tetraphospho(5′)uridine tetrasodium salt
Diquafosol tetrasodium (USAN)
INS365
P1,P4-Diuridine 5′-tetraphosphate tetrasodium salt
Prolacria
U2P4
UNII:X8T9SBH9LL
INS-365; DE-089; KPY-998
Title: Diquafosol
CAS Registry Number: 59985-21-6
CAS Name: Uridine 5¢-(pentahydrogen tetraphosphate) P¢¢¢®5¢-ester with uridine
Additional Names:P1,P4-diuridine 5¢-tetraphosphate; UP4U
Molecular Formula: C18H26N4O23P4
Molecular Weight: 790.31
Percent Composition: C 27.36%, H 3.32%, N 7.09%, O 46.56%, P 15.68%
Literature References: Uridine nucleotide analog. P2Y2 purinoceptor agonist; stimulates mucin secretion from goblet cells. Prepn: M. J. Stutts, III et al.,WO9640059 (1996 to Univ. North Carolina at Chapel Hill); and receptor activity: W. Pendergast et al.,Bioorg. Med. Chem. Lett.11, 157 (2001). Ocular pharmacology: T. Fujihara et al.,J. Ocul. Pharmacol. Ther.18, 363 (2002). Review of development and therapeutic potential: J. Fischbarg, Curr. Opin. Invest. Drugs4, 1377-1383 (2003); K. K. Nichols et al.,Expert Opin. Invest. Drugs13, 47-54 (2004). Clinical trial in dry eye disease: J. Tauber et al., Cornea23, 784 (2004).
Derivative Type: Tetrasodium salt
CAS Registry Number: 211427-08-6
Manufacturers’ Codes: INS-365
Molecular Formula: C18H22N4Na4O23P4
Molecular Weight: 878.23
Percent Composition: C 24.62%, H 2.52%, N 6.38%, Na 10.47%, O 41.90%, P 14.11%
Therap-Cat: In treatment of dry eye disease.
Keywords: Purinoceptor P2Y Agonist.
Company:
Santen (Originator)
Sales:
$80 Million (Y2015); 
$71.7 Million (Y2014);
$79.3 Million (Y2013);
$67.1 Million (Y2012);
$36 Million (Y2011);
ATC Code:
S01
Approved Countries or Area 2010-04-16, JAPAN

Diquafosol tetrasodium was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on April 16, 2010. It was developed and marketed as Diquas® by Santen Pharmaceutical Corporation in Japan.

Diquafosol tetrasodium is a P2Y2 purinoceptor receptor agonist. It is indicated for improve dry eye symptoms by promoting secretion of mucin and water, thereby bringing the tear film closer to a normal state. No serious ocular or systemic adverse drug reactions were found during the clinical trials. Dry eye begins with symptoms of ocular discomfort such as burning, stinging or a foreign body sensation.

Diquas® is available as solution for ophthalmic use, containing 3% of Diquafosol tetrasodium. The recommended dose is 1 drop at a time, 6 times a day.

Index:

Diquafosol (tradename Diquas) is a pharmaceutical drug for the treatment of dry eye disease. It was approved for use in Japan in 2010.[1] It is formulated as a 3% ophthalmic solution of the tetrasodium salt.

Its mechanism of action involves agonism of the P2Y2 purinogenic receptor.[2]

SYN

INS-365 can also been obtained by the following ways: 4) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with bis(tributylammonium) pyrophosphate (II) by means of CDI, followed by purification by semipreparative ion璭xchange chromatography. 5) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with pyrophosphoryl chloride (III) in pyridine, followed by chromatographic purification as before. 6) Condensation of uridine (IV) with POCl3 and bis(tributylammonium) pyrophosphate (II) by means of tributylamine in trimethyl phosphate, followed by chromatographic purification as before. 7) Dimerization of uridine-5′-diphosphate tributylammonium salt (V) by means of CDI in DMF, followed by purification over Dowex 50Wx4 Na+. 8) Condensation of uridine-5′-triphosphate tributylammonium salt (VI) with uridine-5′-monophosphate tributyl-ammonium salt (I) by means of DCC in DMF, followed by chromatographic purification as before. 9) Reaction of uridine-5′-monophosphate tributylammonium salt (I) with CDI in DMF, followed by condensation with uridine-5′-triphosphate (VI) and chromatographic purification as before.

CLIP

Route 1

Reference:1. WO9905155A2.

Route 2

Reference:1. WO1999005155.

2. Bioorg. Med. Chem. Lett. 200111, 157-160.

Route 3

Reference:1. WO1999005155.

Route 4

Reference:1. WO2014103704.

SYN

Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium

    • Pengfei Xu
Cite this: Org. Process Res. Dev. 2020, XXXX, XXX, XXX-XXX
Publication Date:June 30, 2020
Abstract Image
https://doi.org/10.1021/acs.oprd.0c00209

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.0c00209/suppl_file/op0c00209_si_001.pdf

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00209

A scalable and practical route to synthesize the P2Y2 receptor agonist diquafosol tetrasodium has been described. Diquafosol tetrasodium was obtained via a four-step process starting from commercially available 5′-uridylic acid disodium salt. The whole procedure gives the target product in a 45% overall yield with high purity (>99%). Key steps in this process including isolation of impurities and the target product by using anion-exchange resin are discussed in detail. The optimized process has been successfully demonstrated on a large scale to support the development of diquafosol tetrasodium in China.

References

  1. ^ “Santen and Inspire Announce Approval of DIQUAS for Dry Eye Treatment in Japan”. April 16, 2010.
  2. ^ Pendergast, W; Yerxa, BR; Douglass Jg, 3rd; Shaver, SR; Dougherty, RW; Redick, CC; Sims, IF; Rideout, JL (2001). “Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates”. Bioorganic & Medicinal Chemistry Letters11 (2): 157–60. doi:10.1016/S0960-894X(00)00612-0PMID 11206448.
Diquafosol
Diquafosol.svg
Names
IUPAC name

[[[[(2R,3S,4R,5R)-5-(2,4-Dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl] [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl hydrogen phosphate
Other names

P1,P4-Bis(5′-uridyl) tetraphosphate; INS-365; Diquafosol tetrasodium
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
Properties
C18H26N4O23P4
Molar mass 790.306 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

///////////// INS 365, Diquafosol, INS-365,  DE 089,  KPY 998, JAPAN 16

59985-21-6 (Diquafosol );
211427-08-6 (Diquafosol Tetrasodium);

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DR ANTHONY CRASTO

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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