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AZD 1080

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AZD 1080 

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile

2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile

AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively, shows >14-fold selectivity against CDK2, CDK5, CDK1 and Erk2.

Cas 612487-72-6, AZD1080,

AZD-1080, a glycogen synthase kinase 3 (GSK-3) inhibitor, had been in early clinical trials for the treatment of Alzheimer’s type dementia by AstraZeneca

Astrazeneca Ab

PATENTS

WO 2003082853

http://www.google.com/patents/WO2003082853A1?cl=en

PAPER

Organic Process Research & Development (2008), 12(3), 540-543.

http://pubs.acs.org/doi/abs/10.1021/op800020r

Abstract Image

A mild and robust method for the large-scale palladium-catalysed cyanation of aryl bromides has been developed. The reaction is sensitive to cyanide poisoning of the catalyst, and it was found that the order of adding the reagents had a strong impact on the performance of the reaction. Addition of the cyanide source to a preheated mixture of the other reagents was critical for achieving a robust and scaleable process. This improved protocol allowed the reaction to be run to full conversion within 3 h at 50 °C on a 6.7 kg scale. Furthermore, it led to the identification of several new efficient catalysts for the reaction.

2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile (2) (5.2 kg, 15.6 mol), 90% yield with a purity of >90% by HPLC. 1H NMR (d6-DMSO, 400 MHz) δ 14.79 (broad s, 1H), 10.86 (broad s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.27 (dd,J = 8.0, 0.9 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.57 (t, J = 4.4 Hz, 4H), 3.36 (s, 2H), 2.36 (broad s, 4H); 13C NMR (d6-DMSO, 100 MHz) δ 168.8, 148.6, 141.8, 137.0, 136.1, 125.4, 123.9, 122.3, 121.1, 118.8, 118.3, 108.7, 101.3, 84.6, 66.1, 58.4, 52.8. MS (ES) m/z [M + 1] 335.

PAPER

Topics in Organometallic Chemistry (2012), 42(Organometallics as Catalysts in the Fine Chemical Industry), 125-134.

http://link.springer.com/chapter/10.1007%2F3418_2011_25

 

 

PATENT

https://www.google.co.in/patents/WO2007089193A1?cl=en

Figure imgf000005_0001

In the above scheme, preferably Rl is bromo and X is chloro.

 

 

Synthesis of 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl] lH-indole-5-carbonitrile citrate

Example 14

2-Hydroxy-3-r5-(moφholin-4-ylmethyl)pyridin-2-yl1 lH-indole-5-carbonitrile citrate salt 2-Hydroxy-3-[5-(moφholin-4-ylmethyl)pyridin-2-yl] lH-indole-5-carbonitrile (5.14 kg, 15.4 mol) was suspended in ethanol (54 L) at room temperature. The suspension was heated to an inner temperature of 700C and a solution of citric acid (3.424 kg, 17.82 mol, 1.300 eq)) in water (103 L) was added keeping the inner temperature above 650C. The mixture was heated to reflux. After this the resulting solution was mixed with activated charcoal (0.412 kg) and reflux continued for 3.5 h after which the reaction mixture was clear filtered at 830C followed by cooling to room temperature over 20 h. After filtration the precipitate was washed twice with a cold mixture of ethanol/water (6.9 L/13.7 L). Drying under vacuum at 5O0C gave 6.648 kg, 82.2% yield of 2-hydroxy-3-[5-(morpholin- 4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile citrate having a purity of at least 98%. The palladium content was less than 1 ppm and the zinc content was lower than 10 ppm. 1H NMR (Jd-DMSO3 400 MHz) δ 14.7 (br s, 1 H), 11.55 (s, 1 H), 10.98 (s, IH), 8.31 (s, 1 H), 8.08 (br d, J= 1.84Hz, IH), 8.02 (s, IH), 7.90 (br d, J = 8.92Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.02 (d, J= 8.0Hz), 4.28 (s, 2 H), 3.97 (m, 2 H), 3.94 (m, 2H), 3.35 (m, 9H), 3.32 (m, 2H) ppm; 13C NMR (d6-DMSO, 400MHz) δ 168.9, 148.5, 142.7, 139.8, 137.5,126.4, 124.9, 124.8, 120.9, 119.4, 118.4, 113.3, 109.0, 101.6, 85.7, 63.1, 55.5, 50.3, 40.1, 39.9, 39.7, 39.2, 39.0, 38.8ppm; MS (ES) m/z [M++l] 335.


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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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