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AZD 3264 an IKK2 Inhibitor from Astra Zeneca

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Figure

AZD 3264

MW 441.50

CAS 1609281-86-8

MF C21 H23 N5 O4 S
3-​Thiophenecarboxamide​, 2-​[(aminocarbonyl)​amino]​-​5-​[4-​(3,​5-​dimethyl-​4-​isoxazolyl)​-​2-​[(3S)​-​3-​pyrrolidinyloxy]​phenyl]​-
2-(Carbamoylamino)-5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3S)-pyrrolidin-3-yloxy]phenyl]thiophene-3-carboxamide

Inhibition of IkB-kinase IKK2 has been identified as one of the novel pathways to treat inflammatory conditions such as asthma, chronic pulmonary obstructive disorder (COPD) and rheumatoid arthritis

Astrazeneca Ab,

……………………..

PATENT

WO 2003010158

https://www.google.com/patents/WO2003010158A1?cl=en

 

Figure

 

The synthesis began with the aromatic nucleophilic substitution reaction of 2-fluorobromobenzene (2) with (S)-N-Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which was borylated via halogen metal exchange using n-hexLi in THF followed by treatment with triisopropyl borate and acidic work-up to give the boronic acid intermediate 5. Suzuki coupling of the boronic acid 5 with bromothiophene 6(2)afforded the intermediate 7. Intermediate 7 was subjected to regioselective bromination using bromine in acetic acid. This reaction was nonregioselective and yielded 17% of the required isomer 8. The bromo compound 8 was coupled with isoxazole boronate ester 9 by another Suzuki reaction to get the title compound. The overall yield of the synthesis was <6%.

 

 

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PAPER

Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500105n

http://pubs.acs.org/doi/full/10.1021/op500105n

 

Abstract Image

An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.

AZD3264 (1)

A stirred solution of tert-butyl (3S)-3-[2-(4-carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in tetrahydrofuran (25 L) w……………………………………………………title compound in 91% yield.
Purification

To a stirred suspension of crude AZD3264 (1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64 L) was added formic acid (0.24 kg, 5.18 mol), and the mixture was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol). The product was isolated by filtration.
 1H NMR (DMSO-d6, 400 MHz): δ 1.92–2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 3H), 5.11–5.12 (m, 1H), 6.90 (br, 2H), 7.00–7.03 (m, 2H), 7.30 (br, 1H), 7.70–7.72 (m, 2H), 7.83 (s, 1H), 10.93 (s, 1H).
 13C NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76, 114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84, 150.12, 152.54, 154.50, 158.13, 165.14, 167.06.
DEPT NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01, 79.35, 114.17, 120.70, 121.20, 126.92.
HRMS calcd for C21H24N5O4S (M + H)+: 442.1543, found 442.1554.
[α]25D −13.80 (c 0.5, DMSO)
 
Journal of Medicinal Chemistry (2013), 56(18), 7232-7242 reports similar analogues

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2 Comments

  1. DR ANTHONY MELVIN CRASTO Ph.D's avatar DR ANTHONY MELVIN CRASTO Ph.D says:
    May 16, 2015 at 1:49 am

    Reblogged this on DRUG REGULATORY AFFAIRS INTERNATIONAL.

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  2. Unknown's avatar Proposition d’optimisation de la synthèse du AZD 3264 (sur le papier version française) – (-84% sur coût MP ; +2 étapes en one-pot) | Mon labo sur le Net says:
    July 31, 2016 at 1:14 am

    […] Exploiting the Differential Reactivities of Halogen Atoms: Development of a Scalable Route to IKK2 Inhibitor AZD3264, Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Hebbal, OffBellary Road, Bangalore 560024, India, Org. Process Res. Dev.2014, 18, 646−651 Détails da la publication ici: https://newdrugapprovals.org/2015/05/15/azd-3264-an-ikk2-inhibitor-from-astra-zeneca/ […]

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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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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