A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 2. Synthesis of ZD6021 Cyano Acid

Moseley, Jonathan D.; Moss, William O.; Welham, Matthew J.; Ancell, Claire L.; Banister, John; Bowden, Sharon A.; Norton, G.A.; Young, Maureen J.

doi:10.1021/op020065h

Cited by 17 publications

(26 citation statements)

References 9 publications

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“…There are numerous approaches to removing precious and transition metals, mainly palladium . Removal of copper from organic compounds has been performed with EDTA, thioacetamid, ammonia, TFA/H 2 SO 4 , oxalic acid, and pyridine . To remove the last amounts of copper, precipitation of copper sulfide via gaseous hydrogen sulfide treatment was used initially.…”

Section: Resultsmentioning

confidence: 99%

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A Large Scale Process for the Preparation of Thymitaq

Malmgren¹,

Bäckström²,

Sölver³

et al. 2008

Org. Process Res. Dev.

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The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coupling between 4-mercaptopyridine and the bromoquinazolinone. During process development, sodium hydride was replaced with sodium hydroxide and a method for removal of copper, based on 2,4,6-trimercapto-s-triazine, was developed. A number of purification operations were performed to ensure a product of pharmaceutical quality.

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Section: Resultsmentioning

confidence: 99%

“…An equilibrium is probably responsible for the phenomena. Mosely et al were also forced to use repeated addition when removing copper with EDTA . To keep 1 in solution a low pH was maintained by addition of hydrochloric acid.…”

Section: Resultsmentioning

confidence: 99%

A Large Scale Process for the Preparation of Thymitaq

Malmgren¹,

Bäckström²,

Sölver³

et al. 2008

Org. Process Res. Dev.

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“…The treatment of 1,8-naphthalic anhydride with 1.1 equiv. N-bromosuccinimide in H 2 SO 4 provided the desired brominated compound 4 in >90% purity after trituration with EtOH [44]. The bromoanhydride was then converted to the corresponding methoxyethyl imide 5 using microwave irradiation (Scheme 1, see supplementary material for full details).…”

Section: Methodsmentioning

confidence: 99%

Direct Amidation to Access 3-Amido-1,8-Naphthalimides Including Fluorescent Scriptaid Analogues as HDAC Inhibitors

Hearn

Ashton

Acharya

et al. 2021

Cells

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Methodology to access fluorescent 3-amido-1,8-naphthalimides using direct Buchwald–Hartwig amidation is described. The protocol was successfully used to couple a number of substrates (including an alkylamide, an arylamide, a lactam and a carbamate) to 3-bromo-1,8-naphthalimide in good yield. To further exemplify the approach, a set of scriptaid analogues with amide substituents at the 3-position were prepared. The new compounds were more potent than scriptaid at a number of histone deacetylase (HDAC) isoforms including HDAC6. Activity was further confirmed in a whole cell tubulin deacetylation assay where the inhibitors were more active than the established HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds make them amenable to cellular imaging studies and theranostic applications.

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“…The deceptively simple structure of 11 masks the fact that 1,3-disubstituted naphthalenes are difficult to prepare via standard directing rules for naphthalenes. Fortunately recent reports by Moseley and co-workers appeared outlining the preparation of bromo ester 11 that closely followed an earlier synthesis (Scheme ) . Bromination of readily available naphthalic anhydride 15 with 0.75 equiv of bromine in 70% concentrated nitric acid occurred regioselectively in the 3-position of the naphthalene ring to give 16 in 17% yield.…”

Section: Introductionmentioning

confidence: 90%

A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist

Kuethe

Childers

Humphrey

et al. 2008

Org. Process Res. Dev.

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The development of a scalable synthesis of a potent cholecystokinin (CCK) 1R receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support aggressive timelines and evaluate safety and pharmacological studies. Key improvements involved streamlining the preparation of imidazole acid 7 and discovery of a more efficient preparation of naphthyl piperazine fragment 23, including an improved preparation of 3-bromonaphthallic anhydride 16.

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A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 2. Synthesis of ZD6021 Cyano Acid

Cited by 17 publications

References 9 publications

A Large Scale Process for the Preparation of Thymitaq

A Large Scale Process for the Preparation of Thymitaq

Direct Amidation to Access 3-Amido-1,8-Naphthalimides Including Fluorescent Scriptaid Analogues as HDAC Inhibitors

A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist

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