Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

Nekkaa, Imane; Palkó, Márta; Mándity, István M.; Fülöp, Ferenc

doi:10.3762/bjoc.14.20

Cited by 12 publications

(11 citation statements)

References 57 publications

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“…Introduction of the thioxo group (compounds 8−14) followed the procedure of Xu and Yadan using phenyl thionochloroformate [28]. Compound 8 as well has been described in the literature [29]. The synthesis of the benzothiazole-linker was already described by García-Reyes and Witt et al [15].…”

Section: Synthesis Of New Iwp-based Inhibitor Compoundsmentioning

confidence: 99%

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Liu

Witt

Ianes

et al. 2019

IJMS

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Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts.

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Section: Synthesis Of New Iwp-based Inhibitor Compoundsmentioning

confidence: 99%

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Liu

Witt

Ianes

et al. 2019

IJMS

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“…Our previous investigations on the CF rDA reactions of condensed pyrimidinone derivatives revealed that the CF approach is superior to existing conventional batch methods. [9] In this work, starting materials were selected with the aim of testing the viability of the proposed CF rDA protocol with more complex fused pyrimidinone moieties, and also of investigating molecules that have never been subjected to rDA reactions under batch conditions. We started our study with readily available aminocarboxamides 1a-1d, which were prepared by known literature approaches.…”

Section: Resultsmentioning

confidence: 99%

“…It is important to note that toluene is known to be an effective solvent under superheated CF rDA conditions. [9,33] This effect is even more pronounced when MeOH is used as a cosolvent. The transformation of diexo-methylene-bridged 2-spiroquinazolinone 8 is illustrative.…”

Section: Resultsmentioning

confidence: 99%

“…We recently revealed the potential of the use of continuous‐flow (CF) technology for the synthesis of various functionalized pyrimidinone systems through rDA reactions . Our interest in CF processes can be explained, at least in part, by the number of potential advantages that CF processes have over traditional batch chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…[8] We recently revealed the potential of the use of continuousflow (CF) technology for the synthesis of various functionalized pyrimidinone systems through rDA reactions. [9] Our interest in processes. These results were achieved through careful optimization of the reaction parameters.…”

Section: Introductionmentioning

confidence: 99%

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Continuous‐Flow retro‐Diels–Alder Reaction: A Process Window for Designing Heterocyclic Scaffolds

et al. 2018

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The synthesis of racemic and enantiopure tricyclic and tetracyclic pyrrolopyrimidinones, pyrimidoisoindoles, and spiropyrimidinones, as valuable new chemical entities (NCE), based on a highly controlled continuous‐flow (CF) retro‐Diels–Alder protocol is presented. This approach ensures enhanced safety, and gave the target pyrimidinone derivatives 17–25 in yields higher than those obtained in batch and microwave processes. These results were achieved through careful optimization of the reaction parameters. We also developed an alternative time‐efficient route for the synthesis of intermediate quinazolinones 2–16 involving a three‐step domino ring‐closure reaction followed by spirocyclization under continuous‐flow conditions, starting from β‐aminonorbornene carboxamides 1a–1d and γ‐keto acids or cycloalkanones.

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Scalable Synthesis of Norbornadienes via in situ Cracking of Dicyclopentadiene Using Continuous Flow Chemistry

et al. 2021

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The norbornadiene (NBD)-quadricyclane (QC) photoswitch has recently attracted attention due to its use in molecular solar thermal energy systems (MOST). Normally for device testing, several grams are needed. One way of synthesizing NBDs efficiently is through the Diels-Alder reaction between alkynes and cyclopentadiene. However, scaling up the reaction can be troublesome in a research lab environment. Also, dicyclopentadiene needs cracking before utilization which is a timeconsuming step. Here, we developed a method where we both scale up the synthesis in a single reaction step that involves both in situ cracking of dicyclopentadiene and the direct reaction of cyclopentadiene with acetylene derivatives using a tubular coiled stainless steel flow reactor. As a proof-of-concept, we synthesized six different NBD compounds and scaled the synthesis to produce 87 g of a novel NBD in 9 h. The NBD is further characterized, showing promising properties for MOST applications. Our new method shows that flow chemistry is an attractive technique for the fast and efficient synthesis of large quantities of NBDs, needed to develop future real-life devices and applications.

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Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

Cited by 12 publications

References 57 publications

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Continuous‐Flow retro‐Diels–Alder Reaction: A Process Window for Designing Heterocyclic Scaffolds

Scalable Synthesis of Norbornadienes via in situ Cracking of Dicyclopentadiene Using Continuous Flow Chemistry

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