A Convenient Preparation of 1-Aroylpiperazines

Desai, Mahesh; Watthey, Jeffrey W. H.; ZUCKERMAN, M.

doi:10.1080/00304947609355594

Cited by 16 publications

(11 citation statements)

References 4 publications

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“…Intermediates 63–67 were prepared using reported procedure [18], [19]. N -3-(morpholinopropyl)piperazine ( 70 ) was prepared by a reaction of piperazine with 4-(3-chloropropyl)morpholine ( 69 ), which was obtained by a reaction of morpholine with 1-bromo-3-chloropropane [20].…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Figure 4 , for the synthesis of piperazinylquinoxalines 9–53 , similar materials and procedures were applied as synthesis of compounds 4–8 except for the use of compounds 60–67 and 70 instead of N -carbamoylpiperazine. Intermediates 63–67 were prepared using reported procedure [18] , [19] . N -3-(morpholinopropyl)piperazine ( 70 ) was prepared by a reaction of piperazine with 4-(3-chloropropyl)morpholine ( 69 ), which was obtained by a reaction of morpholine with 1-bromo-3-chloropropane [20] .…”

Section: Resultsmentioning

confidence: 99%

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Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Guan

et al. 2012

PLoS ONE

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BackgroundDevelopment of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers.Methodology/Principal FindingOur approach was to perform structural modification and optimization based on previously identified morpholinoquinoxaline derivative WR1 and piperidinylquinoxaline derivative WR23 with a total of forty-five novel piperazinylquinoxaline derivatives synthesized. Most target compounds showed low micromolar to nanomolar antiproliferative potency against five human cancer cell lines using MTT method. Selected compounds showed potent PI3Kα inhibitory activity in a competitive fluorescent polarization assay, such as compound 22 (IC50 40 nM) and 41 (IC50: 24 nM), which induced apoptosis in PC3 cells. Molecular docking analysis was performed to explore possible binding modes between target compounds and PI3K.Conclusions/SignificanceThe identified novel piperazinylquinoxaline derivatives that showed potent PI3Kα inhibitory activity and cellular antiproliferative potency may be promising agents for potential applications in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Guan

et al. 2012

PLoS ONE

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“…In fact, piperazine and homopiperazine are very special as they are believed to stay as monoacetate salt in glacial acetic acid. 14 Thus, they can be selectively monoacylated in glacial acetic acid to allow high selectivity. However, in batch reactors under conventional heating, the reactions were often incomplete even after prolonged reaction time and the yields of monoacylated product were only moderate.…”

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confidence: 99%

“…In addition, there is no direct evidence for the existence of the piperazine completely as piperazine monoacetate in glacial acetic acid. 14 However the results can be explained by assuming that piperazine and/or homopiperazine exists in equilibrium of diacetate and monoacetate salt in the glacial acetic acid. And upon heating the equilibrium is shifted towards monoacetate salt which in turn reacts with the acylating agent to complete the reaction.…”

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Efficient and continuous monoacylation with superior selectivity of symmetrical diamines in microreactors

2012

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“…There have been few reports of the direct transformation of diamines to mono benzoyl diamines, − the main difficulty with this simple transformation being the formation of dibenzoyl diamines . Under normal basic conditions using, for example, pyridine as the base and solvent, the dibenzoylated compound 4a was the dominant product, even through a large excess (10 equiv) of piperazine 1a was used (Scheme ).…”

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Benzoylation of Dianions: Preparation of Monobenzoylated Derivatives of Symmetrical Secondary Diamines

1999

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Monoacylated symmetrical secondary diamines are building blocks 1 or intermediates 2 widely used in the drug discovery process that are present in several investigational and established drugs. 3 Examples include the cardiotonic agent vesnarinone and the antihypertensive agent prazosin (Chart 1). Direct monoacylation of symmetrical diamines is frequently fraught with the complication associated with the tendency for bis-acylation to occur. To date, there are a number of indirect, multistep preparations of monoacylated symmetric secondary diamines from diamines 4,5 with the most common pathway involving the selective monoprotection of one nitrogen atom, followed by acylation of the remaining nitrogen and finally deprotection, to afford the desired product. 5 There have been few reports of the direct transformation of diamines to mono benzoyl diamines, 6-9 the main difficulty with this simple transformation being the formation of dibenzoyl diamines. 6 Under normal basic conditions using, for example, pyridine as the base and solvent, the dibenzoylated compound 4a was the dominant product, even through a large excess (10 equiv) of piperazine 1a was used (Scheme 1). A possible explanation of the uncontrollable dibenzoylation of symmetrical secondary diamines under these conditions is that the monobenzoylated intermediate 3a is more soluble in the solvent than piperazine 1a and reacts preferentially with the benzoyl chloride to provide predominantly the observed dibenzoylated product 4a.This problem has been resolved to some degree by application of a rather laborious procedure involving the multistep addition of starting materials with very cautious control of the pH (range 3.8-5.4) of the reaction mixture. 5,6 Similarly, Watthey and co-workers described the direct monoaroylation of piperazine and homopiperazine in moderate yields (46-60%) using AcOH as the solvent. 7 In this case, the authors took advantage of the fact that piperazine was mostly present as a monoacetate salt and the product remained in that form after the benzoylation. Alternative procedures have utilized benzoic acid 8 and benzoic esters 9 as coupling partners.After encountering several of these problems in the preparation of monobenzoylated piperazine derivatives, we sought a more reliable and predictable procedure that would be of general applicability. The criteria established for this new methodology were: (a) simple and readily available starting materials; (b) mild, preferably room temperature conditions; (c) the formation of the product cleanly in high yield.It was rationalized that the reactivity of the diamine could be altered by making the mono or disalt 5 of diamine 1, which should be more reactive toward an aroyl chloride than diamine 1 itself, thus affording the monoacylated product 3a under kinetical control (Scheme 2). In developing this strategy, several experimental protocols were explored: 1 (a) 1 equiv of BuLi, (b) 1 equiv of BzCl; 10 2 (a) 1 equiv of BuLi, (b) 1 equiv of TMSCl, (c) 1 equiv of BzCl; 11 3 (a) 2 equiv of BuLi, (b) ...

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A Convenient Preparation of 1-Aroylpiperazines

Cited by 16 publications

References 4 publications

Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Efficient and continuous monoacylation with superior selectivity of symmetrical diamines in microreactors

Benzoylation of Dianions: Preparation of Monobenzoylated Derivatives of Symmetrical Secondary Diamines

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