Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

Drev, Miha; Grošelj, Uroš; Mevec, Špela; Pušavec, Eva; Štrekelj, Janja; Golobič, Amalija; Dahmann, Georg; Stanovnik, B.; Svete, Jurij

doi:10.1016/j.tet.2014.09.020

Cited by 26 publications

(13 citation statements)

References 26 publications

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“…For the final amidation step 1,1'-carbonyldiimidazole (CDI), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and bis(pentafluorophenyl) carbonate (BPC) were tested as the reagents for the activation of the carboxy group of 4. As we already experienced previously in amidation of related hetarenecarboxylic acids, [22][23][24][25][26] BPC proved to be the most suitable reagent, because it gave the corresponding carboxamides 5 reproducibly and in good yields. Thus, upon activation of 4 with BPC to form the intermediate pentafluorophenyl ester 4', further treatment with 1:1 mixtures of amines and triethylamine for 12 h furnished the target carboxamides 5a-h in 55-87% yields upon chromatographic workup (Scheme 1).…”

Section: Resultsmentioning

confidence: 57%

“…23,26 Subsequent cyclisation of 2 with methyl 5-amino-1H-pyrazole-4-carboxylate (1) 27 was performed in acetic acid at 80 °C for 24 h to afford methyl 5-(N-Boc-N-benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxylate (3) in 95% yield. Notably, heating at temperatures above 80 °C shortened the reaction times at the expense of the product yield due to partial acidolytic removal of the Boc group and concomitant formation of undesired by-products.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, heating at temperatures above 80 °C shortened the reaction times at the expense of the product yield due to partial acidolytic removal of the Boc group and concomitant formation of undesired by-products. Somewhat expectedly, 23,25 attempted hydrolysis of the ester function with aq. NaOH failed.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo- 4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K

Lukić¹,

Grošelj

Novinec

et al. 2017

ACSi

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Eight novel 5-(N-Boc-N-benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides were prepa red in three steps from methyl 3-amino-1H-pyrazole-4-carboxylate and methyl 5-(benzyl(tert-butoxycarbonyl)amino)-3-oxopentanoate. The synthetic procedure comprises cyclocondensation of the above starting compounds, hydrolysis of the ester, and bis(pentafluorophenyl) carbonate (BPC)-mediated amidation. Title carboxamides were tested for inhibition of cathepsins K and B. The N-butylcarboxamide 5a exhibited appreciable inhibition of cathepsin K (IC 50 ~ 25 µM), while the strongest inhibition of cathepsin B was achieved with N-(2-picolyl)carboxamide 5c (IC 50 ~ 45 µM).

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

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Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo- 4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K

Lukić¹,

Grošelj

Novinec

et al. 2017

ACSi

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“…So far, different synthetic routes towards pyrazolo [1,5-a]pyrimidines have been reported. These methods have been mainly included the condensation of 3-aminopyrazoles with 1,3-bis electrophilic substrates [51][52][53][54][55][56][57][58][59] , 1,2-allenic lactones 60 , β-halovinyl aldehyde 61 , and activated alkynes 62,63 .…”

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confidence: 99%

An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity

Peytam

Adib

Shourgeshty

et al. 2020

Sci Rep

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In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC 50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC 50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones. Recently, the world health organization (WHO) has identified the diabetes mellitus (DM) as a critical health challenge in the 21st century. The prevalence of diabetes has been increasing at alarming rate over the past three decades. This metabolic disorder, characterized by chronic hyperglycemia, leads to further severe damages like abnormally great thrust, excessive appetite, overweigh, blindness, excessive urination, cardiovascular complications, as well as renal and neurodegenerative diseases 1-6. There are three main diabetes types among which type 2 or non-insulin dependent (T2DM) is the most common one, mainly treated by controlling the digestive enzyme activities such as α-glucosidase 7-9. α-Glucosidase, found in the brush-border surface membrane of intestinal cells, plays catalyzing role in the carbohydrate digestion process by which the postprandial blood glucose levels increases. Preventing the glucose release in the bloodstream, the α-glucosidase inhibitors control T2DM 10. Additionally, this enzyme has a pivotal role in the biosynthesis of glycoprotein, therefore, its inhibitors have possessed anticancer, antitumor, antiviral, and immunoregulatory properties 11-15. Acrabose, miglitol, voglibose, and deoxynojirimycin have clinically been used to restrict the α-glucosidase activity 16. Considering the side effects and absorption problems associated with these drugs, new scaffolds should be synthesized and evaluated by medicinal chemists to extend the library of compounds 17-25. Pyrazoles are common structural motif in numerous drugs 26 and biologically active compounds showing activities such as anti-cancer 27,28 , anti-inflammatory 29 , anti-hypertensive 30 , cannabinoid receptor antagonist 31 , dopaminergic receptor antagonist 32 , and α-glucosidase inhibitors 33. Pyrazoles have been used to synthesize

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“…9 In contrast, cyclocondensation of aminopyrazole with ethyl benzoylacetate is known to provide the 5-phenyl regioisomer (Scheme 2). 10 Noting that ynoates would likely be required to achieve the desired regioselectivity (rather than β-ketoesters, vinylogous carbamates, 11 or other 1,3-dielectrophiles), we aimed to devise a high throughput sequence for the conversion of aryl halides to β-aryl ynoates. β-Aryl ynoates are common key intermediates in the synthesis of bioactive molecules 12,13 so a parallel approach to their synthesis would be beneficial.…”

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confidence: 99%

A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5-a]pyrimidin-5-ones

et al. 2018

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A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to β-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector.

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Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

Cited by 26 publications

References 26 publications

Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo- 4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K

Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo- 4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K

An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity

A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5-a]pyrimidin-5-ones

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