Synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives and their application as disperse dyes

A series of novel monoazo-disperse dyes containing pyrazolo[1,5-a]pyrimidine structures were synthesized starting with the coupling reaction between ethyl cyanoacetate and 4-hydroxybenzenediazonium chloride, followed by treatment of the resulting hydrazone product with hydrazine hydrate. The pyrazolohydrazone 6 is then treated with either 2,4-pentandione and enaminonitrile or aryl-substituted enaminoketones to give the target pyrazolo[1,5-a]pyrimidine dyes 7 and 15a-d. Structural assignments to the dyes were made using NMR spectroscopic methods. A new high temperature method, using microwave heating, was employed to apply these dyes to polyester fibers. Most of the dyed fabrics tested displayed moderate light fastness and excellent washing fastness properties.     

18F-labeled pyrazolo[1,5-a]pyrimidine derivatives: synthesis from 2,4-dinitrobenzamide and tosylate precursors and comparative biological evaluation for tumor imaging with positron emission tomography

We previously reported 18F-labeled pyrazolo[1,5-a]pyrimidine derivatives: 7-(2-[18F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([18F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[18F]fluoro-4-nitro- benzamide ([18F]2). Preliminary biodistribution experiments of both compounds showed s slow clearance rate from excretory tissues which warranted further investigation for tumor imaging with PET. Here we modified [18F]1 and [18F]2 by introducing polar groups such as ester, hydroxyl and carboxyl and developed three additional 18F-18 labeled pyrazolo[1,5-a] pyrimidine derivatives: (3-Cyano-7-(2-[18F]fluoroethylamino)pyrazolo[1,5-a]-pyrimidin-5- yl)methyl acetate ([18F]3), 7-(2-[18F]fluoroethylamino)-5-(hydroxymethyl)pyrazolo[1,5-a]- pyrimidine-3-carbonitrile ([18F]4) and (S)-6-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)-2-(2-[18F]fluoro-4-nitrobenzamido)hexanoic acid ([18F]5). The radiolabeled probes were synthesized by nucleophilic substitution of the corresponding tosylate and nitro precursors with 18F-fluoride. In Vitro studies showed higher uptake of [18F]3 and [18F]4 than that of [18F]5 by S180 tumor cells. In Vivo biodistribution studies in mice bearing S180 tumors showed that the uptake of both [18F]3 and [18F]4 in tumors displayed an increasing trend while the uptake of [18F]5 in tumor decreased through the course of the 120 min study. This significant difference in tumor uptake was also found between [18F]1 and [18F]2. Thus, we compared the biological behavior of the five tracers and reported the tumor uptake kinetic differences between 2-[18F]fluoroethylamino- and 2-[18F]fluoro-4-nitro- benzamidopyrazolo[1,5-a] pyrimidine derivatives.     

On the reactivity of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines with 1,3- and 1,4-bisnucleophiles

Reaction of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidine 1 with 1,3- and 1,4-bisnucleophiles has been investigated; obtainment of new polycyclic heterocyclic derivatives is reported. A convenient procedure leading to new pyrazolo[1,5-a]quinazolines is described; a modest bioactivity of these compounds against two human tumor cell lines was also ascertained.     

Reactions of 3-aroylacrylates with α-aminoazoles*

Dihydro derivatives of pyrazolo[3,4-b]pyridine-, pyrazolo[1,5-a]pyrimidine-, and [1,2,4]triazolo-[1,5-a]pyrimidinecarboxylates have been prepared by cyclocondensation of β-aroylacrylates with 5-aminopyrazoles and 3-amino-1,2,4-triazole. Heating dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylates with hydrazine hydrate led to recyclization of the pyrimidine ring to form 6-arylpyridazin-3(2H)-ones.     

Pyrazolo[1,5-a]pyrimidines. Identification of the privileged structure and combinatorial synthesis of 3-(hetero)arylpyrazolo[1,5-a]pyrimidine-6-carboxamides

The pyrazolo[1,5-a]pyrimidine class of compounds has been identified as a privileged structure for library synthesis on the basis of several key characteristics of the core molecule. A chemical set in excess of 400 compounds was synthesized to give 3,6,7-substituted pyrazolo[1,5-a]pyrimidinecarboxamides 9. To facilitate the rapid preparation of this library, a preparative strategy included the synthesis of activated p-nitrophenyl esters, followed by subsequent scavenging of the p-nitrophenol leaving group. Excess reagents were also removed using scavenging reagents that were found to be compatible with the synthetic methodology and that afforded target compounds in acceptable purity and yields.     

Synthesis and structure-activity relationship of a new series of potent angiotensin II receptor antagonists: pyrazolo[1,5-a]pyrimidine derivatives.

We have already reported 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives, which are potent in vitro angiotensin II (AII) antagonists, but have no oral antihypertensive activity. Removal of the carboxylic acid and replacement of the heteroaromatic system afforded potent in vitro antagonists. Removal of the carbonyl oxygen and changing the position of the biphenyltetrazole substituent were critical to the display of oral activity. To improve the in vitro and oral activities, modifications were made of the substituents at the 3- and 5-positions of the pyrazolo[1,5-a]pyrimidine. Structure-activity studies showed the methyl substituent at the 3-position to be essential for potent in vivo activity. We present the design, syntheses, and biological data of a series of pyrazolo[1,5-a]pyrimidine derivatives, which are orally active AII receptor antagonists.     

Reactivity of 2‐Thiazolylhydrazonomalononitrile toward Carbon and Nitrogen Nucleophilic Reagents: Applications to the Synthesis of New Heterocycles

2‐Thiazolylhydrazonomalononitrile ( 1 ) was used as key intermediate for the synthesis of polyfunctionally substituted heterocycles (e.g. pyridazine, tetrazole, pyrimidines, 1,5‐benzo diazepine, benzoimidazo[1,2‐a]pyrimidine, triazolo[4,3‐a]pyrimidine, pyrazole, pyrazolo[1,5‐a]triazines, pyrazolo[1,5‐a]pyrimidine and 1,5‐benzoxazocine) incorporating thiazole moiety via its reactions with some carbon and nitrogen nucleophiles. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. The mechanistic aspects for the formation of the new compounds were also discussed.     

2-[4-(2-Thienyl)-1,3-thiazol-2-yl]ethanenitrile in Heterocyclic Synthesis of Biological Interist

Abstract

Thiazolylacetonitrile was used in the synthesis of coumarin, pyrazolo[4,3]pyrimidines, 1,3,4-thiadiazolines, aminothiophenes, and thiazoles in a good yields. Also, pyrazolo[4,5-d]triazolino[4,5-a]pyrimidines, pyrazolo[4,5-d]thiazolino[3,2-a]pyrimidines, and pyrazolo[4,5-d]tetrazolino[1,5-a]pyrimidines were synthesized from pyrazolo[4,5-d]pyrimidine. Structures of the newly synthesized were elucidated by elemental analysis, spectral data, and alternative synthesis routes whenever possible. Some synthesized compounds were tested for their antimicrobial activity.     

Pyrimidine Derivatives and Related Compounds II: Synthesis of some derivatives of pyrimido[1,2:2′,3′]pyrazolo[1,5-a]pyrimidines,a new ring system

3,5-Diamino-4-phenylazo-pyrazoles ( 1a–1c ) react with acetylacetone and with ethyl acetoacetate to yield the corresponding pyrazolo[1,5-a]pyrimidine derivatives 2a–2c and 3a–3c , respectively. Whereas 1a–1c add readily to methyl acrylate yielding the 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine derivatives 5a–5c, 1a–1c add to methylacrylonitrile or methyl methacrylate only under drastic conditions to yield 5d–5f . The pyrimido[1,2:2′,3′]pyrazolo[1,5-a]pyrimidine derivatives 10a–10c are prepared by the action of acrylonitrile on 2a–2c . Compounds 10a–10c are readily converted into the corresponding oxo derivatives 12a–12c on treatment with acetic acid-hydrochloric acid mixture.     

Microwave-assisted three-component synthesis of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxamides and their selective reduction

Multicomponent reactions (MCRs) and microwave-assisted organic synthesis (MAOS) have been used as key methods for the synthesis of fused dihydropyrimidine derivatives. The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes and acetoacetamides under microwave irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamide libraries. In addition, the selective reduction of the formed dihydrotriazolopyrimidines to trans-trans-2-alkylthio-7-aryl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamides was established. The described synthetic protocols provide rapid access to novel and diversely substituted dihydroazolopyrimidine libraries.     

Studies with Polyfunctionally Substituted Heterocycles: New Synthesis of Pyrido[5′, 4′:2,3][1,3,4]oxadiazolo[3,2-a]pyridine; Pyridazine; 1,3,4-Oxadiazote; and Pyrazolo[1,5-a]Pyrimidine Derivatives

Cyanoacetohydrazide 1a reacts with 2-arylhydrazoketons 2a,b and 3a,b in refluxing ethanol to yield pyrido[5′,4′:2,3][1,3,4]oxadiazolo[3,2-a]pyridine and pyridazine derivatives; in the absence of solvent pyrazolo[1,5-a]pyrimidine derivatives were obtained. The reaction of 2a,b and 3a,b will) benzoylhydrazine afforded 1,3,4-oxadiazole and pyrazole derivatives.     

Novel route for the transformation of a pyrimidine ring using hydrazides

It has been shown from X-ray structural analytical data that the reaction of 2-ethoxycarbonylmethyl-1,4,6-trimethylpyrimidinium iodide with carboxylic acid hydrazides gives pyrazolo[1,5-a]pyrimidine derivatives and not the isomeric triazolo[4,3-a]pyridines previously reported. This novel and previously unreported rearrangement of 1,2-dialkylpyrimidinium salts occurs via recyclization of the pyrimidine ring with inclusion of a fragment of the nucleophilic reagent into the transformation product. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 262–275, February, 2006.     

Acid-catalyzed reactions of 3-(α-hydroxybenzyl)pyrazolo[1,5-a]pyridines

Treatment of 3-(or-hydroxybenzyl)pyrazolo[1,5-a]pyridines with trifluoroacetic acid in dichloromethane resulted in the formation of pyrazolo[1,5-a]pyridines, bis[α-(pyrazolo[1,5-a]pyrid-3-yl)benzyl] ethers, and phenylbis(pyrazolo[1,5-a]pyrid-3-yl)methanes, depending upon the presence or absence of the substituents at the 2- and/or 4-positions and the reaction conditions employed.     

Au(i)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide pyrazolo[1,5-a]pyridines

Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated adducts were further converted to 6-arylpyrazolo[1,5-a]pyridines via Suzuki-Miyaura coupling reaction and 6-cyanopyrazolo[1,5-a]pyridine by Ullmann condensation reaction. One of the cyclization adducts, 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine, was converted to a p38 kinase inhibitor, 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine, in two steps.     

A new synthesis of 2,8-disubstituted pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A practical synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines, which are key intermediates in the preparation of adenosine receptor antagonists, is developed. The method allows introduction of a variety of aryl substituents at position 2 of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine system via cyclocondensation of 5-amino-4-iminopyrazolo[3,4-d]pyrimidine with benzaldehydes accompanied with oxidation by iodobenzene diacetate. Some unexpected reactions are observed and the structures of the products are confirmed using NMR spectroscopy and X-ray crystallography.     

Synthesis of heterocyclic compounds possessing the 4H-thieno[3,2-b]pyrrole moiety

A series of novel heterocyclic combinatorial libraries containing 4H-thieno[3,2-b]pyrrole, thieno[2',3':4,5]-pyrrol[1,2-d][1,2,4]triazine and thieno[2',3':4,5]pyrrolo[1,2-a]pyrazine heterocyclic moieties were obtained by parallel solution-phase synthesis. Key steps include different reactions of initial alkyl 4H-thieno[3,2-b]-pyrrole-5-carboxylates, such as alkylation with alkylating agents; transformation of the carboxylate group into different reactive functionalities, followed by reactions with electrophilic species; intramolecular cyclizations; and amide bond formation. Simple manual techniques for parallel reactions were coupled with easy purification procedures to give high-purity final products.     

Aminoazoles in Heterocycles Synthesis: II. Trifluoromethyl-containing Diketones in the Synthesis of Pyrazolo[1,5-a]pyrimidines

A regioselective synthesis was carried out of 7-trifluoromethylpyrazolo[1,5-a]pyrimidines by reaction of 3(5)aminopyrazoles with 1,3-diketones containing CF₃ group. The characteristic chemical shifts were established for C⁵ and C⁷ atoms of the pyrimidine ring and of substituents thereof in the ¹H, ¹³C, and ¹⁹F NMR spectra of pyrazolo[1,5-a]pyrimidines.     

Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke

We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f.HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.     

Recyclization of Condensed Carbethoxypyrimidines Accompanied by Substitution of a Carbon Atom into the Heterocycle

Condensation in ethanol of ethyl ethoxymethyleneacetoacetate with systems containing an amidine fragment (substituted 3-aminopyrazoles and 3-amino-1,2,4-triazole) gave 6-carbethoxy-7-methylpyrazolo[1,5-a]pyrimidines. Addition of base to solutions of the obtained bicyclic carbethoxy derivatives in the course of several minutes caused rearrangement to 6-acetyl-7-hydroxypyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine respectively. A more prolonged refluxing in 15% aqueous alcohol solution of base caused 6-carbethoxy-7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidine to recyclize to 7-methylpyrazolo[1,5-a]pyrimidine.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 569–576, April, 2005.     

Synthesis of new substituted pyrazolo[1,5-a]-pyrimidines and pyrazolo[1,5-a]1,3,5-triazines

5-Substituted 3-amino-1H-pyrazole-4-carbonitriles 2a-d react with appropriate biselectrophilic reagents in the presence of (TEA) to give the substitution products pyrazolo[1,5-a]pyrimidines 4a-d, 6a-d and pyrazolo[1,5-a ]1,3,5-triazines 8a-d. Compounds 6a and 8a react with secondary amines to 10a-c and 11a-c. Treatment of 2a with malonodinitrile results in the substituted pyrazolo-[1,5-a]pyrimidine 16. Condensation of 2a, 2c and 2d with ethyli-dene-malodintriles leads to racemic dihydro-pyrazolo[1,5-a] pyr-imidines 18a-e. Reaction of diene 20 with the heterodienophile 21 leads to formation of Diels-Alder adduct 22.