Startseite Microwave-assisted synthesis and antibacterial evaluation of new derivatives of 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one
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Microwave-assisted synthesis and antibacterial evaluation of new derivatives of 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

  • Zahra Ebrahimpour , Ali Shiri , Mehdi Bakavoli EMAIL logo , Seyed Mohammad Seyedi , Masoumeh Bahreini und Fatemeh Oroojalian
Veröffentlicht/Copyright: 23. Januar 2016
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Heterocyclic Communications
Aus der Zeitschrift Heterocyclic Communications Band 22 Heft 1

Abstract

Synthesis of new 1,2-dihydro-3H-pyrazolo[3,4-d] pyrimidin-3-ones 4–6 starting with ethyl 4-hydroxy-2-methylthio-pyrimidine-5-carboxylate (1) under classical heating and microwave-induced conditions is reported. The antibacterial activities of the synthesized compounds were evaluated using chloramphenicol and streptomycin as reference drugs.

Keywords: antibacterial; microwave; pyrazolo[3,4-d]pyrimidin-3-one; synthesis

Introduction

Pyrazolo[3,4-d]pyrimidines and related fused derivatives are a pharmaceutically important class of compounds [1]. They exhibit diverse pharmaceutical activities such as antifungal [2], antibacterial [2, 3], neuroleptic [4], antihypertensive [5] and antileishmanial [6] properties. Also, pyrazolopyrimidines have been exploited as ATP competitive inhibitors of kinases [7], cAMP phosphodiesterase [8] and DNA polymerase [9]. Some of these compounds have demonstrated antitumor activities [10] by inhibiting different types of enzymes such as cyclin-dependent kinase [10, 11, 12] adenosine deaminase [12] glycogen synthase kinase-3 [13] and epidermal growth factor receptor protein tyrosine kinase [14].

Most synthetic approaches to pyrazolopyrimidines start from substituted pyrimidines or pyrazoles [15]. The cyclization of pyrimidines with hydrazines provides pyrazolopyrimidines via the construction of the fused pyrazole ring [16]. Alternatively, pyrazolopyrimidines can also be synthesized through the construction of the pyrimidine ring using substituted pyrazoles [10]. Recently, some new methods have been reported based on using microwave irradiation [16], ionic liquids [17], supported solid catalysts [17, 18] and under solvent-free conditions [19].

As part of our ongoing program aimed at developing new protocols for preparation of biologically active heterocyclic compounds [20], we wish to report the result of our investigations on the synthesis and antimicrobial activities of new derivatives of pyrazolo[3,4-d]pyrimidin-3(2H)-ones.

Results and discussion

The starting material, ethyl 4-hydroxy-2-methylthio-pyrimidine-5-carboxylate (1 in Scheme 1), was prepared according to the previously published method [21]. The treatment of 1 with morpholine, pyrolidine and piperidine, led to the selective SNAr displacement of the thiomethyl moiety and gave the respective pyrimidines 2a–c. Then, the chloropyrimidines 3a–c were obtained by heating compounds 2a–c in a mixture of PCl5 and POCl3 (1:14) [22–24]. Compounds 3a–c served as direct precursors to the desired products 4a–c, 5a–c and 6a–c by the reaction with hydrazine, methylhydrazine and phenylhydrazine, respectively. Classical synthesis of pyrazolo[1,5-a]pyrimidines 4–6 was performed by heating the reactants in ethanol in the presence of sodium ethoxide (Method A in Scheme 1). The observed different regioselectivities for the reaction with methylhydrazine to give product 5 and for the reaction with phenylhydrazine leading to product 6 are in full agreement with the literature data [25–27]. A similar, microwave-assisted organic synthesis (MAOS) [28, 29] is designated in Scheme 1 as Method B. Comparison of the results of the two methodologies reveals that the use of microwave irradiation greatly reduces the reaction time (from 2–8 h to 2–6 min) and significantly increases the yield. The structures of products 4–6 are fully supported by the results of IR, 1H NMR, 13C NMR, MS and elemental analysis. A literature survey [30, 31] reveals that synthetic approaches to pyrazolopyrimidines mostly involve a heterocyclization reaction of pyrimidine moiety onto the pyrazole core [15]. Our synthetic protocol is different and based on the construction of the pyrazole moiety at the pyrimidine core.

Scheme 1
Scheme 1

Compounds 4–6 were tested for antibacterial activity against Gram-positive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 11778) and Gram-negative (Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 9027) bacteria. The results of antibacterial properties of active compounds are shown in Table 1. The results indicate that compound 6c shows the strongest antibacterial properties against all tested bacteria. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of compound 6c against E. coli are significantly better than those of chloramphenicol, the reference drug. Inhibition activity of 6c against P. aeruginosa is the same as that of streptomycin. Finally, the antibacterial activity of 6c against S. aureus is higher than that of chloramphenicol and is equal to streptomycin.

Table 1

Antibacterial activities (MIC and MBC μg/mL) of active compounds.

EntryB. subtilis ATCC 12711S. aureus ATCC 25923E. coli ATCC 25922P. Aeruginosa ATCC 9027
MICMBCMICMBCMICMBCMICMBC
5a416.684478104104208416416
5b500500250500250250500500
6a50050062.5125250500500500
6b12525062.5125125125250250
6c62.51253162.53131125125
Chloramphenicol250250125250125250250250
Streptomycin62.562.53131250250125125

Conclusion

In summary, we applied classical conditions and MAOS to the preparation of pyrazolo[3,4-d]pyrimidin-3(2H)-ones 4a–c, 5a–c and 6a–c. In all cases, reaction times and yields of products were dramatically improved under the MAOS protocol. Compound 6c has a very good antimicrobial activity compared to chloramphenicol and streptomycin.

Experimental

Melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra were obtained in KBr discs on an Avatar 370 FT-IR Thermo Nicolet instrument. The 1H NMR (400 MHz) and the 13C NMR (100 MHz) spectra were recorded in DMSO-d6 on a Bruker Avance DRX-400 spectrometer. The electron impact mass spectra were scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer. The in vitro antibacterial activities of the compounds were determined using the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) recommended MIC protocol with minor modifications [32]. The minimum bactericidal concentrations (MBC) we also determined [33]. Volumes of 5 μL of every well without growth were transferred to agar plates and incubated at 37°C for 24 h. The lowest concentration of the synthetic compounds where no viable bacteria were identified was taken as MBC [33].

General procedure for the synthesis of compounds 3a-c

Phosphorus pentachloride (2.7 mmol, 0.5 g) was added to a suspension of ethyl 2-(substituted)amino-6-oxo-1,6-dihydropyrimidine-5-carboxylate (3.5 mmol, 1.0 g) in phosphorus oxychloride (7 mL). After the mixture had been heated under reflux for 3 h, the residue was cooled and poured onto ice (~30 g). The resulting solid was filtrated and crystallized from petroleum ether.

Ethyl 4-chloro-2-(morpholin-1-yl)dihydropyrimidine-5-carboxylate (3a)

Yield 68%; white solid; mp 82°C; 1H NMR: δ 1.39 (t, 3H, J = 7.2 Hz, CH3), δ 3.77 (t, 4H, J = 5.1 Hz, 2-CH2N), 3.93 (t, 4H, J = 5.1 Hz, 2-CH2O), 4.36 (q, 2H, J = 7.1 Hz, CH2), 8.84 (s, 1H, CH-pyrimidine); IR: ν 2974, 2913, 2859, 1724, 1696, 1587 cm-1; MS: m/z 271 (M+). Anal. Calcd for C11H14ClN3O3: C, 48.63; H, 5.19; N, 15.47. Found: C, 48.55; H, 5.24; N, 15.62.

Ethyl 4-chloro-2-(pyrrolidin-1-yl)-pyrimidine-5-carboxylate (3b)

Yield 67%; white solid; mp 60°C; 1H NMR: δ 1.39 (t, 3H, J = 7.2 Hz, CH3), 2.04 (m, 4H, 2-CH2), 3.67 (t, 4H, J = 6.3 Hz, 2-CH2N), 4.36 (q, 2H, J = 7.2 Hz, CH2), 8.85 (s, 1H, CH-pyrimidine); IR: ν 2978, 2855, 1716, 1586 cm-1; MS: m/z 255 (M+). Anal. Calcd for C11H14ClN3O2: C, 51.67; H, 5.52; N, 16.43. Found: C, 51.85; H, 5.37; N, 16.65.

Ethyl 4-chloro-2-(piperidin-1-yl)-pyrimidine-5-carboxylate (3c)

Yield 70%; white solid; mp 50°C; 1H NMR: δ 1.36 (t, 3H, J = 7.2 Hz, CH3), 1.65 (m, 6H, 3-CH2), 3.85 (t, 4H, J = 5.1 Hz, 2-CH2N), 4.32 (q, 2H, J = 7.2 Hz, CH2), 8.79 (s, 1H, CH-pyrimidine); IR: ν 3113, 3039, 2960, 2921, 2859, 1746, 1641, 1585 cm-1; MS: m/z 269 (M+). Anal. Calcd for C12H16ClN3O2: C, 53.43; H, 5.98; N, 15.58. Found: C, 53.55; H, 5.94; N, 15.72.

General procedures for the synthesis of 4a-c, 5a-c and 6a–c

Method A

A solution of sodium ethoxide obtained from sodium metal (1 mmol, 0.023 g)] and absolute ethanol (5 mL) was treated with 3a–c (1 mmol) and hydrazine, methylhydrazine or phenylhydrazine (1.2 mmol). The mixture was heated on a water bath at 60°C and, after completion of the reaction as was monitored by TLC using CHCl3/MeOH (20:1), the solvent was removed under reduced pressure. The solid residue was dissolved in water and the solution acidified with acetic acid. The resulting precipitate was filtered, washed with water (2 × 30 mL), dried and crystallized from methanol to give the product 4a–c, 5a–c or 6a–c.

Method B

A mixture of compound 3a–c (1 mmol) and an excess amount of the appropriate hydrazine (0.1 mL) was subjected to microwave irradiation in the absence of solvent (maximum power 400W during 2–6 min at room temperature) using a focused microwave reactor (Milestone). After the completion of the reaction, water (5 mL) was added. The solid product was collected by filtration and crystallized from methanol to give the corresponding compounds 4a–c, 5a–c or 6a–c.

6-(Morpholin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4a)

Reaction time 5 h (method A), 4 min (method B); yield 68% (A), 84% (B); yellow solid; mp 297–299°C; 1H NMR: δ 3.64 (t, 4H, J = 4.8 Hz, 2-CH2N), 3.74 (t, 4H, J = 4.4 Hz, 2-CH2O), 8.66 (s, 1H, CH-pyrimidine), 11.19 (br s, 2H, 2-NH, D2O exchangeable); 13C NMR: δ 44.7, 66.4, 98.7, 153.9, 157.6, 158.8, 161.5; IR: ν 3120, 2965, 2917, 2847, 1631, 1564 cm-1; MS: m/z 221 (M+). Anal. Calcd for C9H11N5O2: C, 48.86; H, 5.01; N, 31.66. Found: C, 48.91; H, 4.98; N, 31.72.

6-(Pyrrolidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4b)

Reaction time 6 h (A), 5 min (B); yield 58% (A), 80% (B); yellow powder; mp 325–328°C (decomp.); 1HNMR: δ 1.96 (m, 4H, 2-CH2), 3.53 (t, 4H, J = 6.8 Hz, 2-CH2N), 8.77 (s, 1H, CH-pyrimidine), 12.64 (br s, 2H, 2-NH); 13C NMR: δ 25.3, 47.2, 112.5, 159.9, 160.0, 160.9, 166.3; IR: ν 3158, 2974, 2884, 1635, 1556 cm-1; MS: m/z 205 (M+). Anal. Calcd for C9H11N5O: C, 52.67; H, 5.40; N, 34.13. Found: C, 52.71; H, 5.37; N, 34.09.

6-(Piperidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4c)

Reaction time 6 h (A), 4 min (B); yield 75% (A), 87% (B); brown powder; mp 298–300°C; 1H NMR: δ 1.50 (m, 4H, 2-CH2),1.62 (m, 2H, CH2) 3.78 (t, 4H, J = 5.2 Hz, 2-CH2N), 8.61 (s, 1H, CH-pyrimidine), 10.94 (br s, 1H, NH, D2O exchangeable), 11.21 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 24.7, 25.7, 45.1, 98.1, 130.6, 154.1, 160.0, 161.4; IR: ν 3154, 3131, 3043, 2931, 2853, 1630, 1564 cm-1; MS: m/z 219 (M+). Anal. Calcd for C10H13N5O: C, 54.78; H, 5.98; N, 31.94. Found: C, 54.73; H, 6.03; N, 32.01.

1-Methyl-6-morpholino-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5a)

Reaction time 2 h (A), 2 min (B); yield 73% (A), 89% (B); white powder; mp 231–235°C; 1H NMR: δ 3.53 (s, 3H, CH3), 3.65 (t, 4H, J = 4.8, 2-CH2N), 3.77 (t, 4H, J = 4.8, 2-CH2O), 8.60 (s, 1H, CH-pyrimidine), 12.23 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 32.4, 44.7, 66.4, 98.4, 153.2, 155.1, 155.6, 160.8; IR: ν 3007, 2970, 2904, 2868, 1672, 1621, 1563 cm-1; MS: m/z 235 (M+); Anal. Calcd for C10H13N5O2, C, 51.06; H, 5.57; N, 29.77. Found: C, 51.13; H, 5.49; N, 29.80.

1-Methyl-6-(pyrrolidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5b)

Reaction time 2 h (A), 2 min (B); yield 69% (A), 86% (B); white powder; mp 230–236°C; 1H NMR: δ 1.90 (m, 4H, 2-CH2), 3.49 (s, 3H, CH3), 3.52 (t, 4H, J = 6.7 Hz, 2-CH2N), 8.61 (s, 1H, CH-pyrimidine), 10.91 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 25.3, 32.5, 46.4, 97.7, 153.2, 155.6, 156.5, 159.7; IR: ν 3023, 2970, 2929, 2761, 2667, 2569, 1658, 1617, 1587 cm-1; MS: m/z 219 (M+). Anal. Calcd for C10H13N5O: C, 54.78; H, 5.98; N, 31.94. Found: C, 54.83; H, 6.07; N, 31.89.

1-Methyl-6-(piperidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5c)

Reaction time 2 h (A), 2 min (B); yield 76% (A), 88% (B); yellow powder; mp 249–251°C; 1H NMR: δ 1.53 (m, 4H, 2-CH2), 1.63 (m, 2H, CH2), 3.34 (s, 3H, CH3), 3.82 (t, 4H, J = 5.6 Hz, 2-CH2N), 8.63 (s, 1H, CH-pyrimidine), 11.04 (s, 1H, NH, D2O exchangeable); 13C NMR: δ 24.6, 25.7, 32.5, 45.1, 97.5, 153.9, 154.1, 156.4, 161.0; IR: ν 3007, 2923, 2851, 2774, 2689, 1682, 1627, 1565 cm-1; MS: m/z 233 (M+). Anal. Calcd for C9H11N5O2: C, 56.64; H, 6.48; N, 30.02. Found: C, 56.60; H, 6.42; N, 30.08.

6-Morpholino-2-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (6a)

Reaction time 8 h (A), 6 min (B); yield 77% (A), 90% (B); brown powder; mp 198–201°C; 1H NMR: δ 3.68 (t, 4H, J = 4.8 Hz, 2-CH2N), 3.82 (t, 4H, J = 4.4 Hz, 2-CH2O), 7.19 (t, 2H, phenyl), 7.47 (t, 1H, phenyl), 8.11 (d, 2H, Phenyl), 8.81 (s, 1H, CH-pyrimidine), 11.97 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 44.8, 66.4, 100.0, 119.3, 124.6, 129.5, 139.5, 153.5, 154.8, 155.6, 161.0; IR: ν 3035, 2974, 2900, 2753, 2680, 2573, 1666, 1613, 1596 cm-1; MS: m/z 297 (M+); Anal. Calcd for C15H15N5O2: C, 60.60; H, 5.09; N, 23.56. Found: C, 60.63; H, 5.02; N, 23.54.

2-Phenyl-6-(pyrrolidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (6b)

Reaction time 8 h (A), 6 min (B); yield 68% (A), 85% (B); white powder; mp 221–224°C; 1H NMR: δ 1.94 (m, 4H, 2-CH2), 3.56 (t, 4H, J = 6.8 Hz, 2-CH2N), 7.14 (t, 2H, phenyl), 7.45 (t, 1H, phenyl), 8.18 (d, 2H, phenyl), 8.75 (s, 1H, CH-pyrimidine), 11.60 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 25.5, 46.9, 99.2, 118.9, 124.3, 129.4, 139.8, 153.3, 155.2, 155.7, 159.5; IR: ν 3068, 3019, 2970, 2869, 1615, 1539; MS: m/z 281 (M+). Anal. Calcd for C15H15N5O: C, 64.04; H, 5.37; N, 24.90. Found: C, 64.12; H, 5.30; N, 24.95.

2-Phenyl-6-(piperidin-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (6c)

Reaction time 8 h (A), 6 min (B); yield 78% (A), 87% (B); yellow powder; mp 198–202°C; 1H NMR: δ 1.55 (m, 4H, 2-CH2), 1.62 (m, 2H, CH2), 3.83 (t, 4H, J = 5.2 Hz, 2-CH2N), 7.17 (t, 2H, phenyl), 7.43 (t, 1H, phenyl), 7.95 (d, 2H, phenyl), 8.75 (s, 1H, CH-pyrimidine), 11.73 (br s, 1H, NH, D2O exchangeable); 13C NMR: δ 24.9, 25.8, 47.2, 102.3, 114.8, 120.7, 125.2, 130.8, 146.6, 152.9, 158.3, 160.4; IR: ν 3051, 2942, 2916, 2851, 1656, 1614 cm-1; MS: m/z 295 (M+). Anal. Calcd for C16H17N5O: C, 65.07, H, 5.80; N, 23.71. Found: C, 65.14; H, 5.81; N, 23.68.

Dedication: In the memory of Professor Mohammad Rahimizadeh

Corresponding author: Mehdi Bakavoli, Faculty of Science, Department of Chemistry, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran, e-mail: ;

Acknowledgments

The authors gratefully acknowledge Ferdowsi University of Mashhad for partial support of this project (3/25439).

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Received: 2015-7-27
Accepted: 2015-10-14
Published Online: 2016-1-23
Published in Print: 2016-2-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Artikel in diesem Heft

  1. Frontmatter
  2. Preliminary Communication
  3. Design, synthesis, and anticancer activity of novel aryl/heteroaryl chalcone derivatives
  4. Research Articles
  5. A simple and convenient method for the synthesis of 1,3,5-triazine-nitrolic acids. The first X-ray investigation of Z-isomeric nitrolic acid
  6. Pot, atom and step-economic (PASE) synthesis of medicinally relevant spiro[oxindole-3,4′-pyrano[4,3-b]pyran] scaffold
  7. An efficient asymmetric approach to the R-enantiomer impurity of esomeprazole
  8. Synthesis, optical and electrochemical properties of 2-[(9H-fluoren-2-yl)aryl]-1H-benz[d]imidazole and 2,7-bis[(1H-benz[d]imidazol-2-yl)aryl]- 9H-fluorene derivatives
  9. Synthesis and fluorescence of pyrazolines substituted with pyrimidine and ferrocene subunits
  10. Design and synthesis of a novel rhodamine-based chemosensor and recognition study to Fe3+
  11. An efficient, one-pot three-component synthesis of 4H-thiazolo[3,2-a][1,3,5]triazin-6-one derivatives
  12. Microwave-assisted synthesis and antibacterial evaluation of new derivatives of 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one
  13. Efficient assembly of quinoxaline derivatives from benzene-1,2-diamines, dialkyl acetylenedicarboxylates and ninhydrin
https://doi.org/10.1515/hc-2015-0145
Schlagwörter für diesen Artikel
antibacterial; microwave; pyrazolo[3,4-d]pyrimidin-3-one; synthesis
Creative Commons
BY-NC-ND 3.0

Artikel in diesem Heft

  1. Frontmatter
  2. Preliminary Communication
  3. Design, synthesis, and anticancer activity of novel aryl/heteroaryl chalcone derivatives
  4. Research Articles
  5. A simple and convenient method for the synthesis of 1,3,5-triazine-nitrolic acids. The first X-ray investigation of Z-isomeric nitrolic acid
  6. Pot, atom and step-economic (PASE) synthesis of medicinally relevant spiro[oxindole-3,4′-pyrano[4,3-b]pyran] scaffold
  7. An efficient asymmetric approach to the R-enantiomer impurity of esomeprazole
  8. Synthesis, optical and electrochemical properties of 2-[(9H-fluoren-2-yl)aryl]-1H-benz[d]imidazole and 2,7-bis[(1H-benz[d]imidazol-2-yl)aryl]- 9H-fluorene derivatives
  9. Synthesis and fluorescence of pyrazolines substituted with pyrimidine and ferrocene subunits
  10. Design and synthesis of a novel rhodamine-based chemosensor and recognition study to Fe3+
  11. An efficient, one-pot three-component synthesis of 4H-thiazolo[3,2-a][1,3,5]triazin-6-one derivatives
  12. Microwave-assisted synthesis and antibacterial evaluation of new derivatives of 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one
  13. Efficient assembly of quinoxaline derivatives from benzene-1,2-diamines, dialkyl acetylenedicarboxylates and ninhydrin
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