Next Article in Journal
Thiophene-3-carbonyl Chloride
Previous Article in Journal
1-(4-Formyl-2,6-dimethoxyphenoxy)-4-chlorobut-2-yne
Short Note

4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

1
N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia
2
Nanotechnology Education and Research Center, South Ural State University, 76 Lenina Avenue, 454080 Chelyabinsk, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Norbert Haider
Molbank 2021, 2021(3), M1253; https://doi.org/10.3390/M1253
Received: 6 July 2021 / Accepted: 20 July 2021 / Published: 22 July 2021
(This article belongs to the Section Organic Synthesis)

Abstract

A novel 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was prepared by a rational and short two-step synthesis from commercially available ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate via 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. The structure of the synthesized compounds was established by elemental analysis, high-resolution mass-spectrometry, 1H, 13C-NMR and IR spectroscopy and mass-spectrometry. 4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine is a convenient intermediate for various disubstituted 1-methyl-1H-pyrazolo[3,4-d]pyrimidines, which may be of interest as substances with useful pharmacological properties.
Keywords: 1H-pyrazolo[3,4-d]pyrimidines; 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine; condensation; biological activity 1H-pyrazolo[3,4-d]pyrimidines; 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine; condensation; biological activity

1. Introduction

1H-Pyrazolo[3,4-d]pyrimidine is an important structural fragment present in naturally occurring nucleosides (Formycin A and Formycin B), which have significant antitumor activity [1,2]. Additionally, 1H-pyrazolo[3,4-d]pyrimidines exhibit various biological activities, including antiviral and analgesic activity, treatment of male erectile dysfunction and hyperuricemia, prevention of gout, and many others [1,3,4]. Functionally substituted 1H-pyrazolo[3,4-d]pyrimidines showed good antibacterial and antiproliferative activity [5]. Therefore, new derivatives of 1H-pyrazolo[3,4-d]pyrimidines are of great interest. 1-Substituted 4-chloro-6-(chloromethyl)-1H-pyrazolo[3,4-d]pyrimidines can be considered important intermediates for the preparation of previously unknown disubstituted 1H-pyrazolo[3,4-d]pyrimidines. Herein, we report the synthesis of a new 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine via its precursor 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one.

2. Results and Discussion

The only representative of 1-substituted 4-chloro-6-(chloromethyl)-1H-pyrazolo[3,4-d]pyrimidines, 1-phenyl derivative 1a was obtained by the reaction of carboxamide 2a with POCl3 [5]. Pyrimidinones 2 were prepared by a two-step synthesis, including saponification of 5-amino-1H-pyrazole-4-carbonitriles 3 to 5-amino-1-phenyl-1H-pyrazole-4-carboxamides 4 followed by reaction with choloroacetyl chloride [5,6,7,8] (Scheme 1).
We decided to carry out the synthesis of heterocycle 1b by a shorter route from the cheaper and more accessible reagent-ester of 5-amino-1H-pyrazole-4-carboxylate 5. We found that the reaction of commercially available ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate 5 with chloroacetonitrile in dioxane led to the formation of pyrimidinone 2b in high yield (83%). It should be noted that the yield of compound 2b according to the method described in [8] was much lower (29%). Treatment of compound 2b with POCl3 gave the target product 1b (Scheme 2).
The structure of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b and its precursor 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 2b was fully confirmed by elemental analysis, high resolution mass-spectrometry, 1H, 13C-NMR and IR spectroscopy, and mass-spectrometry. The 1H-NMR spectrum of 1b showed characteristic singlets of Me group (4.08 ppm), ClCH2 group (4.92 ppm) and C-H-pyrazole group (8.46 ppm).
In conclusion, 1H-pyrazolo[3,4-d]pyrimidine containing two reactive chlorine atoms-4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b, was obtained using a rational and short path. This compound opens up possibilities for the synthesis of various functional derivatives of disubstituted 1H-pyrazolo[3,4-d]pyrimidines, which may be of interest as compounds with useful pharmacological properties.

3. Materials and Methods

The solvents and reagents were purchased from commercial sources and used as received. Elemental analysis was performed on a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA). Melting point was determined on a Kofler hot-stage apparatus and is uncorrected. 1H and 13C-NMR spectra were taken with a Bruker AM-300 machine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 MHz) with TMS as the standard. MS spectrum (EI, 70 eV) was obtained with a Finnigan MAT INCOS 50 instrument (Hazlet, NJ, USA). IR spectrum was measured with a Bruker “Alpha-T” instrument in KBr pellet. High-resolution MS spectrum was measured on a Bruker micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI).
Synthesis of 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 2b (Supplementary Materials).
HCl gas was passed through a solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate 5 (0.15 mol, 25.35 g) and chloroacetonitrile (0.15 mol, 9.5 mL) in dioxane (500 mL) at a temperature of 15–18 °C for 10 h. The volatiles were evaporated, water (300 mL) was added to the residue, and the reaction mixture was alkalized with aqueous ammonia to pH = 7. The precipitate was filtered, washed with water and dried in air. Yield 24.71 g (83%), light beige solid, mp 286–287 °C. IR spectrum (KBr), ν, cm–1: 3434, 3106, 2978, 2890, 2858 (all C-H), 1727 (C=O), 1658, 1614 (C=N), 1407, 1200, 1070, 865, 849, 777, 724, 673, 616, 506. 1H-NMR (DMSO-d6, ppm): δ 3.90 (3H, s), 4.57 (2H, s), 8.05 (1H, s), 12.47 (1H, broad s). 13C-NMR (DMSO-d6, ppm): δ 34.1 (CH3), 42.7 (CH2Cl), 104.6, 134.2 (C-H), 151.6, 155.2, 157.6 (C=O). Mass spectrum (EI, 70 Ev), m/z (I, %): 200 (M+2, 37), 198 (M+, 100), 163 (10), 149 (57), 136 (18), 41(15). HRMS (ESI-TOF): calcd. for C7H8ClN4O [M + H]+ 199.0381; found m/z 199.0387, calcd. for C7H7ClN4NaO [M + Na]+ 221.0201; found m/z 221.0203. Anal. calcd. for C7H7ClN4O: C, 42.33; H, 3.55; Cl, 17.85; N, 28.21; found: C, 42.25; H, 3.63; Cl, 17.96; N, 28.29%.
Synthesis of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b (Supplementary Materials).
A mixture of 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 2b (0.1 mol, 19.85 g), POCl3 (0.2 mol, 18.6 mL) and diethylisopropylamine (0.3 mol, 52 mL) was refluxed in toluene (400 mL) for 18 h. The reaction mixture was poured into ice water (500 mL). The organic phase was separated, washed with a saturated solution of NaHCO3, brine and passed through the Al2O3 layer on the filter. The solvent was removed. Yield 15.62 g (72%), white solid, mp 68–69 °C. IR spectrum (KBr), ν, cm–1: 3434, 3125, 3030, 2977, 2950 (all C-H), 1722, 1591, 1547 (C=N), 1498, 1444, 1406, 1295, 1217, 1132, 965, 899, 844, 794, 750, 721, 666, 607, 547, 520, 424. 1H-NMR (DMSO-d6, ppm): δ 4.08 (3H, s), 4.92 (2H, s), 8.46 (1H, s). 13C-NMR (DMSO-d6, ppm): 34.4 (CH3), 46.5 (CH2Cl), 111.7, 132.0 (C-H), 153.2, 153.8, 161.8 (C-Cl). Mass spectrum (EI, 70 Ev), m/z (I, %): 220 (M+4, 10), 218 (M+2, 63), 216 (M+, 100), 181 (35), 145 (13), 49 (30), 15 (35). HRMS (ESI-TOF): calcd. for C7H7Cl2N4 [M + H]+ 217.0042; found m/z 217.0050, calcd. for C7H6Cl2N4Na [M + Na]+ 238.9862; found m/z 238.9870. Anal. calcd. for C7H6Cl2N4: C, 38.74; H, 2.79; Cl, 32.66; N, 25.81; found: C, 38.66; H, 2.85; Cl, 32.56; N, 25.93%.

Supplementary Materials

The following are available online: copies of 1H, 13C-NMR, IR, HRMS and mass-spectra for the compounds 1b and 2b.

Author Contributions

Synthetic experiments, analysis of experimental results and NMR data, V.A.O.; conceptualization, writing—review and editing supervision and project administration, O.A.R. Both authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Elnagdi, M.H.; Al-Awadi, N.; Abdelhamid, I.A. Bicyclic 5-6 Systems: Other Four Heteroatoms 2:2. In Comprehensive Heterocyclic Chemistry III; Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier: Oxford, UK, 2008; Volume 10, pp. 600–658. [Google Scholar] [CrossRef]
  2. Kumar, V.; Kaur, K.; Gupte, G.P.; Sharma, A.K. Pyrazole containing natural products: Synthetic preview and biological significance. Eur. J. Med. Chem. 2013, 69, 735–753. [Google Scholar] [CrossRef] [PubMed]
  3. Zhang, L.; Ju, Q.; Sun, J.; Huang, L.; Wu, S.; Wang, S.; Li, Y.; Guan, Z.; Zhu, Q.; Xu, Y. Discovery of novel dual extracellular regulated protein kinases (erk) and phosphoinositide 3-kinase (pi3k) inhibitors as a promising strategy for cancer therapy. Molecules 2020, 25, 5693. [Google Scholar] [CrossRef] [PubMed]
  4. Janetka, J.W.; Hopper, A.T.; Yang, Z.; Barks, J.; Dhason, M.S.; Wang, Q.; Sibley, L.D. Optimizing pyrazolopyrimidine inhibitors of calcium dependent protein kinase 1 for treatment of acute and chronic toxoplasmosis. J. Med. Chem. 2020, 63, 6144–6163. [Google Scholar] [CrossRef] [PubMed]
  5. Devarakonda, M.; Doonaboina, R.; Vanga, S.; Vemu, J.; Boni, S.; Mailavaram, R.P. Synthesis of novel 2-alkyl-4-substituted-amino-pyrazolo[3,4-d]pyrimidines as new leads for anti-bacterial and anti-cancer activity. Med. Chem. Res. 2013, 22, 1090–1101. [Google Scholar] [CrossRef]
  6. Shaaban, M.A.; Elshaier, Y.A.M.M.; Hammad, A.H.; Farag, N.A.; Haredy, H.H.; AbdEl-Ghany, A.A.; Mohamed, K.O. Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors. Bioorg. Med. Chem. Lett. 2020, 30, 127337. [Google Scholar] [CrossRef] [PubMed]
  7. Burdi, D.F.; Tanaka, D. Tricyclic Piperazine Derivative. US Patent 2016/83391, 24 March 2016. [Google Scholar]
  8. Bol’but, A.V.; Vovk, M.V. Condensed pyrimidine systems. 5.6-Methyl-functionalized in pyrazolo[3,4-d]pyrimidin-4(5H)-ones. Zhurn. Organ. Farm. Khim. 2006, 4, 57–61. [Google Scholar]
Scheme 1. Known synthesis of 4-chloro-6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 1a.
Scheme 1. Known synthesis of 4-chloro-6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 1a.
Molbank 2021 m1253 sch001
Scheme 2. Synthesis of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b.
Scheme 2. Synthesis of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b.
Molbank 2021 m1253 sch002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop