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Lingzhi Zhang, Q. Ju, Jinjin Sun, Lei-ming Huang, Shi-Qi Wu, Shu-Ping Wang, Yin Li, Zhe Guan, Qihua Zhu, Yungen Xu (2020)
Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer TherapyMolecules, 25
Murty Devarakonda, Raghava Doonaboina, Sreedher Vanga, Jahnavi Vemu, Sathoshini Boni, R. Mailavaram (2013)
Synthesis of novel 2-alkyl-4-substituted-amino-pyrazolo[3,4-d]pyrimidines as new leads for anti-bacterial and anti-cancer activityMedicinal Chemistry Research, 22
Vinod Kumar, Kamalneet Kaur, G. Gupta, A. Sharma (2013)
Pyrazole containing natural products: synthetic preview and biological significance.European journal of medicinal chemistry, 69
J. Janetka, A. Hopper, Ziping Yang, J. Barks, M. Dhason, Qiuling Wang, L. Sibley (2020)
Optimizing pyrazolopyrimidine inhibitors of calcium dependent protein kinase 1 for treatment of acute and chronic toxoplasmosis.Journal of medicinal chemistry
M. Elnagdi, N. Al-Awadi, Ismail Abdelhamid (2008)
Bicyclic 5-6 Systems: Other Four Heteroatoms 2:2, 10
Cl), 104.6, 134.2 (C-H), 151.6, 155.2, 157.6 (C=O)
M. Shaaban, Y. Elshaier, Ali Hammad, Nahla Farag, Haredy Haredy, A. Abdel-ghany, Khaled Mohamed (2020)
Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors.Bioorganic & medicinal chemistry letters, 30 16
(2016)
Tricyclic Piperazine Derivative
(2004)
Condensed pyrimidine systems. 5.6-Methyl-functionalized in pyrazolo
(2006)
Condensed pyrimidine systems. 5.6-Methyl-functionalized in pyrazolo[3,4-d]pyrimidin-4(5H)-ones
(2013)
Synthesis of novel 2-alkyl-4-substitutedamino-pyrazolo[3,4-d]pyrimidines as new leads for anti-bacterial and anti-cancer activity
17.96; N, 28.29%. Synthesis of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo
molbank Short Note 4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidine 1 1 , 2 , Vladimir A. Ogurtsov and Oleg A. Rakitin * N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia; vaog@mail.ru Nanotechnology Education and Research Center, South Ural State University, 76 Lenina Avenue, 454080 Chelyabinsk, Russia * Correspondence: orakitin@ioc.ac.ru; Tel.: +7-499-135-5327 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- 1 13 resolution mass-spectrometry, H, C-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 Citation: Ogurtsov, V.A.; Rakitin, 1. Introduction O.A. 4-Chloro-6-(chloromethyl)- 1-methyl-1H-pyrazolo[3,4- 1H-Pyrazolo[3,4-d]pyrimidine is an important structural fragment present in naturally d]pyrimidine. Molbank 2021, 2021, occurring nucleosides (Formycin A and Formycin B), which have significant antitumor M1253. https://doi.org/10.3390/ activity [1,2]. Additionally, 1H-pyrazolo[3,4-d]pyrimidines exhibit various biological ac- M1253 tivities, including antiviral and analgesic activity, treatment of male erectile dysfunction and hyperuricemia, prevention of gout, and many others [1,3,4]. Functionally substi- Academic Editor: Norbert Haider tuted 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 Received: 6 July 2021 interest. 1-Substituted 4-chloro-6-(chloromethyl)-1H-pyrazolo[3,4-d]pyrimidines can be Accepted: 20 July 2021 considered important intermediates for the preparation of previously unknown disubsti- Published: 22 July 2021 tuted 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)- Publisher’s Note: MDPI stays neutral 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one. with regard to jurisdictional claims in published maps and institutional affil- 2. Results and Discussion iations. 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 POCl [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- Copyright: © 2021 by the authors. 4-carboxamides 4 followed by reaction with choloroacetyl chloride [5–8] (Scheme 1). Licensee MDPI, Basel, Switzerland. We decided to carry out the synthesis of heterocycle 1b by a shorter route from the This article is an open access article cheaper and more accessible reagent-ester of 5-amino-1H-pyrazole-4-carboxylate 5. We distributed under the terms and found that the reaction of commercially available ethyl 5-amino-1-methyl-1H-pyrazole- conditions of the Creative Commons 4-carboxylate 5 with chloroacetonitrile in dioxane led to the formation of pyrimidinone Attribution (CC BY) license (https:// 2b in high yield (83%). It should be noted that the yield of compound 2b according to the creativecommons.org/licenses/by/ 4.0/). Molbank 2021, 2021, M1253. https://doi.org/10.3390/M1253 https://www.mdpi.com/journal/molbank Molbank 2021, 2021, x FOR PEER REVIEW 2 of 4 Molbank 2021, 2021, M1253 2 of 3 Molbank 2021, 2021, x FOR PEER REVIEW 2 of 4 method described in [8] was much lower (29%). Treatment of compound 2b with POCl gave the target product 1b (Scheme 2). Scheme 1. Known synthesis of 4-chloro-6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 1a. 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 Scheme 1. Known synthesis of 4-chloro-6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine Scheme 1. Known synthesis of 4-chloro-6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 1a. gave the target product 1b (Scheme 2). 1a. 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). Scheme Scheme 2 2.. Synthesis Synthesis of 4- of 4-chlor chlor o-6-(chlor o-6-(chloromet omethyl)-1-methyl-1 hyl)-1-methyl-1H H -pyrazolo[3,4- -pyrazolo[3,4-dd ]pyrimidine ]pyrimidine1b 1b . . The structure of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 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- 1b and its precursor 6-(сhloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrim- 4-one 2b was fully confirmed by elemental analysis, high resolution mass-spectrometry, idin-4-one 2b was fully confirmed by elemental analysis, high resolution mass-spectrom- 1 13 1 H, C-NMR and IR spectroscopy, and mass-spectrometry. The H-NMR spectrum of 1 13 1 etry, H, C-NMR and IR spectroscopy, and mass-spectrometry. The H-NMR spectrum 1b showed characteristic singlets of Me group (4.08 ppm), ClCH group (4.92 ppm) and of 1b showed characteristic singlets of Me group (4.08 ppm), ClCH2 group (4.92 ppm) and C-H-pyrazole group (8.46 ppm). C-H-pyrazole group (8.46 ppm). In conclusion, 1H-pyrazolo[3,4-d]pyrimidine containing two reactive chlorine atoms-4- In conclusion, 1H-pyrazolo[3,4-d]pyrimidine containing two reactive chlorine atoms- Scheme 2. Synthesis of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b. chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b, was obtained using a 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b, was obtained us- rational and short path. This compound opens up possibilities for the synthesis of various The structure of 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine ing a rational and short path. This compound opens up possibilities for the synthesis of functional derivatives of disubstituted 1H-pyrazolo[3,4-d]pyrimidines, which may be of 1b vario and us functional d its precursore 6- riv(aсhloromethyl)-1-met tives of disubstituted 1 hyl-1, H 5-d -pyraz ihydol ro- o[ 43,4- H-p dyraz ]pyrol imi o[3 d,ine 4-ds]pyrim , which - interest as compounds with useful pharmacological properties. idin may be -4-one of 2b int was erestfu as comp lly confirmed ounds w by e ithl u ement seful ph al an arm alysi acologic s, high re al pro solut pert ion m ies. ass-spectrom- 1 13 1 etry, H, C-NMR and IR spectroscopy, and mass-spectrometry. The H-NMR spectrum 3. Materials and Methods 3. Materials and Methods of 1b showed characteristic singlets of Me group (4.08 ppm), ClCH2 group (4.92 ppm) and The solvents and reagents were purchased from commercial sources and used as C-H-pyrazole group (8.46 ppm). The solvents and reagents were purchased from commercial sources and used as re- received. Elemental analysis was performed on a 2400 Elemental Analyzer (Perkin Elmer In conclusion, 1H-pyrazolo[3,4-d]pyrimidine containing two reactive chlorine atoms- ceived. 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 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 1b, was obtained us- Inc., Waltham, MA, USA). Melting point was determined on a Kofler hot-stage appa- 1 13 and is uncorrected. H and C-NMR spectra were taken with a Bruker AM-300 machine ing a rational and short pa 1th. This 13 compound opens up possibilities for the synthesis of ratus and is uncorrected. H and C-NMR spectra were taken with a Bruker AM-300 ma- (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 MHz) various functional derivatives of disubstituted 1H-pyrazolo[3,4-d]pyrimidines, which chine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 with TMS as the standard. MS spectrum (EI, 70 eV) was obtained with a Finnigan MAT may be of interest as compounds with useful pharmacological properties. MHz) with TMS as the standard. MS spectrum (EI, 70 eV) was obtained with a Finnigan INCOS 50 instrument (Hazlet, NJ, USA). IR spectrum was measured with a Bruker “Alpha- MAT INCOS 50 instrument (Hazlet, NJ, USA). IR spectrum was measured with a Bruker T” instrument in KBr pellet. High-resolution MS spectrum was measured on a Bruker 3. Materials and Methods “Alpha-T” instrument in KBr pellet. High-resolution MS spectrum was measured on a micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray Bruk The solvents er micrOTOF and re II insagents trument ( were purch Bruker Da ased from com ltonik Gmbh, Brem mercial so en, urc Germany) es and use using e d as re- lec- ionization (ESI). ceived. E trospray ion lemental ization analysis was per (ESI). formed on a 2400 Elemental Analyzer (Perkin Elmer Synthesis of 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4- Inc., W Synthesis of altham, MA 6-( , Uсhloromet SA). Melt hyl)-1-methyl-1,5-dih ing point was detery m dro ined -4H on -p a yr Ko azofl lo[ er 3 hot ,4-d]py -starg im e ap idin- pa4-- one 2b (Supplementary Materials). 1 13 rat one us and 2b (Supp is unco lementary rrected M . H and aterials). C-NMR spectra were taken with a Bruker AM-300 ma- HCl gas was passed through a solution of ethyl 5-amino-1-methyl-1H-pyrazole-4- chine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 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 MHz) wi carboxylate th TMS as the standa 5 (0.15 mol, 25.35 rd. g) M and ch S spe lo ct roacet rum (onit EI, 70 ril eV) e (0.1 w 5 m as o ob l, t9. ai5 m nedL w ) in d ith a iox Fiane ( nnig5 a00 n (500 mL) at a temperature of 15–18 C for 10 h. The volatiles were evaporated, water MAT INCOS 50 instrument (Hazlet, NJ, USA). IR spectrum was measured with a Bruker (300 mL) was added to the residue, and the reaction mixture was alkalized with aqueous “Alpha-T” instrument in KBr pellet. High-resolution MS spectrum was measured on a ammonia to pH = 7. The precipitate was filtered, washed with water and dried in air. Yield –1 B 24.71 ruker g mi (83%), crOTOF light II i beige nstrume solid, nt ( mp Bru 286–287 ker Daltonik C. IR Gm spectr bh, Brem um (KBr), en, Germany) , cm : using e 3434, 3106, lec- trospray ionization (ESI). 2978, 2890, 2858 (all C-H), 1727 (C=O), 1658, 1614 (C=N), 1407, 1200, 1070, 865, 849, 777, 724, 673, Synthesis of 616, 506.6-( H-NMR сhloromet (DMSO- hyl)-1-methyl-1,5-dih d , ppm): 3.90 y (3H, dro-s), 4H4.57 -pyr(2H, azolo[ s), 3,8.05 4-d]py (1H, rim s), id12.47 in-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 Molbank 2021, 2021, M1253 3 of 3 (1H, broad s). C-NMR (DMSO-d , ppm): 34.1 (CH ), 42.7 (CH Cl), 104.6, 134.2 (C-H), 6 3 2 151.6, 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 C H ClN O [M + H] 7 8 4 199.0381; found m/z 199.0387, calcd. for C H ClN NaO [M + Na] 221.0201; found m/z 7 7 4 221.0203. Anal. calcd. for C H ClN O: C, 42.33; H, 3.55; Cl, 17.85; N, 28.21; found: C, 42.25; 7 7 4 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), POCl (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 NaHCO , brine and passed through the Al O layer on the filter. The solvent was removed. 3 2 3 –1 Yield 15.62 g (72%), white solid, mp 68–69 C. IR spectrum (KBr), , cm : 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. H-NMR (DMSO-d , ppm): 4.08 (3H, s), 4.92 (2H, s), 8.46 (1H, s). C-NMR (DMSO-d , ppm): 34.4 (CH ), 46.5 (CH Cl), 111.7, 132.0 6 3 2 (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 + + C H Cl N [M + H] 217.0042; found m/z 217.0050, calcd. for C H Cl N Na [M + Na] 7 7 2 4 7 6 2 4 238.9862; found m/z 238.9870. Anal. calcd. for C H Cl N : C, 38.74; H, 2.79; Cl, 32.66; N, 7 6 2 4 25.81; found: C, 38.66; H, 2.85; Cl, 32.56; N, 25.93%. 1 13 Supplementary Materials: The following are available online: copies of H, C-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. [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. [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. [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. [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. [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. 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Molbank – Multidisciplinary Digital Publishing Institute
Published: Jul 22, 2021
Keywords: 1H-pyrazolo[3,4-d]pyrimidines; 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine; condensation; biological activity
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