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An Efficient One-Pot Synthesisof Pyrazolopyrimidines, Intermediatesfor Potential Phosphodiesterase Inhibitors Raid J. Abdel-Jalil1;Ã, Monther Khanfar1, Kayed Abu-Safieh1,Samer Al-Gharabli2, Mustafa El-Abadelah2, and Wolfgang Voelter3;Ã 1 Chemistry Department, Faculty of Science, Hashemite University, Zarka-Jordan2 Chemistry Department, Faculty of Sciences and Arts, University of Jordan, 3 Abteilung f€uur Physikalische Biochemie des Physiologisch-chemischen Received August 3, 2004; accepted August 16, 2004Published online January 14, 2005 # Springer-Verlag 2005 Summary. A simple high-yielding procedure is presented for the synthesis of pyrazolopyrimidinonesovercoming limitations found in earlier work and of considerable utility for the production of inter-mediates for potential phosphodiesterase inhibitors.
Keywords. Pyrazolopyrimidones; Viagra+; Phosphodiesterase inhibitors.
Sildenafil (1, Viagra+, Fig. 1) is a well-known selective phosphodiesterease type 5(PDE5) inhibitor, used worldwide as an efficacious, orally active agent for thetreatment of male erectile dysfunction (MED) [1–4]. 5-(2-Methoxyphenyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-one (4a, Scheme 1),the key intermediate for the synthesis of Viagra+, is traditionally prepared by thereaction of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide (2) with 2-ethoxy-benzoyl chloride followed by cyclization using different reagents, e.g. t-BuOK=t-BuOH [5], H2O2 [6], or polyphosphoric acid (PPA) [7].
However, the reported methods for the preparation of this key intermediate suf- fer from moderate yields and tedious procedures. Herewith we would like to reportan alternative approach for pyrazolopyrimidinone moieties (e.g. 4a–4f) via con-densing carboxamide 2 with the appropriate benzaldehydes to the corresponding à Corresponding authors. E-mails:; Fig. 1. Structure of Sildenafile (Viagra+) Schiff ’s bases (e.g. 3a–3f) and subsequent ring closure in a mixture of tert-butanol=potassium tert-butoxide (Scheme 1).
Recently we have reported the synthesis of new and selective phospho-diesterasetype 5 (PDE5) inhibitors [8, 9] which showed a significant activity in MED. In anattempt to improve and facilitate the synthesis of these inhibitors, a modificationwas investigated by replacing the appropriate benzoylchloride by benzaldehyde toyield the corresponding Schiff ’s bases which were then transformed by potassiumtert-butoxoide=tert-butanol to pyrazolopyrimidinones. The formation of the Schiff ’sbases 3a–3f were achieved within 30 min in almost quantitative yield by the reac-tion of 2 with substituted benzaldehydes in ethanol. The Schiff ’s bases 3a–3f werethen cyclized in refluxing tert-butanol in the presence of tert-butoxide to give thecorresponding pyrazolopyrimidinones in high yields (84–91%, Scheme 1).
As we demonstrate herein, this two step approach can be achieved in a one-pot reaction. Thus, 2, prepared by following the published procedure [10], was refluxedwith the appropriate aldehyde in tert-butanol for 30 min, followed by the addition of An Efficient One-Pot Synthesis of Pyrazolopyrimidines one equivalent of potassium tert-butoxide, and then the reflux was continued for 4hours to afford the corresponding pyrazolopyrimidinones (4a–4f) in similar yields.
The structures of the Schiff ’s bases and the pyrazolopyrimidinone derivatives were determined on the basis of their spectral data and elemental analyses. Thus,the 1H NMR of compounds 3a–3f showed a singlet around 8.2 ppm assigned tothe methine hydrogen, and the disappearance of this signal in the 1H NMR of4a–4f indicates the successful formation of the pyrazolopyrimidinones. The massspectra of 3a–3f and 4a–4f show the correct molecular ion peaks as base peaks.
The elemental analyses and physical properties of the Schiff ’s bases as well asthe pyrazolopyrimidinone derivatives are in coincidence with the correspondingstructures.
In conclusion, this alternative approach for the preparation of pyrazolopyrimi- dones is a simpler procedure of lower cost and higher yield compared to thosepublished in literature.
1H NMR were measured on a Bruker AM 250 FT spectrophotometer operating at 300 K and usingTMS as internal standard. Mass spectra (electron impact) were obtained on a Varian CH-7 spectro-photometer at 70 eV at an ion source formation of 200C. Melting points were recorded on anelectrothermal melting temperature apparatus. Elemental analyses were determined on a Perkin-Elmerelemental analyzer, model 240. Their results agreed favourably with the calculated values. Arylalde-hydes were purchased from Aldrich and used without further purification. Compound 2 was obtainedaccording to Ref. [10].
General Procedure for the Synthesis of Pyrazolopyrimidinones 4a–4f (i) A mixture of 2.01 g of 2 (1 mmol) and 2 mmol of the corresponding aryl aldehyde in 10 cm3 of absolute ethanol was heated under reflux for 1 h and then cooled to room temperature. The solidproduct was collected by filtration and recrystallized from ethanol to give pure 3a–3f.
(ii) Potassium tert-butoxide (12 mmol) was added to a stirred suspension of 12 mmol of Schiff ’s base in 30 cm3 of tert-butanol, the resulting mixture was heated under reflux for 4–6 h, and then allowedto cool to room temperature. Water (30 cm3) was then added and the resulting solution neutralized(pH 7) with dilute HCl (5%) and cooled to 5–10C. The precipitated solid product was collectedand dried.
A mixture of 2.01 g of 2 (1 mmol) and 2 mmol of aryl aldehyde in 10 cm3 of tert-BuOH was heatedunder reflux for 30 min. Potassium tert-butoxide (12 mmol) was then added and the heating continuedfor additional 4 h. The reaction mixture was worked up as described in A(ii) above.
4-[(2-Ethoxybenzylidene)amino]-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide(3a, C17H22N4O2) Yield 93%; mp 153–154C; 1H NMR (CDCl3):  ¼ 1.03 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.47 (t,J ¼ 7.0 Hz, –OCH2CH3), 1.75 (m, –CH2CH CH J ¼ 7.0 Hz, –OCH2CH3), 4.20 (s, N1–CH3), 5.91 (bs, –NHH), 7.00–7.94 (m, C6H4), 8.77 (bs, –NHH),9.04 (s, –N¼CH–Ar); MS–EI: m=z ¼ 314 (Mþ).
4-[(3-Fluorobenzylidene)amino]-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide(3b, C15H17FN4O) Yield 97%; mp 135–136C; 1H NMR (CDCl3):  ¼ 1.02 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.75(m, –CH2CH2CH3), 2.73 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.21 (s, N1–CH3), 5.96 (bs, –NHH), 7.16–7.57 (m, C6H4), 8.44 (bs, 1H, –NHH), 8.53 (s, –N¼CH–Ar); MS–EI: m=z ¼ 288 (Mþ).
4-[(4-Fluorobenzylidene)amino]-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide(3c, C15H17FN4O) Yield 89%; mp 125–127C; 1H NMR (CDCl3):  ¼ 1.04 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.72(m, –CH2CH2CH3), 2.72 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.19 (s, N1–CH3), 6.04 (bs, –NHH), 7.30–7.84 (m, C6H4), 8.44 (bs, 1H, –NHH), 8.51 (s, –N¼CH–Ar); MS–EI: m=z ¼ 288 (Mþ).
2-Methyl-5-propyl-4-[(pyridin-2-ylmethylene)amino]-2H-pyrazole-3-carboxylic acid amide(3d, C14H17N5O) Yield 90%; mp 155–156C; 1H NMR (CDCl3):  ¼ 1.02 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.78(m, –CH2CH2CH3), 2.79 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.22 (s, N1–CH3), 6.30 (bs, –NHH), 7.39(ddd, J ¼ 1.2, 4.9, 7.6 Hz, 1H-py), 7.82 (ddd, J ¼ 1.8, 7.6, 8.1 Hz, 1H-py), 8.02 (ddd, J ¼ 0.9, 1.2,8.1 Hz, 1H-py), 8.73 (ddd, J ¼ 0.9, 1.5, 4.9 Hz, 1H-py), 8.57 (bs, –NHH), 8.69 (s, –N¼CH–Ar);MS–EI: m=z ¼ 271 (Mþ).
2-Methyl-5-propyl-4-[(thien-2-ylmethylene)amino]-2H-pyrazole-3-carboxylic acid amide(3e, C13H16N4OS) Yield 94%; mp 150–151C; 1H NMR (CDCl3):  ¼ 1.02 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.75(m, –CH2CH2CH3), 2.77 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.19 (s, N1–CH3), 5.76 (bs, –NHH), 7.16(dd, J ¼ 3.7, 4.9 Hz, 1H-th), 7.47 (dd, J ¼ 0.9, 3.7 Hz, 1H-th), 7.52 (dd, J ¼ 0.9, 4.9 Hz, 1H-th), 8.53(bs, –NHH), 8.64 (s, –N¼CH–Ar); MS–EI: m=z ¼ 276 (Mþ).
4-[(Furan-2-ylmethylene)amino]-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide(3f, C13H16N4O2) Yield 94%; mp 172–173C; 1H NMR (CDCl3):  ¼ 1.01 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.74(m, –CH2CH2CH3), 2.73 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.19 (s, N1–CH3), 5.84 (bs, –NHH), 6.58(dd, J ¼ 1.8, 3.4 Hz, 1H-fu), 6.92 (dd, J ¼ 0.6, 3.4 Hz, 1H-fu), 7.62 (d, J ¼ 1.8 Hz, 1H-fu), 8.78 (bs,–NHH), 8.34 (s, –N¼CH–Ar); MS–EI: m=z ¼ 260 (Mþ).
5-(2-Ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4a, C17H20N4O2) Yield 85%; mp 144–145C; 1H NMR (CDCl3):  ¼ 1.04 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.60 (t,J ¼ 7.0 Hz, –OCH2CH3), 1.88 (m, –CH2CH2CH3), 2.93 (t, J ¼ 7.9 Hz, –CH2CH2CH3), 4.30 (q,J ¼ 7.0 Hz, –OCH2CH3), 4.27 (s, N1–CH3), 7.03–8.46 (m, C6H4), 11.13 (bs, –NH); MS–EI:m=z ¼ 260 (Mþ).
An Efficient One-Pot Synthesis of Pyrazolopyrimidines 5-(3-Fluorophenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4b, C15H15FN4O) Yield 89%; mp 188–190C; 1H NMR (CDCl3):  ¼ 1.02 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.75(m, –CH2CH2CH3), 2.73 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.21 (s, N1–CH3), 7.16–7.57 (m, C6H4),11.75 (bs, –NH); MS–EI: m=z ¼ 286 (Mþ).
5-(4-Fluorophenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4c, C15H15FN4O) Yield 91%; mp 241–242C; 1H NMR (CDCl3):  ¼ 1.02 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.85(m, –CH2CH2CH3), 2.89 (t, J ¼ 7.4 Hz, –CH2CH2CH3), 4.25 (s, N1–CH3), 7.17–8.15 (m, C6H4),11.75 (bs, –NH); MS–EI: m=z ¼ 286 (Mþ).
1-Methyl-3-propyl-5-pyridin-2-yl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4d, C14H15N5O) Yield 86%; mp 156–157C; 1H NMR (CDCl3):  ¼ 1.04 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.85(m, –CH2CH2CH3), 2.93 (t, J ¼ 7.6 Hz, –CH2CH2CH3), 4.29 (s, N1–CH3), 7.42 (ddd, J ¼ 1.2, 4.9,7.6 Hz, 1H-py), 7.88 (ddd, J ¼ 1.5, 7.6, 7.9 Hz, 1H-py), 8.49 (ddd, J ¼ 0.9, 1.2, 7.9 Hz, 1H-py), 8.62(ddd, J ¼ 0.9, 1.5, 4.9 Hz, 1H-py), 10.91 (bs, –NH), 8.69; MS–EI: m=z ¼ 269 (Mþ).
1-Methyl-3-propyl-5-thien-2-yl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4e, C13H14N4OS) Yield 82%; mp 249–250C; 1H NMR (CDCl3):  ¼ 0.99 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.80(m, –CH2CH2CH3), 2.81 (t, J ¼ 7.5 Hz, –CH2CH2CH3), 4.19 (s, N1–CH3), 7.10 (dd, J ¼ 4.0,5.2 Hz, 1H-th), 7.54 (dd, J ¼ 0.9, 5.2 Hz, 1H-th), 8.07 (dd, J ¼ 0.9, 4.0 Hz, 1H-th), 12.31 (bs, –NH);MS–EI: m=z ¼ 269 (Mþ).
5-Furan-2-yl-1-Methyl-3-propylyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(4f, C13H14N4O2) Yield 86%; mp 228–229C; 1H NMR (CDCl3):  ¼ 0.97 (t, J ¼ 7.3 Hz, –CH2CH2CH3), 1.78(m, –CH2CH2CH3), 2.79 (t, J ¼ 7.5 Hz, –CH2CH2CH3), 4.17 (s, N1–CH3), 6.62 (dd, J ¼ 1.8,3.6 Hz, 1H-fu), 7.48 (dd, J ¼ 0.8, 3.5 Hz, 1H-fu), 7.82 (dd, J ¼ 0.8, 1.8 Hz, 1H-fu), 12.30 (bs, –NH);MS–EI: m=z ¼ 258 (Mþ).
We are grateful to the Hashemite University for financial support. We express our gratitude to Inter-nationales B€ ulich, for a fellowship granted to Dr. R. J. A.-J.
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