Se non diversamente specificato, tutti i solventi ed i reagenti utilizzati per la sintesi sono stati acquistati dalle ditte fornitrici e sono stati utilizzati senza ulteriore purificazione. Come agente essiccante è stata utilizzata P2O5.
L’evaporazione dei solventi è stata effettuata sottovuoto utilizzando l’evaporatore rotante (rotavapor).
Le rese (%) si riferiscono a composti cromatograficamente e spettroscopicamente (1H-
NMR) omogenei.
Le reazioni sono state monitorate mediante cromatografia su strato sottile (T.L.C.) realizzate su foglio di alluminio ricoperto di silice (MERK 60 F-254, spessore 0.2 mm. Le reazioni mediante irraggiamento al microonde sono state effettuate con lo strumento microonde BIOTAGE Initiator 2.5.
Per le colonne cromatografiche è stato utilizzato il gel di silice 60 (230-400 mesh). Gli spettri di risonanza magnetica del protone (1H-NMR) e del carbonio (13C-NMR) sono
stati eseguiti in soluzione di dimetilsolfossido esa-deuterato (DMSO-d6) con uno
spettrometro Bruker AVANCE 400 (400-MHz).
I punti di fusione sono stati determinati con un apparecchio di Reichert Kӧfler e non sono stati corretti.
2-[(dimetilammino)metilen]-1,3-cicloesandione 6[102]
Una miscela di 1,3-cicloesandione (2.00 g, 18.0 mmoli) e DMF-DMA (3.98 mL, 30.0 mmoli) viene scaldata a 100 °C per un’ora (TLC: etere di petrolio 40-60 oC/AcOEt = 1:9).
Dopo raffreddamento alla soluzione viene addizionato etere etilico e, dopo triturazione, si ottiene un precipitato arancione che viene filtrato a pressione ridotta. Si ottengono 2.576 g di prodotto desiderato 6.
Resa: 84 %; P. f. : 110-112 °C.
Procedura generale per la sintesi delle fenil-guanidine 7a-d[106]
L’appropriata anilina (9.98 mmoli) viene solubilizzata in 6.0 mL di etanolo sotto agitazione a 0 °C, quindi si addizionano, goccia a goccia, 0.90 mL di HNO3 concentrato (28.28
mmoli), 0.460 g di cianammide (9.98 mmoli), precedentemente solubilizzata in 0.90 mL di acqua e si scalda a riflusso (100 °C) per 5 ore (TLC: etere di petrolio 40-60 oC/AcOEt =
7:3). Dopo raffreddamento la sospensione ottenuta viene filtrata sottovuoto ed il solido raccolto, costituito dalle guanidine nitrato 7a-d grezze, viene purificato mediante cristallizzazione da etanolo.
N-(4-metossifenil)guanidina nitrato (7a) [107]
Resa: 65 %; P. f. : 142-144 °C; la struttura è stata confermata con lo spettro H1 NMR
riportato in letteratura[107]. N-(3-metossifenil)guanidina nitrato (7b) Resa: 56 %; P. f. : 152-154 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 3.78 (s, 3H), 6.80- 6.82 (m, 2H), 6.87-6.89 (m, 1H), 7.33-7.38 (m, 5H), 9.59 (s, 1H). (3,4-dimetossifenil)guanidine nitrato (7c) Resa: 70%; P. f. : 136-139 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 3.77 (s, 3H), 3.78 (s, 3H), 6.78 (dd, 1H, Jmin = 2.4 Hz, Jmax = 8.8 Hz), 6.85 (d, 1H, J = 2.8 Hz), 7.01 (d, 1H, J = 8.4 Hz), 7.17 (s, 4H), 9.34 (s, 1H).
(3,4,5-trimetossifenil)guanidina (7d)
Resa: 53%; P. f. : 200-202°C. 1H NMR (400 MHz, DMSO-d
6, ppm): 3.67 (s, 3H), 3.79 (s,
6H), 6.56 (s, 2H), 7.28 (s, 4H), 9.46 (s, 1H).
Procedura generale per la sintesi dei derivati 2-(fenilammino)-7,8-diidrochinazolin- 5-(6H)-onici 8a-d
Ad una soluzione di 0.250 g di 2-[(dimetilammino)metilen]-1,3-cicloesandione (6) (1.497 mmoli) in 8 mL di 2-metossietanolo in una vial da 10-20 mL vengono addizionate 2.994 mmoli dell’opportuna guanidina nitrato 7a-d e 4.491 mmoli (0.180 g) di NaOH.. La miscela viene irradiata a 180°C, potenza = 70 W, pre-stirring = 3 minuti, per 1 ora. Dopo raffreddamento, la miscela di reazione viene evaporata a pressione ridotta. Il residuo ottenuto, rappresentato dai derivati 8a-d grezzi, viene purificato mediante cromatografia flash su gel di silice (miscela eluente, etere di petrolio 40-60°C :acetato di etile = 6:4 o 5:5).
2-((4-metossifenil)ammino)-7,8-diidrochinazolin-5(6H)-one (8a) Resa: 60%; P. f. : 157-159 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.03-2.06 (m, 2H), 2.54 (t, 2H, J = 6.0 Hz), 2.86 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 6.92 (d, 2H, J = 9.2 Hz), 7.64-7.66 (m, 2H), 8.76 (s, 1H), 10.14 (s, 1H). 2-((3-metossifenil)ammino)-7,8-diidrochinazolin-5(6H)-one (8b) Resa: 50%; P. f. : 126-128 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.05-2.08 (m, 1H), 2.57 (t, 2H, J = 6.2 Hz), 2.91 (t, 2H, J = 6.0 Hz), 3.75 (s, 3H), 6.63 (d, 1H, J = 7.6 Hz), 7.23 (t, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.55 (s, 1H), 8.82 (s, 1H), 10.27 (s, 1H); 13C NMR (100 MHz, DMSO-d 6, ppm): 21.24, 31.99, 38.17, 55.43, 106.40, 108.44, 112.77, 118.55, 129.81, 140.95, 158.18, 159.55, 160.88, 173.92, 195.47. 2-((3,4-dimetossifenil)ammino)-7,8-diidrochinazolin-5(6H)-one (8c) Resa: 49%; P. f. : 153-157 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.02-2.08 (m, 2H), 2.55 (t, 2H, J = 6.4 Hz), 2.88 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 3.75 (s, 3H), 6.92 (d, 2H, J
= 8.8 Hz), 7.28 (dd, 1H, Jmin = 2.4 Hz, Jmax = 8.4 Hz), 7.54 (bs, 1H), 8.77 (s, 1H), 10.13 (s, 1H); 13C NMR (100 MHz, DMSO-d 6, ppm): 21.28, 32.03, 38.16, 55.88, 56.27, 106.06, 112.58, 118.11, 133.21, 145.28, 148.97, 158.22, 160.85, 173.86, 195.34. 2-((3,4,5-trimetossifenil)ammino)-7,8-diidrochinazolin-5(6H)-one (8d) Resa: 50%; P. f. : 177-181°C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.03-2.10 (m, 2H), 2.56 (t, 2H, J = 6.6 Hz), 2.91 (t, 2H, J = 6.0 Hz), 3.64 (s, 3H), 3.77 (s, 6H), 7.26 (s, 2H), 8.80 (s, 1H), 10.17 (s, 1H); 13C NMR (100 MHz, DMSO-d 6, ppm): 21.25, 32.04, 38.16, 55.82, 60.59, 118.38, 133.73, 135.71, 135.81, 145.62, 153.09, 153.75, 158.16, 160.77, 173.83, 195.40.
Procedura generale per la sintesi dei derivati 6-dimetilamminometilen-2-anilino-7,8- diidro-6H-chinazolin-5-onici 9a-d
Una miscela dell’opportuno 7,8-diidrochinazolinone 8a-d (6,276 mmoli) e DMF-DMA (4,578 mmoli) viene scaldata a 100 °C per 16 ore (TLC: etere di petrolio 40-60°C/AcOEt = 5:5). Dopo raffreddamento alla soluzione viene addizionato etere etilico e, dopo triturazione, si ottiene un precipitato che viene filtrato a pressione ridotta. Si ottengono i derivati 9a-d, sufficientemente puri da poter essere utilizzati come tali senza ulteriore purificazione. 2-((4-metossifenil)amino)-6-((dimetilamino)metilene)-7,8-diidrochinazolin-5(6H)-one (9a) Resa 84 %; P. f. : > 200 °C; 1H-NMR (DMSO-d 6, ppm): 2.71 (t, 2H, J = 7.0 Hz); 2.89 (t, 2H, J = 6.8 Hz); 3.29 (s, 6H); 3.69 (s, 3H); 6.90 (d, 1H, J= 9.2 Hz); 7.44 (s, 1H); 7.67 (d, 1H, J= 9.2 Hz); 8.62 (s, 1H); 9.81 (s, 1H). 2-((3-metossifenil)amino)-6-((dimetilamino)metilene)-7,8-diidrochinazolin-5(6H)-one (9b)
Resa 88 %; P. f. : 205°C; 1H-NMR (DMSO-d 6, ppm): 2.80 (t, 2H, J = 7.0 Hz); 2.97 (t, 2H, J = 6.8 Hz); 3.13 (s, 6H); 3.75 (s, 3H); 6.59 (dd, 1H, Jmax = 8.4 Hz, Jmin = 2.4 Hz), 7.20 (t, 1H, J= 8.0 Hz); 7.36 (d, 1H, J= 9.2 Hz); 7.51 (s,1H); 7.57 (s, 1H); 8.73 (s, 1H); 10,00 (s, 1H). 2-(3,4-dimetossifenilamino)-6-(dimetillamino)metilene)-7,8-diidrochinazolin-5(6H)- one (9c) Resa 75 %; P. f. : 210 °C; 1H-NMR (DMSO-d 6, ppm): 2.59 (t, 2H, J = 7.0 Hz); 3.09 (t, 2H, J = 6.8 Hz); 3.11 (s, 6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.73 (d, 1H, J= 9.2 Hz); 6.82 (s, 1H); 7.23 (d, 1H, J= 9.2 Hz); 7.41 (s, 1H); 8.35 (s, 1H); 9.43 (s, 1H). 2-(3,4,5-trimetossifenilamino)-6-(dimetillamino)metilene)-7,8-diidrochinazolin- 5(6H)-one (9d) Resa 70 %; P. f. : 215°C; 1H-NMR (DMSO-d 6, ppm): 2.60 (t, 2H, J = 7.0 Hz); 3.10 (t, 2H, J = 6.8 Hz); 3.12 (s, 6H); 3.71 (s, 3H); 3.84 (s, 6H); 6.50 (s, 2H), 7.42 (s,1H); 8.35 (s, 1H); 9,43 (s, 1H).
Procedura generale per la sintesi dei composti 5,6-diidropirimido[4,5-f]chinazolin- 2,8-diamminici N2,N8-diarilsostituiti 5a-d
Ad una soluzione di 0.462 mmoli dell’opportuno derivato 9a-d in 8 mL di 2- metossietanolo, all’interno di una vial da 10-20 mL, vengono addizionate 0.924 mmoli dell’appropriata guanidina nitrato 7a-d e 1.386 mmoli (0.055 g) di NaOH. La miscela viene irradiata a 180°C, potenza = 70 W, pre-stirring = 3 minuti, per 1 ora. Dopo raffreddamento, la miscela di reazione viene evaporata a pressione ridotta. Il residuo ottenuto, rappresentato dai derivati 5a-d grezzi, viene purificato mediante cromatografia flash su gel di silice (miscela eluente: etere di petrolio 40-60°C: acetato di etile = 6:4 o 5:5).
N2,N8-bis(4-metossifenil)-5,6-diidropirimido[4,5-f]chinazolin-2,8-diammina (5a): Resa: 29 %; P. f. : 220°C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.87-2.91 (m, 4H); 3.73 (s, 3H); 3.74 (s, 3H); 6.90-6.92 (m, 4H); 7.67-7.71 (m, 4H); 8.28 (s, 1H); 9.00 (s, 1H); 9.30 (s, 1H); 9.88 (s, 1H). N2,N8-bis(3-metossifenil)-5,6-diidropirimido[4,5-f]chinazolin-2,8-diammina (5b): Resa: 40%; P. f. : 170-172 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.93-2.98 (m, 4H);
3.77 (s, 3H); 3.78 (s, 3H); 6.73 (dd, 1H, Jmin = 1.6 Hz, Jmax = 8.0 Hz); 6.61 (dd, 1H, Jmin =
2.4 Hz, Jmax = 6.8 Hz); 7.19-7.25 (m, 2H); 7.34-7.39 (m, 2H); 7.59 (s, 1H); 7.64 (s, 1H); 8.37 (s, 1H); 9.09 (s, 1H); 9.55 (s, 1H); 10.10 (s, 1H). N2,N8-bis(3,4-dimetossifenil)-5,6-diidropirimido[4,5-f]chinazolin-2,8-diammina (5c): Resa: 30%; P. f. : 210-212 °C; 1H NMR (400 MHz, DMSO-d 6, ppm): 2.91-2.96 (m, 4H); 3.76 (s, 3H); 3.77 (s, 3H); 3.83 (s, 3H); 3.84 (s, 3H); 6.73 (d, 1H, J= 9.0 Hz); 6.74 (d, 1H, J= 9.0 Hz); 6.82 (s, 1H); 6.83 (s, 1H); 7.23 (d, 1H, J= 8.8 Hz); 7.24 (d, 1H, J= 8.8 Hz); 8.86 (s, 1H); 8.92 (s, 1H); 9.43 (s, 1H); 9.44(s, 1H).
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