78
MATERIALI E METODI
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.
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).
Per le colonne cromatografiche è stato utilizzato il gel di silice 60 (230-400 mesh).
Gli spettri di risonanza magnetica del protone (1H-NMR) sono stati eseguiti in soluzione di cloroformio deuterato (CDCl3-d), oppure in una soluzione di
dimetilsolfossido esa-deuterato (DMSO-d6) con uno spettrometro Brucker-400 (400-MHz) utilizzando (CH3)4Si (TMS) come standard interno.
I punti di fusione sono stati determinati con un apparecchio di Reichert Kӧfler e non sono stati corretti.
79
Sintesi dei 2-[(dimetilamino)metilen]-5-fenil-1,3-cicloesanedione 89[64]
Il composto 88 (2,00g, 0.010 moli) è solubilizzato in 2,00 ml (0.015 moli) di DMF-DMA e scaldato a 100 °C per circa 1 ora controllando l’andamento della reazione mediante T.L.C. (etere di petrolio 40-60/acetato di etile 1: 9). Dopo raffreddamento la sospensione ottenuta viene triturata con etere etilico ed il solido ottenuto, raccolto per filtrazione sotto vuoto corrisponde al composto desiderato
89.
Resa 95%
80
Sintesi 4-(6-fenil-4-oxo-4,5,6,7-tetraidro-1H-indazol-1-il)benzenesolfonamide (84c)[61]
Il composto 89 ( 1,00 g, 0,004 moli) è solubilizzato in etanolo e addizionato di 1,103 g (0,005 moli) di 4-solfonammidofenilidrazina cloridrato. La reazione viene scaldata a 90° per un periodo che va dalle 4 alle 5 ore controllandone l’andamento mediante T.L.C. (miscela eluente: etere di petrolio 40-60/acetato di etile = 1:9). Dopo raffreddamento il solido ottenuto viene raccolto mediante filtrazione sottovuoto e successivamente purificato tramite cristallizzazione da etanolo. Resa 54% P.f.:197-199 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54-2.58 (m, 1H), 2.95-3.02 (m, 1H), 3.15- 3.20 (m, 1H), 3.43-3.56 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.33-7.41 (m, 4H), 7.48 (s, 2H, NH2 scamb.), 7.86 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 8.18 (s, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 30.42, 40.99, 44.37, 120.40, 123.45 (2C), 127.04 (2C), 127.11 (2C), 128.50 (2C), 138.42, 140.61, 142.96, 143.17, 149.73, 191.46
81
Sintesi dei derivati 4-(4-oxo-6-fenill-4,5,6,7-tetraidro-1H-indazol-1-il)-N- fenilbenzenesolfonamidici 86a-i
Procedura generale
Il composto 84c (0,300 g, 0,817 mmoli) è addizionato di 0,007 g (0,04 mmoli) di CuI, 0,981 mmoli dell’opportuno iodobenzene, 0,282g (2,045 mmoli) di K2CO3,
0,04 ml di N,N’-dimetiletilendiammina (DMEDA) solubilizzati in 10 ml di Acetonitrile . La reazione viene condotta in corrente di N2 e scaldata a 100 °C,
mantenendola in agitazione, per un periodo che va da 8 a 24 ore, controllandone l’andamento mediante T.L.C. (miscela eluente: etere di petrolio 40-60/acetato di etile = 5:5). Dopo raffreddamento la miscela viene addizionata di 3 ml di acqua distillata e quindi acidificata con HCl 2N, fino a pH 4. Si esegue, quindi, un’estrazione con Acetato di Etile, da cui si raccolgono le fasi organiche che vengono seccate su MgSO4 ed evaporate a pressione ridotta. I composti grezzi
ottenuti vengono purificati mediante cromatografia flash su gel di silice (diametro: 3 cm, altezza: 17 cm, miscela eluente: etere di petrolio 40-60/acetato di etile = 5:5).
82 4-(4-oxo-6-fenill-4,5,6,7-tetraidro-1H-indazol-1-il)-N-fenilbenzenesolfonamide 86a Resa: 15.0 % P.f.: 98-100 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54-2.55 (m, 1H), 2.93-3.01 (m, 1H), 3.11- 3.16 (m, 1H), 3.40-3.55 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.21-7.27 (m, 3H), 7.32-7.40 (m, 4H), 7.83 d, J = 8.8 Hz, 2H), 7.90 d, J = 8.8 Hz, 2H), 8.16 (s, 1H), 10.40 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): δ 30.57, 41.13, 44.47, 120.31 (2C), 120.561, 123.52 (2C), 124.36, 126.93, 127.15 (2C), 128.27 (2C), 128.58 (2C), 129.28 (2C), 137.46, 138.53, 138.66, 141.50, 143.02, 149.92, 191.51. N-(4-metossifenill)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesolfonamide 86b Resa: 15.0 % P.f.: 108-110 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54-2.56 (m, 1H), 2.94-3.01 (m, 1H), 3.12- 3.16 (m, 1H), 3.41-3.54 (m, 2H), 3.65 (s, 3H), 6.80 (AA′XX′, JAA’/XX’ = 2.4 Hz, JAX = 8.8 Hz, 2H), 6.98 (AA′XX′, JAA’/XX’ = 3.0 Hz, JAX = 8.8 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.32-7.41 (m, 4H), 7.82 (s, 4H), 8.17 (s, 1H), 10.02 (s, 1H,
scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): 13C NMR (100 MHz, DMSO-d6):
δ 30.50, 41.04, 44.32, 55.09, 114.32 (2C), 120.50, 123.35 (2C), 123.71 (2C), 126.85, 127.06 (2C), 128.20 (2C), 128.50 (2C), 129.73, 138.38, 138.56, 141.26, 142.94, 149.80, 156.67, 191.45.
83 N-(4-clorofenill)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesolfonamide 86c Resa: 35.0 % P.f.: 100-102 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.53-2.55 (m, 1H), 2.94-3.01 (m, 1H), 3.13- 3.16 (m, 1H), 3.41-3.52 (m, 2H), 7.10-7.12 (m, 2H), 7.24-7.40 (m, 7H), 7.84-7.91 (m, 4H), 8.17 (s, 1H), 10.56 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO- d6): 13C NMR (100 MHz, DMSO-d6): δ 30.53, 41.06, 44.35, 120.56 (2C), 121.83 (2C), 123.48 (2C), 126.86, 127.08 (2C), 128.21 (2C), 128.40, 128.51 (2C), 129.20, (2C), 138.08, 138.63, 141.56, 142.94, 149.87, 191.45. N-(4-nitrofenil)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesulfonamide 86d Resa: 80.0 % P.f.: 137-139 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54-2.56 (m, 1H), 2.94-3.01 (m, 1H), 3.14- 3.19 (m, 1H), 3.41-3.52 (m, 2H), 7.23-7.27 (m, 1H), 7.32-7.40 (m, 6H), 7.89 (AA′XX′, JAA’/XX’ = 2.2 Hz, JAX = 8.0 Hz, 2H), 8.03 (AA′XX′, JAA’/XX’ = 2.2
Hz, JAX = 8.0 Hz, 2H), 8.12-8.17 (m, 3H), 11.42 (s, 1H, scamb.) ppm. 13C NMR
(100 MHz, DMSO-d6): δ 30.52, 41.06, 44.36, 118.13 (2C), 120.60 (2C), 123.66
(2C), 125.39 (2C), 126.85, 127.06 (2C), 128.32, 128.50 (2C), 137.80, 138.69, 141.93, 142.71, 142.91, 143.85, 149.94, 191.45.
84 4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1-il)-N-(p- tolil)benzenesolfonamide 86e Resa: 25.0 % P.f.: 101-103 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.16 (s, 3H), 2.55 (d, J = 3.2 Hz, 1H), 2.93- 3.01 (m, 1H), 3.10-3.15 (m, 1H), 3.40-3.53 (m, 2H), 6.97 (AA′XX′, JAA’/XX’ = 2.0 Hz, JAX = 8.4 Hz, 2H), 7.02 (AA′XX′, JAA’/XX’ = 2.0 Hz, JAX = 8.4 Hz, 2H), 7.26 (tt, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.32-7.40 (m, 4H), 7.82 (AA′XX′, JAA’/XX’ = 2.0 Hz, JAX = 6.8 Hz, 2H), 7.86 AA′XX′, JAA’/XX’ = 2.0 Hz, JAX =
6.8 Hz, 2H), 8.17 (s, 1H), 10.22 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): δ 20.23, 30.46, 41.04, 44.39, 120.50, 120.86 (2C), 123.40 (2C), 126.84, 127.05 (2C), 128.17, 128.49 (2C), 129.59 (2C), 133.66, 134.66, 138.44, 138.55, 141.32, 142.93, 149.81, 191.42. N-(3-metossifenill)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesolfonamide 86f Resa: 15% P.f.: 90-92 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.55 (d, J = 3.2 Hz, 1H), 2.94-3.01 (m, 1H), 3.11-3.16 (m, 1H), 3.40-3.53 (m, 2H), 3.64 (s, 3H), 6.59-6.61 (m, 1H), 6.66-6.70 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 7.26 (tt, J = 1.6 Hz, J = 7.6 Hz, 1H), 7.32-7.40 (m, 4H), 7.84 (AA′XX′, JAA’/XX’ = 2.0 Hz, JAX = 9.2 Hz, 2H), 7.86 (AA′XX′,
JAA’/XX’ = 2.0 Hz, JAX = 9.2 Hz, 2H), 8.17 (s, 1H), 10.22 (s, 1H, scamb.) ppm. 13C
85 112.21, 120.65, 123.61, (2C), 125.13 (2C), 126.99, 127.20 (2C), 128.37, 128.64 (2C), 130.21, 137.42, 138.49, 138.72, 141.58, 143.06, 149.98, 159.81, 191.62. N-(3-clorofenill)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesolfonamide 86g Resa: 27% P.f.: 93-95 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54 (d, J = 2.8 Hz, 1H), 2.94-3.01 (m, 1H), 3.12-3.17 (m, 1H), 3.41-3.53 (m, 2H), 7.07-7.12 (m, 3H), 7.24-7.40 (m, 5H), 7.86 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H), 10.71 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): δ 14.23, 41.24, 44.56, 118.47, 119.52, 120.73, 123.78 (2C), 124.24, 127.07, 127.25 (2C), 128.42 (2C), 128.71 (2C), 131.21, 133.60, 138.16, 138.83, 139.13, 141.83, 143.09, 150.12, 191.76. N-(3-nitrofenil)-4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1- il)benzenesulfonamide 86h Resa: 55.0 % P.f.: 105-107 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.54-2.55 (m, 1H), 2.93-3.00 (m, 1H), 3.12- 3.17 (m, 1H), 3.40-3.52 (m, 2H), 7.23-7.27 (m, 1H), 7.32-7.39 (m, 4H), 7.54-7.56 (m, 2H), 7.86-7.90 (m, 3H), 7.96-7.98 (m, 3H), 8.17 (s, 1H), 11.06 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): δ 30.53, 41.04, 44.36, 113.60, 118.67, 120.58, 123.61 (2C), 125.50 (2C), 126.85, 127.05 (2C), 128.26, 128.49 (2C), 130.89, 137.72, 138.66, 138.77, 141.80, 142.91, 148.19, 149.91, 191.44.
86 4-(4-oxo-6-fenil-4,5,6,7-tetraidro-1H-indazol-1-il)-N-(m- tolil)benzenesolfonamide 86i Resa: 18% P.f.: 87-89 °C 1 H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 2.55 (d, J = 2.8 Hz, 1H), 2.94- 3.01 (m, 1H), 3.11-3.15 (m, 1H), 3.40-3.53 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 7.08-7.12 (m, 1H), 7.25-7.27 (m, 1H), 7.32-7.40 (m, 4H), 7.83 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 8.17 (s, 1H), 10.34 (s, 1H, scamb.) ppm. 13C NMR (100 MHz, DMSO-d6): δ 20.83, 30.61, 41.15, 44.48, 117.36, 120.62, 120.85, 123.56 (2C), 125.13 (2C), 126.96, 127.17 (2C), 128.30, 128.61 (2C), 129.11, 137.42, 138.59, 138.64, 138.69, 141.49, 143.05, 149.94, 191.56.
88
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