| 87% |
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 6h;Inert atmosphere; |
Example 5Preparation ofN-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amme (I, gefitinib) [0035] Under N2, the mixture of 4-[(3-chloro-4-fluorophenyl) amino]-7- methoxyquinazolin-6-ol (VII, 30.0 g, 93.8 mmol, 1.0 eq.), 4-(3-chloropropyl) morpholine (VIII, 16.lg, 1.05 eq.), K2C03 (25.9 g, 2.0 eq.) and N,N-dimethylformamide DMF (360 mL) was heated to 85C for 6 h. After the reaction completion, the mixture was cooled to 20-25C. The mixture was filtered and washed with DMF (60 mL*2). The conc. HCI (3.0 eq.) was added dropwise into filtrate. A lot of solid precipitated. The mixture was filtered, washed with DMF (60 mL*2). The filter-cake was dissolved in water (360 mL) at 75C. The iN NaOH aq. was added to the mixture to adjust pH value about 12-13. The mixture was filtered, washed with H20 (60 mL*2) and dried in vacuo at 50C to afford gefitinib as off-white solid (38.0 g) with 96.7% purity in 87% yield.1H NMR (400 MHz, d6-DMSO) O 9.44 (5, 1H), 8.50 (5, 1H), 8.12 (dd, J= 6.9, 2.7 Hz,1H), 7.80 (m, 2H), 7.44 (t, 1H), 7.20 (5, 1H), 4.18 (t, J= 6.7 Hz, 2H), 3.94 (5, 3H), 3.59(t, J = 4.4 Hz, 4H), 2.49 (t, J = 6.9 Hz, 2H), 2.41 (bs, 4H), 2.00 (m, 2H). l3 NMR (100 MHz, d6-DMSO) O 156.48, 154.94, 153.57 (J = 241 Hz), 153.05,148.74, 147.43, 137.33 (J = 3 Hz), 123.91, 122.77 (J = 7 Hz), 119.19 (J = 19 Hz),116.90 (J=21 Hz), 109.26,107.72,103.14,67.59,66.43,56.31,55.35,53.73,26.13. |
| 85.2% |
With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 85℃; for 4h; |
100 g (0.31 mol) of the compound of the formula IX was added to a 2 L three-necked flask, and 141 g (1.02 mol) of potassium carbonate was added thereto.DMF 800 mL, warmed to 80-85 C, and added N-(3-chloropropyl)morpholine 53.3 g (0.32 mol) in 200 mL DMF solution.The reaction was carried out for 4 hours, and the reaction was monitored by HPLC. About 600 mL of DMF was distilled off under reduced pressure, poured into 3 L of water and stirred for 1 hour, and filtered.The solid was collected, dried at 50 C to obtain a white-like crude gefitinib 130 g, purity 96%.130 g of the crude gefitinib obtained above was added to 2.6 L of methanol, heated to reflux to dissolve, and cooled to 25 C.After crystallization for 3 hours, filtration, collecting solid, drying at 60 C to obtain white gefitinib 118 g, molar yield 85.2%, pureDegree 99.6%. |
| 84% |
|
Under N2 protection, 6.4 g (20 mmol) of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (compound 6)It was added to 300 mL of DMF, heated to 75 C., 5 g (24 mmol) of 4-(3-chloropropyl)morpholine was added dropwise over a period of about 1 h, and during the addition, 1.4 g (10 mmol) was added in portions.Potassium carbonate (in 6 batches, 1 h was added), and the reaction was continued for 6 h after the addition was complete. After the reaction was completed, the mixture was filtered, the filter cake was washed with a little DMF, and the filtrate was concentrated under reduced pressure. The concentrate was stirred with 100 g of ice water and filtered to give a crude product. After the crude product was added to methanol, the solution was concentrated with concentrated hydrochloric acid to obtain gefitinib salt. The acid salt, the hydrochloride salt was further added to water, and the pH was adjusted to 8 with aqueous ammonia to obtain a large amount of a white powder, ie, gefitinib (7.5 g) in a yield of 84%. |
| 67% |
With potassium carbonate; In N,N-dimethyl-formamide; |
Step 6 N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine: Potassium carbonate (800 mg, 5.80 mmol, 5.79 equiv) was added to a solution of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol (320 mg, 1.00 mmol, 1.00 equiv), 4-(3-chloropropyl)-morpholine (190 mg, 1.16 mmol, 1.16 equiv), and N,N-dimethylformamide (10 mL). The resulting solution was stirred at about 80 C. for about 2 hours. The resulting crude product was purified by silica gel chromatography (ethyl acetate/methanol (6:1)) to give the title product as a white solid (0.3 g; yield=67%). 1H NMR (300 MHz, DMSO) delta: 9.57 (s, 1H), 8.51 (s, 1H), 8.11-8.14 (dd, J=6.6, 2.4 Hz 1H), 7.78-7.82 (m, 2H), 7.43-7.49, (t, 1H), 7.22 (s, 1H), 4.18-4.22 (t, 2H), 3.95 (s, 3H), 3.58-3.61 (t, 4H), 2.50-2.53 (m, 2H), 2.40-2.51 (t, 2H), 1.99-2.03 (t, 2H); LC-MS: m/z=447/449 (MH)+. |
| 50% |
With potassium carbonate; In N,N-dimethyl-formamide; |
EXAMPLE 1 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1 g), 3-morpholinopropyl chloride (J. Amer. Chem. Soc., 1945, 67, 736; 0.62 g), potassium carbonate (2.5 g) and DMF (50 ml) was stirred and heated to 80 C. for 2 hours. A further portion (0.1 g) of 3-morpholinopropyl chloride was added and the mixture was heated to 80 C. for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 4:1 mixture of ethyl acetate and methanol as eluent. The material so obtained was recrystallized from toluene. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.69 g, 50% m.p. 119-120 C.; NMR Spectrum: 2.0 (m, 2H), 2.45 (m, 6H), 3.6 (m, 4H), 3.95 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1H), 7.8 (m, 2H), 8.1 (m, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Elemental Analysis: Found C, 58.7; H, 5.3; N, 12.2; C22 H24 ClFN4 O3 requires C, 59.1; H, 5.4; N, 12.5%. |
| 40% |
With tetrabutylammomium bromide; In acetonitrile; for 16h;Heating / reflux;Product distribution / selectivity; |
Example 12 : Preparation of Gefitinib; Acetonitrile (500 ml), N-(4-fluoro-3-chloro phenyl)-6-hydroxy-7-methoxy quinazoline-4- amine (50 gm), 3-morpholinopropyl chloride (35 gm) and tetrabutyl ammonium bromide (5 gm) were refluxed for 16 hours. The reaction mass was distilled off to remove acetonitrile completely at 40-45C. To the residue, water (500 ml) was charged and stirred for 15 minutes at 25-300C. The solid obtained was filtered, washed with methanol (50 ml) and dried at 45-50C. The crude solid was dissolved in a mixture of toluene (1200 ml) and methanol (200 ml). The reaction mass was distilled off under reduced pressure at 40-450C to 400 ml volume, cooled to 10-150C, stirred for 30 minutes, the solid filtered, washed with toluene (40 ml) and dried to yield gefitinib (28 gm, 40% yield). |
| 154.7 g |
|
About 123.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 1100.0 mL of N,N-dimethylformamide were placed in a flask. The resulting mixture was suspended with stirring while about 186.0 g of potassium carbonate and about 4.7 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10, slowly added with about 77.0 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15 for about 1 hr. Then about 75.5 g of 4-(3-chloropropyl)morpholine was diluted with about 130.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80 and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20, slowly added with 2460.0 mL of purified water, and stirred for 30 min, and the produced solid was filtered. The obtained solid was washed with about 490.0 mL of purified water and then dried in a vacuum at about 50 for about 3 hr, yielding about 154.7 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.[98]HPLC purity: 99.21% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.3%)[99]1H-NMR (400MHz, DMSO-d6): 2.0 (m,2H), 2.4 (m,6H), 3.7 (m,4H), 3.9 (s,3H), 4.2 (t,2H), 7.2 (s,1H), 7.4 (t,1H), 7.8 (m,2H), 8.2 (m,1H), 8.5 (s,1H), 9.6 (s,1H) |
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