Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline
A fluoroanilino, methoxyl technology, applied in the field of pharmaceutical preparation, can solve the problems of not getting rid of high-risk, high-polluting halogenated reagents, low total yield, long reaction steps, etc., and achieves cost reduction, total yield improvement, Effects of short synthesis steps
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Embodiment 1
[0038] Embodiment 1, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy]quinoline, followed by Do the following steps:
[0039] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):
[0040] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (89.4g, 1.31mol) and formic acid (480ml), mix and heat to 80°C, add hydroxylamine sulfate (114.8g, 0.70mol ), hydroxylamine sulfate was equally divided into six parts, and one part was added every 30 minutes; after the addition was completed, it was heated and stirred at 80°C for 5 hours.
[0041]The mixture obtained by the reaction was cooled to room temperature, 250ml of saturated saline solution was added, stirred, filtered, the separated precipitate was separated, washed with water, and dried to obtain an off-white solid, which was 3-hydroxy-4-methoxybenzonitrile (79.0g , yield 80%). 1 H NMR (DMSO-d 6 , 300MHz): 3.83(s, 3H), 7.00-7.13(m,...
Embodiment 2
[0056] Embodiment 2, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxyl]quinoline, sequentially Do the following steps:
[0057] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):
[0058] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (135.1g, 1.98mol) and formic acid (600ml), mix and heat to 85°C, add hydroxylamine sulfate (162.4g, 0.99mol ), hydroxylamine sulfate was divided into six equal portions, and each portion was added every 30 minutes; after the addition was completed, it was heated and stirred at 85°C for 6 hours.
[0059] The resulting mixture was treated in the same manner as in Example 1 to obtain a white solid (86.5 g, yield 88%).
[0060] 2), the preparation of 4-methoxy-3-[3-(4-morpholinyl) propoxy]benzonitrile (structural formula is 3):
[0061] 3-Hydroxy-4-methoxybenzocyanide (80.0g, 0.54mol), sodium carbonate (138.9g, 1.35mol), sodium iodide (4.5g, 0....
Embodiment 3
[0073] Embodiment 3, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy]quinoline, sequentially Do the following steps:
[0074] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):
[0075] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (130.0g, 1.91mol) and formic acid (600ml), mix and heat to 90°C, add hydroxylamine sulfate (162.4g, 0.99mol ), hydroxylamine sulfate was equally divided into six parts, and the parts were added every 30 minutes; after the addition was completed, it was heated and stirred at 90°C for 5 hours.
[0076] The resulting mixture was treated in the same manner as in Example 1 to obtain a white solid (84.6 g, yield 86%).
[0077] 2), the preparation of 4-methoxy-3-[3-(4-morpholinyl) propoxy]benzonitrile (structural formula is 3):
[0078] 3-Hydroxy-4-methoxybenzocyanide (80.0g, 0.54mol), lithium carbonate (90.4g, 1.35mol), sodium iodide (4.5g, 0.030m...
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