AU2016102283A4 - Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method - Google Patents
Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method Download PDFInfo
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- AU2016102283A4 AU2016102283A4 AU2016102283A AU2016102283A AU2016102283A4 AU 2016102283 A4 AU2016102283 A4 AU 2016102283A4 AU 2016102283 A AU2016102283 A AU 2016102283A AU 2016102283 A AU2016102283 A AU 2016102283A AU 2016102283 A4 AU2016102283 A4 AU 2016102283A4
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Abstract
Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method, comprising the following steps: equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 130-170rpm, raised the solution temperature to 60-65 0C, held at reflux for 3-4h, added 0.71-0.73mol fluorobenzene (3), after the temperature was raised to 70-75 0C, continued reactions for 19-21 h, reducing the solution temperature to 10-15 0C , 230ml potassium chloride solution was added, added 90ml oxalic acid solution, holding stirring speed 140-160rpm, maintaining 90-120min, the precipitated solid was suction filtered, washed with salt solution, dehydrated with dehydrating agent, washed with cyclohexane solution , recrystallized from acetonitrile solution, got white crystals N-(4-fluorobenzyl) phthalimide .
Description
Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method
TECHNICAL FIELD
The present invention relates to astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method.
BACKGROUND ART
Astemizole are potent and long-acting HI receptor antagonists, it has no drowsiness and lethargy central role. It is mainly for the treatment of allergic rhinitis, allergic conjunctivitis, chronic urticaria and other allergic symptoms. It has not easy through the blood-brain barrier, and therefore it does not have central sedation, nor anticholinergic effects. Amine histamine HI receptor has competition effector cells and tissues to release it on, in order to halt allergic effects. It can very fast absorption after oral administration, 1 to 4 hours post-dose plasma concentration reached its peak, but the effect is slow, 3 to 4 days party markedly. N-(4-fluorobenzyl) phthalimide as astemizole drug intermediates, its synthesis method is of great economic significance for improving drug synthesis product quality, reducing the by-product content.
SUMMARY OF THE INVENTION
Object of the present invention is to provide astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method , comprising the following steps: (i) equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 130-170rpm, raised the solution temperature to 60—65 °C, held at reflux for 3-4h, added 0.71-0.73mol fluorobenzene (3), after the temperature was raised to 70-75 °C, continued reactions for 19-21 h, reducing the solution temperature to 10-15 °C , 230ml potassium chloride solution was added, added 90ml oxalic acid solution, holding stirring speed 140-160rpm, maintaining 90-120min, the precipitated solid was suction filtered, washed with salt solution, dehydrated with dehydrating agent , washed with cyclohexane solution , recrystallized from acetonitrile solution, got white crystals N-(4-fluorobenzyl) phthalimide (1); wherein potassium chloride solution in step (i) has a mass fraction of 10-15%; oxalic acid solution in step (i) has a mass fraction of 25-30%, salt solution in step (i) is any one of potassium bromide solution or sodium sulfate solution; dehydrating agent in step (i) is any one of anhydrous potassium carbonate or phosphorus pentoxide; cyclohexane solution in step (i) has a mass fraction of 65-70%; acetonitrile solution in step (i) has a mass fraction of 90-95%.
The throughout reaction process can be summarized using the following reaction formula:
Advantage of the present invention is that: the reaction intermediate links are reduced, reducing the reaction temperature and reaction time, improving the reaction yield.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
Embodiment 1
Equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 130 rpm, raised the solution temperature to 60 °C, held at reflux for 3 h, added 0.71 mol fluorobenzene (3), after the temperature was raised to 70 °C, continued reactions for 19 h, reducing the solution temperature to 10 °C , 230ml potassium chloride solution with a mass fraction of 10% was added, added 90ml oxalic acid solution with a mass fraction of 25%, holding stirring speed 140 rpm, maintaining 90 min, the precipitated solid was suction filtered, washed with potassium bromide solution, dehydrated with anhydrous potassium carbonate dehydrating agent , washed with cyclohexane solution with a mass fraction of 65% , recrystallized from acetonitrile solution with a mass fraction of 90%, got white crystals N-(4-fluorobenzyl) phthalimide 93.64 g, yield 72%.
Embodiment 2
Equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 150 rpm, raised the solution temperature to 62 °C, held at reflux for 3 h, added 0.72 mol fluorobenzene (3), after the temperature was raised to 72 °C, continued reactions for 20 h, reducing the solution temperature to 12 °C , 230ml potassium chloride solution with a mass fraction of 12% was added, added 90ml oxalic acid solution with a mass fraction of 27%, holding stirring speed 150 rpm, maintaining 110 min, the precipitated solid was suction filtered, washed with sodium sulfate solution, dehydrated with phosphorus pentoxide dehydrating agent, washed with cyclohexane solution with a mass fraction of 68% , recrystallized from acetonitrile solution with a mass fraction of 92%, got white crystals N-(4-fluorobenzyl) phthalimide 98.84 g, yield 76%.
Embodiment 3
Equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 170 rpm, raised the solution temperature to 65 °C, held at reflux for 4 h, added 0.73 mol fluorobenzene (3), after the temperature was raised to 75 °C, continued reactions for 21 h, reducing the solution temperature to 15 °C , 230ml potassium chloride solution with a mass fraction of 15% was added, added 90ml oxalic acid solution with a mass fraction of 30%, holding stirring speed 160 rpm, maintaining 120 min, the precipitated solid was suction filtered, washed with potassium bromide solution, dehydrated with anhydrous potassium carbonate dehydrating agent , washed with cyclohexane solution with a mass fraction of 70% , recrystallized from acetonitrile solution with a mass fraction of 95%, got white crystals N-(4-fluorobenzyl) phthalimide 106.64 g, yield 82%.
While a number of preferred embodiments have been described, it will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
Claims (4)
1. Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, the reaction vessel was added 0.21 mol stannous chloride, 230ml nitromethane, 0.51mol N-aminomethyl phthalimide (2), controlling the stirring speed 130-170rpm, raised the solution temperature to 60—65 °C, held at reflux for 3-4h, added 0.71-0.73mol fluorobenzene (3), after the temperature was raised to 70-75 °C, continued reactions for 19-21 h, reducing the solution temperature to 10-15 °C , 230ml potassium chloride solution was added, added 90ml oxalic acid solution, holding stirring speed 140-160rpm, maintaining 90-120min, the precipitated solid was suction filtered, washed with salt solution, dehydrated with dehydrating agent, washed with cyclohexane solution , recrystallized from acetonitrile solution, got white crystals N-(4-fluorobenzyl) phthalimide (1); wherein potassium chloride solution in step (i) has a mass fraction of 10-15%; oxalic acid solution in step (i) has a mass fraction of 25-30%, salt solution in step (i) is any one of potassium bromide solution or sodium sulfate solution.
2. Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method according to claim 1 wherein dehydrating agent in step (i) is any one of anhydrous potassium carbonate or phosphorus pentoxide.
3. Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method according to claim 1 wherein cyclohexane solution in step (i) has a mass fraction of 65-70%.
4. Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method according to claim 1 wherein acetonitrile solution in step (i) has a mass fraction of 90-95%.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109925055 | 2015-12-25 | ||
| CN201510992505.5A CN105523989A (en) | 2015-12-25 | 2015-12-25 | Synthetic method of astemizole drug intermediate N-(4-fluorobenzyl)phthalimide |
| CN2016108277952 | 2016-09-18 | ||
| CN201610827795.2A CN106432047A (en) | 2015-12-25 | 2016-09-18 | Synthesis method of astemizole drug intermediate N-(4-fluorobenzyl)phthalimide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2016102283A4 true AU2016102283A4 (en) | 2017-02-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016102283A Ceased AU2016102283A4 (en) | 2015-12-25 | 2016-12-24 | Astemizole drug intermediates N-(4-fluorobenzyl) phthalimide synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2016102283A4 (en) |
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2016
- 2016-12-24 AU AU2016102283A patent/AU2016102283A4/en not_active Ceased
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| FGI | Letters patent sealed or granted (innovation patent) | ||
| MK22 | Patent ceased section 143a(d), or expired - non payment of renewal fee or expiry |