AU2016102264A4 - Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) – theophylline synthesis method - Google Patents
Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) – theophylline synthesis method Download PDFInfo
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- AU2016102264A4 AU2016102264A4 AU2016102264A AU2016102264A AU2016102264A4 AU 2016102264 A4 AU2016102264 A4 AU 2016102264A4 AU 2016102264 A AU2016102264 A AU 2016102264A AU 2016102264 A AU2016102264 A AU 2016102264A AU 2016102264 A4 AU2016102264 A4 AU 2016102264A4
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- theophylline
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- dihydroxypropyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) theophylline synthesis method , comprising the following steps: quipped with a stiffer, a reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution, 0.71 mol stannous chloride, controlling the stirring speed 130-160rpm, raised the solution temperature to 60--65 C, slowly added 0.56mol theophylline (2), raised the solution temperature to 80 - 85 C, controlled the reaction 90-120min, the temperature of the solution is reduced to 50--55 C, dropped dropwise 1.2-1.4mol 3-amine 1,2 - propylene glycol (3), continued the reaction 120-160min, increased the solution temperature to 130-140 C , continued reaction for 60-70min, vacuum distillation, after removal of water, cooled, hexane solution was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate, washed solid , cooled, suction filtered, washed with salt solution, washed with acetonitrile solution and recrystallized from nitromethane solution, got crystals of 7 (2,3 -dihydroxypropyl) - theophylline .
Description
Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) -theophylline synthesis method
TECHNICAL FIELD
The present invention relates to dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) - theophylline synthesis method.
BACKGROUND ART
Dyphylline is applicable to bronchial asthma, bronchitis, emphysema, etc. to relieve wheezing, asthma is also used for cardiogenic pulmonary edema caused. This product is similar to theophylline asthma role. Aminophylline cardiac stimulation is only 1/20 to 1/10. It has less effect on the heart and nervous system, especially for patients with asthma with tachycardia. This product has a direct airway smooth muscle relaxant effect. Its mechanism is more complex in the past that by inhibiting phosphodiesterase, intracellular CAMP content increased due. 7- (2,3-dihydroxypropyl) - theophylline as dyphylline 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 dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) - theophylline synthesis method , comprising the following steps: (i) equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution, 0.71 mol stannous chloride, controlling the stirring speed 130-160rpm, raised the solution temperature to 60—65 °C, slowly added 0.56mol theophylline (2), raised the solution temperature to 80 - 85 °C, controlled the reaction 90-120min, the temperature of the solution is reduced to 50—55 °C, dropped dropwise 1.2-1.4mol 3-amine 1,2 -propylene glycol (3), continued the reaction 120-160min, increased the solution temperature to 130—140°C , continued reaction for 60-70min, vacuum distillation, after removal of water, cooled, hexane solution was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate, washed solid , cooled, suction filtered, washed with salt solution, washed with acetonitrile solution and recrystallized from nitromethane solution, got crystals of 7- (2,3-dihydroxypropyl) - theophylline (1); wherein potassium hydrogen sulfite solution in step (i) has a mass fraction of 15-20%; vacuum distillation in step (i) has a pressure of 1.8-1.9kPa; hexane solution in step (i) has a mass fraction of 40-45%; ethyl acetate in step (i) has a mass fraction of 70-75%, salt solution in step (i) is any one of sodium bromide solution or potassium sulfate solution; acetonitrile solution in step (i) has a mass fraction of 80-85%; nitromethane solution in step (i) has a mass fraction of 95-98%.
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 reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution with a mass fraction of 15%, 0.71 mol stannous chloride, controlling the stirring speed 130 rpm, raised the solution temperature to 60 °C, slowly added 0.56mol theophylline (2), raised the solution temperature to 80 °C, controlled the reaction 90 min, the temperature of the solution is reduced to 50 °C, dropped dropwise 1.2 mol 3-amine 1,2 - propylene glycol (3), continued the reaction 120 min, increased the solution temperature to 130 °C , continued reaction for 60 min, vacuum distillation, after removal of water, cooled, hexane solution with a mass fraction of 40% was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate with a mass fraction of 70%, washed solid , cooled, suction filtered, washed with sodium bromide solution, washed with acetonitrile solution with a mass fraction of 80% and recrystallized from nitromethane solution with a mass fraction of 95%, got crystals of 7-(2,3-dihydroxypropyl) - theophylline 115.21 g, yield 81%.
Embodiment 2
Equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution with a mass fraction of 17%, 0.71 mol stannous chloride, controlling the stirring speed 140 rpm, raised the solution temperature to 62 °C, slowly added 0.56mol theophylline (2), raised the solution temperature to 82 °C, controlled the reaction 90 min, the temperature of the solution is reduced to 52 °C, dropped dropwise 1.2 mol 3-amine 1,2 - propylene glycol (3), continued the reaction 140 min, increased the solution temperature to 135 °C , continued reaction for 65 min, vacuum distillation with a pressure of 1.85 kPa , after removal of water, cooled, hexane solution with a mass fraction of 42% was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate with a mass fraction of 72%, washed solid , cooled, suction filtered, washed with sodium bromide solution, washed with acetonitrile solution with a mass fraction of 82% and recrystallized from nitromethane solution with a mass fraction of 96%, got crystals of 7- (2,3-dihydroxypropyl) - theophylline 120.90 g, yield 85%.
Embodiment 3
Equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution with a mass fraction of 20%, 0.71 mol stannous chloride, controlling the stirring speed 140 rpm, raised the solution temperature to 65 °C, slowly added 0.56mol theophylline (2), raised the solution temperature to 85 °C, controlled the reaction 90 min, the temperature of the solution is reduced to 55 °C, dropped dropwise 1.2 mol 3-amine 1,2 - propylene glycol (3), continued the reaction 160 min, increased the solution temperature to 140 °C , continued reaction for 65 min, vacuum distillation with a pressure of 1.9 kPa , after removal of water, cooled, hexane solution with a mass fraction of 45% was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate with a mass fraction of 75%, washed solid , cooled, suction filtered, washed with sodium bromide solution, washed with acetonitrile solution with a mass fraction of 85% and recrystallized from nitromethane solution with a mass fraction of 98%, got crystals of 7- (2,3-dihydroxypropyl) - theophylline 126.59 g, yield 89%.
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. Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) - theophylline synthesis method , comprising the following steps: (i) equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, the reaction vessel was added 300ml potassium hydrogen sulfite solution, 0.71 mol stannous chloride, controlling the stirring speed 130-160rpm, raised the solution temperature to 60—65 °C, slowly added 0.56mol theophylline (2), raised the solution temperature to 80 - 85 °C, controlled the reaction 90-120min, the temperature of the solution is reduced to 50—55 °C, dropped dropwise 1.2-1.4mol 3-amine 1,2 -propylene glycol (3), continued the reaction 120-160min, increased the solution temperature to 130—140°C , continued reaction for 60-70min, vacuum distillation, after removal of water, cooled, hexane solution was added heated to reflux, the condensation completely dissolved, filtered while hot, washed the filter cake with ethyl acetate, washed solid , cooled, suction filtered, washed with salt solution, washed with acetonitrile solution and recrystallized from nitromethane solution, got crystals of 7- (2,3-dihydroxypropyl) - theophylline (1); wherein potassium hydrogen sulfite solution in step (i) has a mass fraction of 15-20%; vacuum distillation in step (i) has a pressure of 1.8-1.9kPa; hexane solution in step (i) has a mass fraction of 40-45%; ethyl acetate in step (i) has a mass fraction of 70-75%.
2. Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) -theophylline synthesis method according to claim 1 wherein salt solution in step (i) is any one of sodium bromide solution or potassium sulfate solution.
3. Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) -theophylline synthesis method according to claim 1 wherein acetonitrile solution in step (i) has a mass fraction of 80-85%.
4. Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) -theophylline synthesis method according to claim 1 wherein nitromethane solution in step (i) has a mass fraction of 95-98%.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109913359 | 2015-12-24 | ||
| CN201510991335.9A CN105461719A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine |
| CN201610817120.XA CN106397441A (en) | 2015-12-24 | 2016-09-12 | Synthesis method of dihydroxypropyl theophylline medicine raw material medicine 7-(2,3-dihydroxypropyl)-theophylline |
| CN201610817120X | 2016-09-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2016102264A4 true AU2016102264A4 (en) | 2017-02-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016102264A Ceased AU2016102264A4 (en) | 2015-12-24 | 2016-12-24 | Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) – theophylline synthesis method |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN105461719A (en) |
| AU (1) | AU2016102264A4 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850278B (en) * | 2022-11-30 | 2024-06-07 | 广州合和医药有限公司 | Novel crystal form solid substance of dihydroxypropehylline, preparation method thereof, injection and preparation method thereof |
-
2015
- 2015-12-24 CN CN201510991335.9A patent/CN105461719A/en active Pending
-
2016
- 2016-09-12 CN CN201610817120.XA patent/CN106397441A/en active Pending
- 2016-12-24 AU AU2016102264A patent/AU2016102264A4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| CN106397441A (en) | 2017-02-15 |
| CN105461719A (en) | 2016-04-06 |
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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 |