CN105461719A - Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine - Google Patents
Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine Download PDFInfo
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- CN105461719A CN105461719A CN201510991335.9A CN201510991335A CN105461719A CN 105461719 A CN105461719 A CN 105461719A CN 201510991335 A CN201510991335 A CN 201510991335A CN 105461719 A CN105461719 A CN 105461719A
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- dihydroxypropyl
- theophylline
- diprophylline
- massfraction
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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
The invention relates to a synthesis method of a diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine, which comprises the following steps: adding 300ml of potassium bisulfite solution and 0.71 mol of stannous chloride into a reaction vessel which is provided with a stirrer, a reflux condenser, a dropping funnel and a thermometer, controlling the stirring rate at 130-160 rpm, heating the solution to 60-65 DEG C, slowly adding 0.56 mol of theine, heating the solution to 80-85 DEG C, reacting for 90-120 minutes, cooling the solution to 50-55 DEG C, and dropwisely adding 1.2-1.4 mol of 3-amino-1,2-propanediol; and after finishing addition, continuing reacting for 120-160 minutes, heating the solution to 130-140 DEG C, continuing reacting for 60-70 minutes, distilling under reduced pressure to remove water, cooling, adding hexane, heating under reflux until the condensate is completely dissolved, filtering while the solution is hot, washing the filter cake with ethyl acetate, cooling the washing solution to precipitate a solid, carrying out vacuum filtration, washing with a salt solution, washing with acetonitrile, and recrystallizing in nitromethane to obtain the crystal 7-(2,3-dihydroxypropyl)-theine, wherein the mass percent of the potassium bisulfite solution is 15-20%.
Description
Technical field
The present invention relates to a kind of synthetic method of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline.
Background technology
Indication for being applicable to bronchial asthma, asthmatic bronchitis, obstructive emphysema etc. to alleviate wheezing symptoms, also for asthma that cardiac pulmonary edema causes.This product antiasthmatic effect is similar to theophylline.Cardiac excitation effect is only 1/20 ~ 1/10 of aminophylline.On heart and neural impact less.Especially be applicable to accompany tachycardic asthmatic patient.This product has direct relexation to airway smooth muscle.Its mechanism of action more complicated, thinks in the past by suppressing phosphodiesterase, to make in cell caused by CAMP content improves.Recent experiment thinks that the bronchiectatic activity part of theophylline is the result because endogenous suprarenin and norepinephrine discharge, and in addition, theophylline is purinoceptor retarding agent, can resist the contraction to respiratory tract such as VITAMIN B4.Theophylline can strengthen contraction of diaphragm power, and especially when contraction of diaphragm is unable, effect is more remarkable, therefore contributes to improving respiratory function.This product can be absorbed rapidly, T
1/2it is 2 ~ 2.5 hours.7-(2,3-dihydroxypropyl)-theophylline is as diprophylline medicine material medicine, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide a kind of diprophylline medicine material medicine 7-(2, 3-dihydroxypropyl) synthetic method of-theophylline, comprise the steps: that (i) is being provided with agitator, reflux exchanger, dropping funnel, in the reaction vessel of thermometer, add bisulfite potassium solution 300ml, tin protochloride 0.71mol, control stirring velocity 130-160rpm, raise solution temperature to 60--65 DEG C, slowly add theophylline (2) 0.56mol, raise solution temperature to 80--85 DEG C, reaction 90-120min, reduce solution temperature to 50--55 DEG C, drip 3-amine-1, 2,-propylene glycol (3) 1.2-1.4mol, add rear continuation reaction 120-160min, raise solution temperature to 130--140 DEG C, continue reaction 60-70min, underpressure distillation, except anhydrating, after cooling, add hexane reflux, condenses is all dissolved, filtered while hot, filter cake ethyl acetate is washed, solid is separated out after washings cooling, suction filtration, brine, acetonitrile wash, recrystallization in Nitromethane 99Min., obtain crystal 7-(2, 3-dihydroxypropyl)-theophylline (1), wherein, the massfraction of the bisulfite potassium solution described in step (i) is 15-20%, pressure residing for underpressure distillation described in step (i) is 1.8-1.9kPa, hexane massfraction described in step (i) is 40-45%, ethyl acetate massfraction described in step (i) is 70-75%, salts solution described in step (i) is any one in Sodium Bromide, potassium sulfate, acetonitrile massfraction described in step (i) is 80-85%, and the Nitromethane 99Min. massfraction described in step (i) is 95-98%.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
A kind of synthetic method of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline
Example 1:
Agitator is being installed, reflux exchanger, dropping funnel, in the reaction vessel of thermometer, adding massfraction is 15% bisulfite potassium solution 300ml, tin protochloride 0.71mol, control stirring velocity 130rpm, raise solution temperature to 60 DEG C, slowly add theophylline (2) 0.56mol, raise solution temperature to 80 DEG C, reaction 90min, reduce solution temperature to 50 DEG C, drip 3-amine-1, 2,-propylene glycol (3) 1.2mol, add rear continuation reaction 120min, raise solution temperature to 130 DEG C, continue reaction 60min1.8kPa, underpressure distillation, except anhydrating, after cooling, adding massfraction is 40% hexane reflux, condenses is all dissolved, filtered while hot, filter cake massfraction is 70% ethyl acetate washing, solid is separated out after washings cooling, suction filtration, sodium bromide solution washs, massfraction is 80% acetonitrile wash, be recrystallization in 95% Nitromethane 99Min. at massfraction, obtain crystal 7-(2, 3-dihydroxypropyl)-theophylline 115.21g, yield 81%.
Example 2:
Agitator is being installed, reflux exchanger, dropping funnel, in the reaction vessel of thermometer, adding massfraction is 17% bisulfite potassium solution 300ml, tin protochloride 0.71mol, control stirring velocity 140rpm, raise solution temperature to 62 DEG C, slowly add theophylline (2) 0.56mol, raise solution temperature to 82 DEG C, reaction 110min, reduce solution temperature to 52 DEG C, drip 3-amine-1, 2,-propylene glycol (3) 1.3mol, add rear continuation reaction 140min, raise solution temperature to 135 DEG C, continue reaction 65min, 1.85kPa underpressure distillation, except anhydrating, after cooling, adding massfraction is 42% hexane reflux, condenses is all dissolved, filtered while hot, filter cake massfraction is 72% ethyl acetate washing, solid is separated out after washings cooling, suction filtration, potassium sulfate solution washs, massfraction is 82% acetonitrile wash, be recrystallization in 96% Nitromethane 99Min. at massfraction, obtain crystal 7-(2, 3-dihydroxypropyl)-theophylline 120.90g, yield 85%.
Example 3:
Agitator is being installed, reflux exchanger, dropping funnel, in the reaction vessel of thermometer, adding massfraction is 20% bisulfite potassium solution 300ml, tin protochloride 0.71mol, control stirring velocity 160rpm, raise solution temperature to 65 DEG C, slowly add theophylline (2) 0.56mol, raise solution temperature to 85 DEG C, reaction 120min, reduce solution temperature to 55 DEG C, drip 3-amine-1, 2,-propylene glycol (3) 1.4mol, add rear continuation reaction 160min, raise solution temperature to 140 DEG C, continue reaction 70min, 1.9kPa underpressure distillation, except anhydrating, after cooling, adding massfraction is 45% hexane reflux, condenses is all dissolved, filtered while hot, filter cake massfraction is 75% ethyl acetate washing, solid is separated out after washings cooling, suction filtration, sodium bromide solution washs, massfraction is 85% acetonitrile wash, be recrystallization in 98% Nitromethane 99Min. at massfraction, obtain crystal 7-(2, 3-dihydroxypropyl)-theophylline 126.59g, yield 89%.
Claims (4)
1. the synthetic method of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline, is characterized in that, comprise the steps:
I () is being provided with agitator, reflux exchanger, dropping funnel, in the reaction vessel of thermometer, add bisulfite potassium solution 300ml, tin protochloride 0.71mol, control stirring velocity 130-160rpm, raise solution temperature to 60--65 DEG C, slowly add theophylline (2) 0.56mol, raise solution temperature to 80--85 DEG C, reaction 90-120min, reduce solution temperature to 50--55 DEG C, drip 3-amine-1, 2,-propylene glycol (3) 1.2-1.4mol, add rear continuation reaction 120-160min, raise solution temperature to 130--140 DEG C, continue reaction 60-70min, underpressure distillation, except anhydrating, after cooling, add hexane reflux, condenses is all dissolved, filtered while hot, filter cake ethyl acetate is washed, solid is separated out after washings cooling, suction filtration, brine, acetonitrile wash, recrystallization in Nitromethane 99Min., obtain crystal 7-(2, 3-dihydroxypropyl)-theophylline (1), wherein, the massfraction of the bisulfite potassium solution described in step (i) is 15-20%, pressure residing for underpressure distillation described in step (i) is 1.8-1.9kPa, hexane massfraction described in step (i) is 40-45%, and the ethyl acetate massfraction described in step (i) is 70-75%.
2. the synthetic method of a kind of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline according to claim 1, is characterized in that, the salts solution described in step (i) is any one in Sodium Bromide, potassium sulfate.
3. the synthetic method of a kind of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline according to claim 1, it is characterized in that, the acetonitrile massfraction described in step (i) is 80-85%.
4. the synthetic method of a kind of diprophylline medicine material medicine 7-(2,3-dihydroxypropyl)-theophylline according to claim 1, it is characterized in that, the Nitromethane 99Min. massfraction described in step (i) is 95-98%.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| AU2016102264A AU2016102264A4 (en) | 2015-12-24 | 2016-12-24 | Dyphylline pharmaceutical drug 7- (2,3-dihydroxypropyl) – theophylline synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510991335.9A CN105461719A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105461719A true CN105461719A (en) | 2016-04-06 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510991335.9A Pending CN105461719A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine |
| CN201610817120.XA Pending CN106397441A (en) | 2015-12-24 | 2016-09-12 | Synthesis method of dihydroxypropyl theophylline medicine raw material medicine 7-(2,3-dihydroxypropyl)-theophylline |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610817120.XA Pending CN106397441A (en) | 2015-12-24 | 2016-09-12 | Synthesis method of dihydroxypropyl theophylline medicine raw material medicine 7-(2,3-dihydroxypropyl)-theophylline |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN105461719A (en) |
| AU (1) | AU2016102264A4 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850278A (en) * | 2022-11-30 | 2023-03-28 | 广州合和医药有限公司 | Dihydroxypropyltheophylline new crystal form solid substance and preparation method thereof, and 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
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850278A (en) * | 2022-11-30 | 2023-03-28 | 广州合和医药有限公司 | Dihydroxypropyltheophylline new crystal form solid substance and preparation method thereof, and injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2016102264A4 (en) | 2017-02-23 |
| CN106397441A (en) | 2017-02-15 |
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Application publication date: 20160406 |