A kind of synthetic method of oxprenolol pharmaceutical intermediate o-aminophenolTechnical field
The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to onePlant the synthetic method of oxprenolol pharmaceutical intermediate o-aminophenol.
Background technology
Oxprenolol medicine is mainly used in sinus tachycardia, and paroxysmal is supraventricular and ventricular tachycardia, roomProperty premature beat, angina pectoris, hypertension etc..In addition to the beta receptor (β1receptor) of heart is had blocking effect,The beta receptor (beta 2 receptor) of bronchus and vascular smooth muscle also there is is blocking effect, bronchus convulsion can be causedContraction and nasal mucosa capillary vessel shrink, therefore avoid for asthma and allergic rhinitis patient.Avoid for hole aroused in interestCross slow, severe atrioventricular block, cardiogenic shock, low blood pressure patient.Congestive heart failure patients(except being secondary to tachycardia person), the heart failure such as palpus begins to use this product after being controlled.Should not be with the suppression heartDirty anesthetics (such as ether) share.There are the effect increasing digitalis toxicity, the heart to digitalizationHighly expand, the most jiggly patient of heart rate avoids use.Should not be with oxidase inhibitor (such as pargyline)Share.For the Beta receptor blockers of non-selectivity, there is inherent sympathetic activity and membrane stability.Its blocking effect withPropranolol is similar.It addition, it also can reduce plasma renin activity, reduce renal blood flow and glomerular filtrationRate.O-aminophenol is as oxprenolol pharmaceutical intermediate, and its synthetic method is good and bad for improving pharmaceutical synthesisProduct quality, reduces by-products content and has Important Economic meaning.
Chen Jinfang (Chen Jinfang, Qu Fanqi, Huang Xiaoling. the research of normal pressure catalytic hydrogenation synthesis o-aminophenol[J]. Wuhan University Journal (natural science edition), 1998,06:16-18.) urge with silica sol modified lacquer original nickelAgent, under the conditions of normal pressure liquid-phase catalysis, o-aminophenol prepared by hydrogenation onitrophenol, but this conjunctionOne-tenth method first to catch up with air with nitrogen row in preparation process, then catches up with nitrogen with hydrogen row, makes catalysis with hydrogenAgent activates, and whole preparation process is the most complicated, and the response time was more than 8 hours, although reaction yield is relativelyHeight, mentions in document and can reach 97%, can also reach 90-93% in practical operation, but for simplicityPreparation process, improves safety, shortens the response time, it is necessary to propose a kind of new synthetic method.
Summary of the invention
The technical problem existed based on background technology, it is adjacent that the present invention proposes a kind of oxprenolol pharmaceutical intermediateThe synthetic method of amino-phenol.
The synthetic method of a kind of oxprenolol pharmaceutical intermediate o-aminophenol, comprises the steps:
A, in reaction vessel add potassium nitrate solution 120 150ml, 2-thienyl acetyl nitrile solution 300ml,Cericammoniumsulfate solution 130 160ml, is passed through nitrogen, controls mixing speed 210 260rpm, adds adjacent nitroPhenol 0.31mol, solution of potassium carbonate 310ml, rising solution temperature, to 40 45 DEG C, maintains 70 90min；
B, filtration, add 500ml oxalic acid solution, add 130 150ml sodium sulfite solution in filtrate,Dimethylamine is extracted 57 times, united extraction liquid, and dehydrant is dehydrated, recrystallization in trifluoroacetic acid solution,Obtain crystal o-aminophenol (1).
Preferably, potassium nitrate solution mass fraction is 30 37%.
Preferably, 2-thienyl acetyl nitrile liquid quality fraction is 50 56%.
Preferably, Cericammoniumsulfate liquid quality fraction is 45 53%.
Preferably, solution of potassium carbonate mass fraction is 25 33%.
Preferably, oxalic acid solution mass fraction is 33 39%.
Preferably, sodium sulfite solution mass fraction is 40 47%.
Preferably, any one during dehydrant is activated alumina, anhydrous magnesium sulfate.
Preferably, trifluoroacetic acid liquid quality fraction is 60 67%.
Whole course of reaction can represent with following reaction equation:
Compared to synthetic method disclosed in background technology, oxprenolol pharmaceutical intermediate neighbour's ammonia that the present invention providesThe synthetic method of base phenol need not be passed through fuel gas hydrogen, improve reaction safety, during simultaneous reactionsBetween be greatly shortened, the invention provides a kind of new synthetic route simultaneously, beat for promoting further reaction yieldDescend good basis.
Detailed description of the invention
Embodiment 1:
The synthetic method of a kind of oxprenolol pharmaceutical intermediate o-aminophenol, comprises the steps:
A, in reaction vessel add mass fraction be 35% potassium nitrate solution 120ml, mass fraction is 54%2-thienyl acetyl nitrile solution 300ml, mass fraction is 50% Cericammoniumsulfate solution 130ml, is passed through nitrogen,Controlling mixing speed 210rpm, add onitrophenol 0.31mol, mass fraction is 30% solution of potassium carbonate310ml, rising solution temperature, to 40 DEG C, maintains 70min；
B, filtration, adding 500ml mass fraction in filtrate is 35% oxalic acid solution, adds 130ml mass and dividesNumber is the sodium sulfite solution of 45%, and dimethylamine is extracted 5 times, united extraction liquid, activated alumina dehydrantDehydration, recrystallization in mass fraction is 63% trifluoroacetic acid solution, obtain crystal o-aminophenol 31.58g,Yield 93%.
Embodiment 2:
The synthetic method of a kind of oxprenolol pharmaceutical intermediate o-aminophenol, comprises the steps:
A, in reaction vessel add mass fraction be 33% potassium nitrate solution 130ml, mass fraction is 53%2-thienyl acetyl nitrile solution 300ml, mass fraction is the Cericammoniumsulfate solution 140ml of 48%, is passed through nitrogen,Controlling mixing speed 230rpm, add onitrophenol 0.31mol, mass fraction is the solution of potassium carbonate of 28%310ml, rising solution temperature, to 42 DEG C, maintains 80min,
B, filtration, adding 500ml mass fraction in filtrate is the oxalic acid solution of 36%, adds 140ml massMark is the sodium sulfite solution of 43%, and dimethylamine is extracted 6 times, united extraction liquid, and anhydrous magnesium sulfate is dehydratedAgent is dehydrated, and recrystallization in the trifluoroacetic acid solution that mass fraction is 63% obtains crystal o-aminophenol31.43g, yield 93%.
Embodiment 3:
The synthetic method of a kind of oxprenolol pharmaceutical intermediate o-aminophenol, comprises the steps:
A, in reaction vessel add mass fraction be 37% potassium nitrate solution 150ml, mass fraction is 56%2-thienyl acetyl nitrile solution 300ml, mass fraction is the Cericammoniumsulfate solution 160ml of 53%, is passed through nitrogenGas, controls mixing speed 260rpm, adds onitrophenol 0.31mol, and mass fraction is the potassium carbonate of 33%Solution 310ml, rising solution temperature, to 45 DEG C, maintains 90min,
B, filtration, adding 500ml mass fraction in filtrate is 39% oxalic acid solution, adds 150ml mass and dividesNumber is the sodium sulfite solution of 46%, and dimethylamine is extracted 7 times, united extraction liquid, activated alumina dehydrantDehydration, recrystallization in the trifluoroacetic acid solution that mass fraction is 67%, obtain crystal o-aminophenol 30.41g,Yield 90%.
The response time of embodiment 1-3 is all less than 4 hours, and yield is above 90%, therefore provided by the present inventionSynthetic method be greatly shortened than the synthetic method in background technology, response time.
Below embodiment 4-17 is contrasted with embodiment 1, the percent mass comparison of each solution in research reactionThe impact of yield.
Embodiment 4:
The mass fraction of the sodium nitrate solution in embodiment 1 is adjusted to 20%, 25%, 28%, 30%, itsRemaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 65%, 73%, 83%, 91%.
Embodiment 5:
The mass fraction of the sodium nitrate solution in embodiment 1 is adjusted to 37%, 39%, 42%, 47%, itsRemaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 90%, 82%, 75%, 71%.
From embodiment 4 and 5, the mass fraction of sodium nitrate solution is too high or too low all can affect reaction receiptsRate, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 30-37%.
Embodiment 6:
The mass fraction of the 2-thienyl acetyl nitrile solution in embodiment 1 is adjusted to 40%, 45%, 48%,50%, remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 75%, 78%,83%, 90%.
Embodiment 7:
The mass fraction of the 2-thienyl acetyl nitrile solution in embodiment 1 is adjusted to 56%, 58%, 61%,66%, remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 91%, 85%,79%, 72%.
From embodiment 6 and 7, the mass fraction of 2-thienyl acetyl nitrile solution is too high or too low all can shadowRinging reaction yield, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 50-56%.
Embodiment 8:
The mass fraction of the Cericammoniumsulfate solution in embodiment 1 is adjusted to 35%, 40%, 43%, 45%,Remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 77%, 81%, 85%,91%.
Embodiment 9:
The mass fraction of the Cericammoniumsulfate solution in embodiment 1 is adjusted to 53%, 55%, 58%, 63%,Remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 92%, 85%, 79%,74%.
From embodiment 8 and 9, the mass fraction of Cericammoniumsulfate solution is too high or too low all can affect reactionYield, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 45-53%.
Embodiment 10:
The mass fraction of the solution of potassium carbonate in embodiment 1 is adjusted to 15%, 20%, 23%, 25%, itsRemaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 74%, 81%, 85%, 90%.
Embodiment 11:
The mass fraction of the solution of potassium carbonate in embodiment 1 is adjusted to 33%, 35%, 38%, 43%, itsRemaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 91%, 85%, 80%, 76%.
From embodiment 10 and 11, the mass fraction of solution of potassium carbonate is too high or too low all can affect reactionYield, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 25-33%.
Embodiment 12:
The mass fraction of the oxalic acid solution in embodiment 1 is adjusted to 23%, 25%, 28%, 33%, remainingPreparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 70%, 75%, 82%, 91%.
Embodiment 13:
The mass fraction of the oxalic acid solution in embodiment 1 is adjusted to 39%, 41%, 44%, 49%, remainingPreparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 90%, 82%, 77%, 73%.
From embodiment 12 and 13, the mass fraction of oxalic acid solution is too high or too low all can affect reaction receiptsRate, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 33-39%.
Embodiment 14:
The mass fraction of the sodium sulfite solution in embodiment 1 is adjusted to 30%, 32%, 35%, 40%,Remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 91%, 82%, 77%,73%.
Embodiment 15:
The mass fraction of the sodium sulfite solution in embodiment 1 is adjusted to 47%, 49%, 52%, 57%,Remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 90%, 83%, 80%,75%.
From embodiment 14 and 15, the mass fraction of sodium sulfite solution is too high or too low all can be affectedReaction yield, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 40-47%.
Embodiment 16:
The mass fraction of the trifluoroacetic acid solution in embodiment 1 is adjusted to 50%, 55%, 58%, 60%,Remaining preparation condition is same as in Example 1 with proportioning raw materials, gained yield is respectively 75%, 83%, 87%,90%.
Embodiment 17:
The mass fraction of the trifluoroacetic acid in embodiment 1 is adjusted to 67%, 69%, 72%, 77%, itsRemaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 73%, 79%, 84%, 91%.
From embodiment 16 and 17, the mass fraction of trifluoroacetic acid solution is too high or too low all can be affectedReaction yield, it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 60-67%.
Described in above example, the only present invention preferably detailed description of the invention, but protection scope of the present inventionBe not limited thereto, any those familiar with the art in the technical scope that the invention discloses,According to technical scheme and inventive concept equivalent or change in addition thereof, all should contain in the present inventionProtection domain within.