CN105884627A - Synthetic method of oxprenolol drug intermediate ortho-aminophenol - Google Patents
Synthetic method of oxprenolol drug intermediate ortho-aminophenol Download PDFInfo
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- CN105884627A CN105884627A CN201610257077.6A CN201610257077A CN105884627A CN 105884627 A CN105884627 A CN 105884627A CN 201610257077 A CN201610257077 A CN 201610257077A CN 105884627 A CN105884627 A CN 105884627A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
Abstract
The invention discloses a synthetic method of oxprenolol drug intermediate ortho-aminophenol. The synthetic method includes feeding nitrogen into a mixed solution consisting of potassium nitrate, 2-thenoylacetonitrile and ammonium ceric sulfate, adding the o-nitrophenol and a potassium carbonate solution to react, and subjecting a reacted product to extraction, dehydration and recrystallization so as to obtain the ortho-aminophenol. Without feeding of combustible hydrogen gas in the synthetic method, reaction safety is improved and reaction time is shortened greatly. The synthetic method provides a novel synthetic route for laying a good foundation for increasing reaction yield.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to one
Plant 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, room
Property 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 caused
Contraction and nasal mucosa capillary vessel shrink, therefore avoid for asthma and allergic rhinitis patient.Avoid for hole aroused in interest
Cross 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 heart
Dirty anesthetics (such as ether) share.There are the effect increasing digitalis toxicity, the heart to digitalization
Highly 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 with
Propranolol is similar.It addition, it also can reduce plasma renin activity, reduce renal blood flow and glomerular filtration
Rate.O-aminophenol is as oxprenolol pharmaceutical intermediate, and its synthetic method is good and bad for improving pharmaceutical synthesis
Product 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 nickel
Agent, under the conditions of normal pressure liquid-phase catalysis, o-aminophenol prepared by hydrogenation onitrophenol, but this conjunction
One-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 hydrogen
Agent activates, and whole preparation process is the most complicated, and the response time was more than 8 hours, although reaction yield is relatively
Height, mentions in document and can reach 97%, can also reach 90-93% in practical operation, but for simplicity
Preparation 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 intermediate
The 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 nitro
Phenol 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 provides
The synthetic method of base phenol need not be passed through fuel gas hydrogen, improve reaction safety, during simultaneous reactions
Between be greatly shortened, the invention provides a kind of new synthetic route simultaneously, beat for promoting further reaction yield
Descend 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 carbonate
310ml, 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 divides
Number is the sodium sulfite solution of 45%, and dimethylamine is extracted 5 times, united extraction liquid, activated alumina dehydrant
Dehydration, 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 mass
Mark is the sodium sulfite solution of 43%, and dimethylamine is extracted 6 times, united extraction liquid, and anhydrous magnesium sulfate is dehydrated
Agent is dehydrated, and recrystallization in the trifluoroacetic acid solution that mass fraction is 63% obtains crystal o-aminophenol
31.43g, 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 nitrogen
Gas, 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 divides
Number is the sodium sulfite solution of 46%, and dimethylamine is extracted 7 times, united extraction liquid, activated alumina dehydrant
Dehydration, 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 invention
Synthetic 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 reaction
The impact of yield.
Embodiment 4:
The mass fraction of the sodium nitrate solution in embodiment 1 is adjusted to 20%, 25%, 28%, 30%, its
Remaining 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%, its
Remaining 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 receipts
Rate, 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 shadow
Ringing 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 reaction
Yield, 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%, its
Remaining 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%, its
Remaining 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 reaction
Yield, 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%, remaining
Preparation 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%, remaining
Preparation 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 receipts
Rate, 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 affected
Reaction 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%, its
Remaining 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 affected
Reaction 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 invention
Be 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 invention
Protection domain within.
Claims (10)
1. the synthetic method of an oxprenolol pharmaceutical intermediate o-aminophenol, it is characterised in that include as
Lower step:
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 nitro
Phenol 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.
2. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described potassium nitrate
Liquid quality fraction is 30 37%.
3. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described 2-thiophene
Base acetyl nitrile liquid quality fraction is 50 56%.
4. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described cerous sulfate
Ammonium salt solution mass fraction is 45 53%.
5. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described potassium carbonate
Liquid quality fraction is 25 33%.
6. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described oxalic acid is molten
Liquid mass fraction is 33 39%.
7. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described sulfurous acid
Hydrogen sodium solution mass fraction is 40 47%.
8. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that described dehydrant
For any one in activated alumina, anhydrous magnesium sulfate.
9. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that three described fluoro
Acetic acid solution mass fraction is 60 67%.
10. the synthetic method of o-aminophenol as claimed in claim 1, it is characterised in that include following step
Rapid:
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 carbonate
310ml, 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 divides
Number is the sodium sulfite solution of 45%, and dimethylamine is extracted 5 times, united extraction liquid, activated alumina dehydrant
Dehydration, recrystallization in mass fraction is 63% trifluoroacetic acid solution, obtain crystal o-aminophenol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04164053A (en) * | 1990-10-29 | 1992-06-09 | Konica Corp | Production of aminophenol salts |
| CN1922174A (en) * | 2004-02-20 | 2007-02-28 | 贝林格尔·英格海姆国际有限公司 | Viral polymerase inhibitors |
| JP2014133730A (en) * | 2012-12-10 | 2014-07-24 | Teijin Ltd | Method for producing 3-aminophenol |
-
2016
- 2016-04-22 CN CN201610257077.6A patent/CN105884627A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04164053A (en) * | 1990-10-29 | 1992-06-09 | Konica Corp | Production of aminophenol salts |
| CN1922174A (en) * | 2004-02-20 | 2007-02-28 | 贝林格尔·英格海姆国际有限公司 | Viral polymerase inhibitors |
| JP2014133730A (en) * | 2012-12-10 | 2014-07-24 | Teijin Ltd | Method for producing 3-aminophenol |
Non-Patent Citations (1)
| Title |
|---|
| 陈金芳等: "常压催化加氢合成邻氨基苯酚的研究", 《武汉大学学报(自然科学版)》 * |
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Application publication date: 20160824 |