CN105777560A - Synthetic method for acebutolol drug intermediate 2-amino-4-nitrophenol - Google Patents
Synthetic method for acebutolol drug intermediate 2-amino-4-nitrophenol Download PDFInfo
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- CN105777560A CN105777560A CN201610293635.4A CN201610293635A CN105777560A CN 105777560 A CN105777560 A CN 105777560A CN 201610293635 A CN201610293635 A CN 201610293635A CN 105777560 A CN105777560 A CN 105777560A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention discloses a synthetic method for acebutolol drug intermediate 2-amino-4-nitrophenol. The synthetic method includes adding 2, 4-dinitrophenol into a mixed solution comprising 3-fluorine-5-(trifluoromethyl) acetophenone and a sodium carbonate solution, increasing the temperature, adding 2-(thiophene-2-yl) pyrrolidine dropwise, continuing to stir after adding, precipitating solids after filtration and temperature reduction, dissolving the solids in a dimethylsulfoxide solution, adding an oxalic acid solution, and performing molecular sieve decoloration, suction filtration, washing and recrystallization to obtain the crystal 2-amino-4-nitrophenol. Compared with conventional synthetic methods, the synthetic method has the advantages that reaction yield is increased greatly, and a new synthetic path is provided to lay a good foundation for further increasing the 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 acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol.
Background technology
Acebutolol medicine is applicable to various hypertension, its antihypertensive effect and atenolol or metoprolol phase
Seemingly, heart rate slows down without Progressive symmetric erythrokeratodermia, and is not affected by age, race or renal insufficiency.For treating
Angina pectoris, is reducing angina pectoris attacks number of times, reduction nitroglycerin consumption, is improving exercise tolerance and improve the heart
In the degree of myocardial ischemia, effective as nifedipine.It is also applied for the treatment of ventricular arrhythmia, this product
40% patient's ventricular premature contraction is about made to reduce 75%, and easy-tolerated compared with quinidine.This product absorbed following oral administration is good,
Oral absorption rate is 70%, and oral rear peak time is 2～4h, and bioavailability is 60%, plasma protein
Combination rate is only 15%, but stronger with erythrocyte binding.Apparent volume of distribution is 1.0～3.0L/kg, blood plasma
Elimination half life is 3～4h, and effective blood drug concentration is 0.2～2.0 μ g/ml.The acetylizad metabolism of this product is produced
Thing has more pharmacologically active than original shape medicine, and it eliminates half life > 12h, it is adaptable to sinus tachycardia,
Room or ventricular premature contraction, atrial fibrillation, atrial flutter etc. it is also used for angina pectoris, hypertension.Acebutolol
Epinephrine beta receptor position is had to suppress the effect of catecholamine competitively.Pharmacological action like Propranolol,
But more weak. persistent, T1/2 is 3～8 hours. by weakening or preventing beta receptor excitement from making heart
Contractility and contraction speed decline, by the conduct velocity of conducting system, make heart to motion or should
The habituation swashed.Therefore, for anginal treatment, lower myocardium keto consumption, increase exercise tolerance.By
Adrenergic in retardance heartpacer current potential is excited therefore is used for treating arrhythmia.Possible this product is passed through
Maincenter, adrenergic neuron blockade, anti-renin activity and cardiac output attenuating etc. reduce blood pressure, suitable
For treating hypertension.Due to this product energy antagonism catecholamine effect, it is also used for treating pheochromocytoma and first
Shape adenohypersthenia, makes the activity of β 1 and beta 2 receptor be in inhibitory state.2-Amino-4-nitrophenol
As acebutolol pharmaceutical intermediate, its synthetic method is good and bad for improving pharmaceutical synthesis product quality, reduces
By-products content has Important Economic meaning.
Wang Xianfeng (Wang Xianfeng, Liu Xiaomei, Lou Guiyan, Yang Jun. with dyestuff waste liquid for Material synthesis 2-amino
-4-nitrophenol [J]. Shenyang University of Technology's journal, 1999,01:89-91.) with Disperse Blue 2BLN
In (C.I. Disperse Blue-56) production process, the waste liquid of hydrolyzing process is raw material, recovered 2,4
Dinitro benzene crude product, then makees reducing agent from NaHS, is reduced, refines under the conditions of adding ammonium chloride,
Synthesis 2-Amino-4-nitrophenol, but this synthetic method reaction intermediate link is many, and reaction yield is the highest,
It is about 70%, therefore, in order to improve reaction yield, it is necessary to propose a kind of new synthetic method.
Summary of the invention
The technical problem existed based on background technology, the present invention proposes a kind of acebutolol pharmaceutical intermediate 2-
The synthetic method of Amino-4-nitrophenol.
The synthetic method of a kind of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol, enters according to following steps
OK:
A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add 2,4-dinitro
Base phenol (molecular formula 2) 2.6mol, 3-fluoro-5-(trifluoromethyl) acetophenone solution 12.3mol, sodium carbonate
Solution 230-270ml, rising solution temperature, to 65-72 DEG C, is slowly added to 2-(thiophene-2-base) pyrrolidine
6.2mol, time for adding controls at 2-3h；
B, add after continue stirring, mixing speed is 190-230rpm, keep 90-130min, filter, reduce
Filtrate temperature, to 10-17 DEG C, separates out solid, is dissolved in by solid in 900ml dimethyl sulfoxide solution, adds grass
Acid solution 300ml, molecular sieve decolours, and separates out solid, sucking filtration, and DMA solution washs, at ring
Recrystallization in hexanone solution, obtains crystal 2-Amino-4-nitrophenol (molecular formula 1).
Preferably, described 3-fluoro-5-(trifluoromethyl) acetophenone solution mass fraction is 35-47%.
Preferably, described sodium carbonate liquor mass fraction is 20-31%.
Preferably, described dimethyl sulfoxide solution mass fraction is 30-39%.
Preferably, described oxalic acid solution mass fraction is 15-26%.
Preferably, described DMA liquid quality fraction is 50-66%.
Preferably, described cyclohexanone solution mass fraction is 61-72%.
Whole course of reaction can represent with following reaction equation:
Compared to synthetic method disclosed in background technology, the acebutolol pharmaceutical intermediate 2-ammonia that the present invention provides
The synthetic method of base-4-nitrophenol, reaction yield is greatly improved, and the invention provides a kind of new simultaneously
Synthetic route, lays a good foundation for promoting reaction yield further.
Accompanying drawing explanation
Fig. 1 be the mass fraction of 3-fluoro-5-(trifluoromethyl) acetophenone solution on the impact of reaction yield just
State scattergram.Wherein, abscissa is the mass fraction of 3-fluoro-5-(trifluoromethyl) acetophenone solution；Vertical
Coordinate is reaction yield；
Fig. 2 is the mass fraction of the dimethyl sulfoxide solution normal distribution on the impact of reaction yield.Wherein, horizontal
Coordinate is the mass fraction of dimethyl sulfoxide solution；Vertical coordinate is reaction yield；
Fig. 3 is N, the mass fraction of the accelerine solution normal distribution on the impact of reaction yield.Its
In, abscissa is the mass fraction of DMA solution；Vertical coordinate is reaction yield；
Fig. 4 is the mass fraction of the cyclohexanone solution normal distribution on the impact of reaction yield.Wherein, horizontal seat
It is designated as the mass fraction of cyclohexanone solution；Vertical coordinate is reaction yield.
Detailed description of the invention
Embodiment 1:
The synthetic method of a kind of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol, enters according to following steps
OK:
A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add 2,4-dinitro
Base phenol 2.6mol, mass fraction is 3-fluoro-5-(trifluoromethyl) the acetophenone solution 12.3mol of 40%, matter
Amount mark is the sodium carbonate liquor 230ml of 25%, and rising solution temperature, to 65 DEG C, is slowly added to 2-(thiophene-2-
Base) pyrrolidine 6.2mol, time for adding controls at 2h；
B, add after continue stirring, mixing speed is 190rpm, keep 90min, filter, reduce filtrate temperature
To 10 DEG C, separating out solid, it is in 35% dimethyl sulfoxide solution that solid is dissolved in 900ml mass fraction, adds
Mass fraction is the oxalic acid solution 300ml of 19%, and molecular sieve decolours, and separates out solid, and sucking filtration, mass fraction is
60%N, accelerine solution washs, recrystallization in the cyclohexanone solution that mass fraction is 65%,
Crystal 2-Amino-4-nitrophenol 328.38g, yield 82%.
Embodiment 2:
The synthetic method of a kind of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol, enters according to following steps
OK:
A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add 2,4-dinitro
Base phenol 2.6mol, mass fraction is %3-fluoro-5-(trifluoromethyl) the acetophenone solution 12.3mol of 41, matter
Amount mark is the sodium carbonate liquor 240ml of 26%, and rising solution temperature, to 68 DEG C, is slowly added to 2-(thiophene-2-
Base) pyrrolidine 6.2mol, time for adding controls at 2h；
B, add after continue stirring, mixing speed is 210rpm, keep 110min, filter, reduce filtrate temperature
To 13 DEG C, separate out solid, solid is dissolved in the dimethyl sulfoxide solution that 900ml mass fraction is 36%, adds
Entering the oxalic acid solution 300ml that mass fraction is 21%, molecular sieve decolours, and separates out solid, sucking filtration, mass fraction
It is the DMA solution washing of 55%, recrystallization in the cyclohexanone solution that mass fraction is 67%,
Obtain crystal 2-Amino-4-nitrophenol 324.95g, yield 81%.
Embodiment 3:
The synthetic method of a kind of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol, enters according to following steps
OK:
A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add 2,4-dinitro
Base phenol 2.6mol, mass fraction is 3-fluoro-5-(trifluoromethyl) the acetophenone solution 12.3mol of 47%, matter
Amount mark is the sodium carbonate liquor 270ml of 31%, and rising solution temperature, to 72 DEG C, is slowly added to 2-(thiophene-2-
Base) pyrrolidine 6.2mol, time for adding controls at 3h；
B, add after continue stirring, mixing speed is 230rpm, keep 130min, filter, reduce filtrate temperature
To 17 DEG C, separating out solid, it is in 39% dimethyl sulfoxide solution that solid is dissolved in 900ml mass fraction, adds
Mass fraction is 26% oxalic acid solution 300ml, and molecular sieve decolours, and separates out solid, and sucking filtration, mass fraction is 66%
DMA solution washing, recrystallization in the cyclohexanone solution that mass fraction is 72%, obtain brilliant
Body 2-Amino-4-nitrophenol 324.32g, yield 81%.
From embodiment 1-3, the acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol that the present invention provides
Synthetic method, reaction yield is more than 80%.
Below embodiment 4-9 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 fluoro-for the 3-in embodiment 1 5-(trifluoromethyl) acetophenone solution is adjusted,
Remaining preparation condition is same as in Example 1 with proportioning raw materials, obtains reaction yield as follows:
The impact on reaction yield of the mass fraction of table one: 3-fluoro-5-(trifluoromethyl) acetophenone solution
From embodiment 4, the mass fraction of 3-fluoro-5-(trifluoromethyl) acetophenone solution is too high or mistake
Low all can affect reaction yield, it becomes normal distribution (Fig. 1) with reaction yield, and peak value occurs in quality and divides
Number is 35-47%.
Embodiment 5:
Being adjusted by the mass fraction of the sodium carbonate liquor in embodiment 1, remaining preparation condition is joined with raw material
Ratio is same as in Example 1, obtains reaction yield as follows:
Table two: the mass fraction of the sodium carbonate liquor impact on reaction yield
| Sodium carbonate liquor mass fraction % | 10 | 15 | 18 | 20 | 24 | 28 | 31 | 36 | 40 |
| Reaction yield % | 67 | 70 | 73 | 81 | 82 | 82 | 82 | 83 | 83 |
From embodiment 5, reaction yield improves along with the raising of the mass fraction of sodium carbonate liquor, but
The amplitude that mass fraction increases higher than 20% later substantially slows down, it is considered to cost, the quality of sodium carbonate liquor is divided
Number is preferably 20-31%.
Embodiment 6:
The mass fraction of the dimethyl sulfoxide solution in embodiment 1 is adjusted, remaining preparation condition and raw material
Proportioning is same as in Example 1, obtains reaction yield as follows:
Table three: the mass fraction of the dimethyl sulfoxide solution impact on reaction yield
| Dimethyl sulfoxide solution mass fraction % | 20 | 23 | 28 | 30 | 35 | 41 | 48 | 50 | 53 |
| Reaction yield % | 65 | 67 | 72 | 81 | 82 | 82 | 75 | 70 | 67 |
From embodiment 6, the mass fraction of dimethyl sulfoxide solution is too high or too low all can affect reaction yield,
It becomes normal distribution (Fig. 2) with reaction yield, and it is 30-39% that peak value occurs in mass fraction.
Embodiment 7:
The mass fraction of the oxalic acid solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials
Same as in Example 1, obtain reaction yield as follows:
Table four: the mass fraction of the oxalic acid solution impact on reaction yield
| Oxalic acid solution mass fraction % | 7 | 10 | 13 | 15 | 20 | 26 | 28 | 30 | 32 |
| Reaction yield % | 79 | 80 | 80 | 80 | 82 | 81 | 81 | 80 | 80 |
| Bleaching time min | 57 | 52 | 45 | 35 | 33 | 35 | 48 | 50 | 50 |
From embodiment 7, the mass fraction of oxalic acid solution is little on reaction yield impact, but its too high or
Too low all can affect bleaching time, bleaching time minima occurs in mass fraction when being 15-26%.
Embodiment 8:
Being adjusted by the mass fraction of the DMA solution in embodiment 1, remaining prepares bar
Part is the same as in Example 8 with proportioning raw materials, obtains reaction yield as follows:
Table five: N, the impact on reaction yield of the mass fraction of accelerine solution
From embodiment 8, the mass fraction of DMA solution is too high or too low all can be affected instead
Answering yield, it becomes normal distribution (Fig. 3) with reaction yield, and it is 50-66% that peak value occurs in mass fraction.
Embodiment 9:
Being adjusted by the mass fraction of the cyclohexanone solution in embodiment 1, remaining preparation condition is joined with raw material
Ratio is same as in Example 1, obtains reaction yield as follows:
Table six: the mass fraction of the cyclohexanone solution impact on reaction yield
| Cyclohexanone solution mass fraction % | 50 | 54 | 57 | 61 | 66 | 72 | 75 | 80 | 82 |
| Reaction yield % | 68 | 72 | 77 | 81 | 82 | 82 | 75 | 72 | 67 |
From embodiment 9, the mass fraction of cyclohexanone solution is too high or too low all can affect reaction yield,
It becomes normal distribution (Fig. 4) with reaction yield, and it is 61-72% that peak value occurs in mass fraction.
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 (7)
1. the synthetic method of an acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol, it is characterised in that
Follow the steps below:
A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add 2,4-dinitro
Base phenol 2.6mol, 3-fluoro-5-(trifluoromethyl) acetophenone solution 12.3mol, sodium carbonate liquor 230-270ml,
Rising solution temperature, to 65-72 DEG C, is slowly added to 2-(thiophene-2-base) pyrrolidine 6.2mol, time for adding
Control at 2-3h；
B, add after continue stirring, mixing speed is 190-230rpm, keep 90-130min, filter, reduce
Filtrate temperature, to 10-17 DEG C, separates out solid, is dissolved in by solid in 900ml dimethyl sulfoxide solution, adds grass
Acid solution 300ml, molecular sieve decolours, and separates out solid, sucking filtration, and DMA solution washs, at ring
Recrystallization in hexanone solution, obtains crystal 2-Amino-4-nitrophenol.
2. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described 3-fluoro-5-(trifluoromethyl) acetophenone solution mass fraction is 35-47%.
3. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described sodium carbonate liquor mass fraction is 20-31%.
4. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described dimethyl sulfoxide solution mass fraction is 30-39%.
5. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described oxalic acid solution mass fraction is 15-26%.
6. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described DMA liquid quality fraction is 50-66%.
7. the synthetic method of acebutolol pharmaceutical intermediate 2-Amino-4-nitrophenol as claimed in claim 1,
It is characterized in that, described cyclohexanone solution mass fraction is 61-72%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107253914A (en) * | 2016-12-09 | 2017-10-17 | 青岛海湾集团有限公司 | The method that the nitrophenol of 2 amino 4 is prepared using Disperse Blue 2BLN byproduct |
-
2016
- 2016-05-05 CN CN201610293635.4A patent/CN105777560A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 魏启华 等: "2-氨基-4-硝基苯酚的合成", 《徐州师范大学学报(自然科学版)》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107253914A (en) * | 2016-12-09 | 2017-10-17 | 青岛海湾集团有限公司 | The method that the nitrophenol of 2 amino 4 is prepared using Disperse Blue 2BLN byproduct |
| CN107253914B (en) * | 2016-12-09 | 2019-10-25 | 青岛海湾集团有限公司 | The method for preparing 2- Amino-4-nitrophenol using Disperse Blue 2BLN byproduct |
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Application publication date: 20160720 |