CN106432064A - Synthesis method of disopyramide drug intermediate 2-bromopyridine - Google Patents
Synthesis method of disopyramide drug intermediate 2-bromopyridine Download PDFInfo
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- CN106432064A CN106432064A CN201610830423.5A CN201610830423A CN106432064A CN 106432064 A CN106432064 A CN 106432064A CN 201610830423 A CN201610830423 A CN 201610830423A CN 106432064 A CN106432064 A CN 106432064A
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- solution
- bromopyridine
- acetonitrile
- disopyramide
- mass fraction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
A synthesis method of disopyramide drug intermediate 2-bromopyridine comprises steps as follows: 1.3 mol of 2-aminopyridine and 1.6-1.9 mol of an o-bromotoluene solution are added to a reactor, the temperature of the solution is reduced to 3-5 DEG C, the stirring speed is controlled at 130-170 rpm, 1.5 mol of cuprous bromide and 600 ml of cyclohexane are added, the mixture reacts for 90-120 min, is heated to 40-45 DEG C and continuously reacts for 60-80 min, 300 ml of a sodium sulfite solution is added, the temperature of the solution is reduced to 30-35 DEG C, the mixture reacts for 30-50 min, the solution is extracted with acetonitrile 3-5 times, acetonitrile extracting solutions are combined, washed with a saline solution and dewatered with a dewatering agent, reduced-pressure distillation is performed after acetonitrile is recovered, fractions at the temperature of 90-95 DEG C are collected, recrystallization is performed in ethanediamine, and 2-bromopyridine is obtained.
Description
Technical field
The present invention relates to a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine.
Background technology
Disopyramide medicine is used for maintaining the sinus rhythm that atrial fibrillation and room are flutterred, or prevention Ventricular Tachycardia and ventricular fibrillation
Recurrence.Its cholinolytic effect is more more notable than quinindium, therefore, passes when treating room and flutterring or should give during atrial fibrillation to slow down chamber simultaneously
The medicine led.In addition, the effect of its suppression myocardial contractive power becomes apparent from, can increase or induce heart failure.Therefore, do not make
For antiarrhythmic first-line drug, the patient having congestive heart failure avoids use.Atropine-like effect can cause the retention of urine, mouth
Dry, eye-blurred and increase glaucoma.Once these symptoms occur, should be discontinued.Refractory period, the biography of suppression cardiac excitation can be extended
Lead, effect is stronger than quinindium.5～10 minutes after intravenous take effect, and oral absorption preferably, reaches peak, t1/2 through 2 hours blood concentrations
For 6～7 hours.Can be used for atrial premature beats, paroxysmal auricular tachycardia, atrial fibrillation, VPB etc., to SA
Curative effect like preferably.The arrhythmogenic effect of antiarrhythmic drug refers to this kind of medicine can cause newly and sends out arrhythmia cordis appearance
Or original arrhythmia cordis increases, such as VPB outbreak frequency increases (3--10 times), Ventricular Tachycardia speed quickening (10%
More than), continuation room speed is changed into from non-standing room speed, is quivered for room from the monomorphic Torsade de points or deteriorate of being changed into.Institute
Have antiarrhythmic drug all to have arrhythmogenic effect, its incidence is 6%--36%, the impulsion of its mechanism and electrocardio formed or
Conductive impairment is relevant.Susceptible factor or inducement include recurrent exerbation or continuation room speed, left chamber function be complete, myocardial ischemia, biography
Lead that retardance, Q-T interval prolongation, electrolyte (potassium, magnesium etc.) disorder, medicine improper use, hepatic and renal function be poor, compatibility of drugs is unreasonable
Deng.The antiarrhythmic effect of this kind of medicine almost and is deposited with promoting Arrhythmia, and the anti-arrhythmia of normal myocardium is made
With less, to ill (ischemic, hypertrophy, heart failure) cardiac muscle, its rush Arrhythmia is larger.2- bromopyridine is as disopyramide medicine
Intermediate, its synthetic method quality, for improving pharmaceutical synthesis product quality, reduces by-products content and has Important Economic meaning.
Content of the invention
It is an object of the invention to provide a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine, walk including following
Suddenly：
I () adds PA (2) 1.3mol, o-bromotoluene solution (3) 1.6 1.9mol in reaction vessel, fall
Low solution temperature, to 3--5 DEG C, controls mixing speed 130 170rpm, adds cuprous bromide 1.5mol, hexamethylene 600ml, instead
Answer 90 120min, rise high-temperature to 40--45 DEG C, continue reaction 60 80min, add sodium sulfite solution 300ml, reduce
Solution temperature, to 30--35 DEG C, reacts 30 50min, and solution acetonitrile extracts 35 times, merges acetonitrile extract, and salting liquid is washed
Wash, dehydrating agent is dehydrated, after reclaiming acetonitrile, vacuum distillation, collect 90--95 DEG C of cut, recrystallize in ethylenediamine, obtain 2-
Bromopyridine (1).
Wherein, the hexamethylene mass fraction described in step (i) is 50 55%, the sodium sulfite solution described in step (i)
Mass fraction is 30 35%, and the acetonitrile mass fraction described in step (i) is 60 65%, and the salting liquid described in step (i) is
Any one in potassium nitrate, sodium bromide, the dehydrating agent described in step (i) is Anhydrous potassium carbonate, appointing in solid sodium hydroxide
Meaning is a kind of, and pressure residing for the vacuum distillation described in step (i) is 1.8 1.9kPa, the ethylenediamine mass fraction described in step (i)
For 85 90%.
Whole course of reaction can use following reaction equation to represent：
The invention has the advantages that：Decrease the intermediate link of reaction, reduce reaction temperature and reaction time, improve anti-
Answer yield.
Specific embodiment
With reference to being embodied as example, the invention will be further described：
A kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine
Example 1：
Add PA (2) 1.3mol, o-bromotoluene solution (3) 1.6mol in reaction vessel, reduce solution temperature
Spend to 3 DEG C, control mixing speed 130rpm, add cuprous bromide 1.5mol, mass fraction is 50% hexamethylene 600ml, reaction
90min, rises high-temperature to 40 DEG C, continues reaction 60min, and addition mass fraction is 30% sodium sulfite solution 300ml, reduces molten
Liquid temp, to 30 DEG C, reacts 30min, and solution mass fraction is that 60% acetonitrile extracts 3 times, merges acetonitrile extract, potassium nitrate
Solution washs, and Anhydrous potassium carbonate is dehydrated, after reclaiming acetonitrile, 1.8kPa vacuum distillation, and collect 90--95 DEG C of cut, in quality
Fraction is to recrystallize in 85% ethylenediamine, obtains 2- bromopyridine 172.54g, yield 84%.
Example 2：
Add PA (2) 1.3mol, o-bromotoluene solution (3) 1.7mol in reaction vessel, reduce solution temperature
Spend to 4 DEG C, control mixing speed 140rpm, add cuprous bromide 1.5mol, mass fraction is 53% hexamethylene 600ml, reaction
110min, rises high-temperature to 42 DEG C, continues reaction 70min, and addition mass fraction is 32% sodium sulfite solution 300ml, reduces
Solution temperature, to 32 DEG C, reacts 20min, and solution mass fraction is that 62% acetonitrile extracts 4 times, merges acetonitrile extract, bromination
Sodium solution washs, and solid sodium hydroxide is dehydrated, after reclaiming acetonitrile, 1.85kPa vacuum distillation, and collect 90--95 DEG C of cut,
It is to recrystallize in 87% ethylenediamine in mass fraction, obtain 2- bromopyridine 178.70g, yield 87%.
Example 3：
Add PA (2) 1.3mol, o-bromotoluene solution (3) 1.9mol in reaction vessel, reduce solution temperature
Spend to 5 DEG C, control mixing speed 170rpm, add cuprous bromide 1.5mol, mass fraction is 55% hexamethylene 600ml, reaction
120min, rises high-temperature to 45 DEG C, continues reaction 80min, and addition mass fraction is 35% sodium sulfite solution 300ml, reduces
Solution temperature, to 35 DEG C, reacts 50min, and solution mass fraction is that 65% acetonitrile extracts 5 times, merges acetonitrile extract, nitric acid
Potassium solution washs, and Anhydrous potassium carbonate is dehydrated, after reclaiming acetonitrile, 1.9kPa vacuum distillation, and collect 90--95 DEG C of cut, in matter
Amount fraction is to recrystallize in 90% ethylenediamine, obtains 2- bromopyridine 186.91g, yield 91%.
Claims (4)
1. a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine is it is characterised in that comprise the steps：I () is anti-
Answer addition PA (2) 1.3mol, o-bromotoluene solution (3) 1.6 1.9mol in container, reduction solution temperature to 3--5
DEG C, control mixing speed 130 170rpm, add cuprous bromide 1.5mol, hexamethylene 600ml, react 90 120min, raise
Temperature, to 40--45 DEG C, continues reaction 60 80min, adds sodium sulfite solution 300ml, reduction solution temperature to 30--35
DEG C, react 30 50min, solution acetonitrile extracts 35 times, merge acetonitrile extract, brine, dehydrating agent is dehydrated, return
After receiving acetonitrile, vacuum distillation, collect 90--95 DEG C of cut, recrystallize in ethylenediamine, obtain 2- bromopyridine (1)；Wherein, walk
Suddenly the hexamethylene mass fraction described in (i) is 50 55%, and the sodium sulfite solution mass fraction described in step (i) is 30
35%, the acetonitrile mass fraction described in step (i) is 60 65%, and the salting liquid described in step (i) is potassium nitrate, in sodium bromide
Any one.
2. according to claim 1 a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine it is characterised in that step
I the dehydrating agent described in () is Anhydrous potassium carbonate, any one in solid sodium hydroxide.
3. according to claim 1 a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine it is characterised in that step
I pressure residing for the vacuum distillation described in () is 1.8 1.9kPa.
4. according to claim 1 a kind of synthetic method of disopyramide pharmaceutical intermediate 2- bromopyridine it is characterised in that step
I the ethylenediamine mass fraction described in () is 85 90%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2016102315A AU2016102315A4 (en) | 2015-12-25 | 2016-12-25 | Disopyramide drug intermediates 2-bromopyridine synthesis method |
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|---|---|---|---|
| CN2015109927224 | 2015-12-25 | ||
| CN201510992722.4A CN105439944A (en) | 2015-12-25 | 2015-12-25 | Synthesis method of disopyramide drug intermediate 2-bromopyridine |
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| CN106432064A true CN106432064A (en) | 2017-02-22 |
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| CN201510992722.4A Pending CN105439944A (en) | 2015-12-25 | 2015-12-25 | Synthesis method of disopyramide drug intermediate 2-bromopyridine |
| CN201610830423.5A Pending CN106432064A (en) | 2015-12-25 | 2016-09-19 | Synthesis method of disopyramide drug intermediate 2-bromopyridine |
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Application publication date: 20170222 |