CN106220544A - A kind of purification process of hydrochloric acid Vernakalant - Google Patents
A kind of purification process of hydrochloric acid Vernakalant Download PDFInfo
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- CN106220544A CN106220544A CN201610626735.4A CN201610626735A CN106220544A CN 106220544 A CN106220544 A CN 106220544A CN 201610626735 A CN201610626735 A CN 201610626735A CN 106220544 A CN106220544 A CN 106220544A
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- China
- Prior art keywords
- vernakalant
- hydrochloric acid
- purification process
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- acetonitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the purification process of a kind of hydrochloric acid Vernakalant, its method includes crystallization purifying after the most purified hydrochloric acid Vernakalant addition good solvent and atent solvent mix, wherein, described good solvent includes that one or more in acetonitrile, ethyl acetate, isopropanol, isopropyl acetate, oxolane, described atent solvent include diisopropyl ether or diisopropyl ether and methyl tertiary butyl ether(MTBE), ether, normal hexane, normal heptane, the mixed solvent of one or more of pentane crowd.The method of the invention has the advantage more effectively removing the impurity isomer etc. produced in its production process, has good curative effect for treatment arrhythmia.
Description
Technical field
The present invention relates to chemical field, concrete, the present invention relates to a kind of chemical purification method.
Background technology
Generally, heart normally excitement originates from sinuatrial node, passes, under conducting system in the range of certain time
Arrive at atrium and ventricle successively, make heart contraction and diastole.If sinuatrial node excitement exception or excitement result from beyond sinuatrial node,
Exciting conduction is slow, block or through abnormal passage conduction, arise that arrhythmia.Therefore, arrhythmia is due to heart
Movable origin and (or) conductive impairment cause frequency and (or) the allorhythmia of heartbeat.Arrhythmia is cardiovascular disease
In important one group of disease.It can individually be fallen ill and also can occur together with cardiovascular diseases.Sudden death is caused owing to its morbidity can break out,
The most sustainable involve heart and exhaustion, thus grasp its occur, law of development and prophylactico-therapeutic measures the most important.ARR blood
The clinical manifestation that hydromechanics changes depends primarily on ARR character, type, cardiac function and to hemodynamic effects
Degree, such as slight sinus bradycardia, arrhythmia, accidental atrial premature beat, first degree A-V block
Deng the least to hemodynamic effects, therefore without obvious clinical manifestation.More serious arrhythmia, such as sick sinus syndrome, quickly
Atrial fibrillation, paroxysmal supraventricular tachycardia, sustained ventricular tachycardia etc., can cause cardiopalmus, blood uncomfortable in chest, dizzy, low
Pressure, perspire, severe patient may occur in which faint, Adams Stokes syndrome, even die suddenly.
Known there is atrial arrhythmia and ventricular arrhythmia.Arrhythmia causes lethal main cause to be known as
The ventricular arrhythmia hypotype of ventricular fibrillation.It is reported China patients with arrhythmia about 20,000,000, wherein patients with atrial fibrillation
About 8,000,000, sudden cardiac death the most about 540,000 (2015 annual data).And in recent years, arrhythmia is in young and middle-aged colony
Sickness rate have the trend of rising always, be therefore worth us that it is paid close attention to.
The patent application WO 99/50225 and WO 2004/099137 and US7057053 of PCT Publication discloses a kind of amino
Cyclohexyl ether compound can be used for treating arrhythmia, and has been found that wherein disclosed some compound (i.e. Fig. 1 chemical combination
Thing) hydrochloric acid Vernakalant treat and prevent in arrhythmia notable effectively.The document and patent of many open reports are retouched
Preparation method and the thinking of this compounds many are stated.
But mention its purification process and purification strategy are rare, according to relevant documents and materials introduction, hydrochloric acid wiener card
What Lan Wei was purified has hygroscopic foaming solid for one, after organic solvent then can be used to dissolve, molten according to it
The difference of Xie Du and separate out solid, organic solvent mentioned in prior art can be isopropanol, ethyl acetate and acetone etc..
But in actual experimentation, by existing for employing the most purified for the hydrochloric acid Vernakalant of about 80% purity prepared
Organic solvent described in technology processes, the result in not envisioned and reporting；And attempting good solvent and lazy
In the mix and match of property solvent, the muddy thing separated out can be collected as again grease rapidly.For the most further purification
With purification hydrochloric acid Vernakalant, there is no effective method.
Summary of the invention
In view of prior art lacking the purification to hydrochloric acid Vernakalant and purifying effective method, the special proposition present invention.
Technical scheme is as follows:
The purification process of a kind of hydrochloric acid Vernakalant, described method includes by using the mixed solvent body containing diisopropyl ether
System is purified and purification.Described purification step is
(1) one or more in good solvent are used to be completely dissolved by the most purified hydrochloric acid Vernakalant；
(2) solution in step (1) adds atent solvent to described solution do not continue to molten clear after, crystallize of lowering the temperature,
Obtain hydrochloric acid Vernakalant sterling.
Optionally, the good solvent in described step (1) is acetonitrile, ethyl acetate, isopropanol, isopropyl acetate, tetrahydrochysene
One or more in furan.
Optionally, the good solvent in described step (1) can be the mixed liquor of acetonitrile or acetonitrile and ethyl acetate.
Optionally, described step (1) good solvent is 40-80 with the solution temperature of the most purified hydrochloric acid Vernakalant
℃。
Optionally, in described step (2), atent solvent is the mixed solvent of diisopropyl ether or diisopropyl ether and other atent solvents.
Optionally, in described step (2), atent solvent is diisopropyl ether and methyl tertiary butyl ether(MTBE), ether, normal hexane, positive heptan
The mixed solvent of one or more in alkane, pentane.
Optionally, in described step (2), atent solvent can be the mixed solvent of acetonitrile and diisopropyl ether.
Optionally, in the purification process of described hydrochloric acid Vernakalant, solvent for use is acetonitrile and diisopropyl ether, acetonitrile and isopropyl
The volume ratio of ether is 1: 1-1: 5.
Optionally, in the purification process of hydrochloric acid Vernakalant, the volume ratio of acetonitrile and diisopropyl ether is 1: 2-1: 4.
Optionally, in the purification process of hydrochloric acid Vernakalant, the volume ratio of acetonitrile and diisopropyl ether is 1: 3-1: 4.
Optionally, in the purification process of hydrochloric acid Vernakalant, solvent for use is acetonitrile, ethyl acetate and diisopropyl ether, acetonitrile,
The volume ratio of ethyl acetate and diisopropyl ether is 1: 1: 1-1: 5: 5.
Optionally, in the purification process of hydrochloric acid Vernakalant, the volume ratio of acetonitrile, ethyl acetate and diisopropyl ether is 1: 1:2-1
∶3∶5。
Optionally, in the purification process of hydrochloric acid Vernakalant, the volume ratio of acetonitrile, ethyl acetate and diisopropyl ether is 1: 1: 2-1
∶1∶4。
Optionally, the recrystallization temperature in the purification process of hydrochloric acid Vernakalant is less than 0 DEG C.
The invention provides the purification process of a kind of hydrochloric acid Vernakalant, compared with prior art, the present invention has following
Advantage and beneficial effect:
(1) purification process step of the present invention is simple, and cheaper starting materials is easy to get；
(2) product yield of purification process gained of the present invention is high, and character is good.
(3) purification process products obtained therefrom of the present invention is better than other preparation method institutes for ARR therapeutic effect
The product obtained.
Accompanying drawing explanation
Fig. 1 is the structural formula of hydrochloric acid Vernakalant of the present invention；
Detailed description of the invention
The present invention is further illustrated with specific embodiment below with reference to accompanying drawings.
Embodiment one
(1) hydrochloric acid Vernakalant (grease, HPLC purity 78%) the most purified for 10g is placed in the reaction of 250ml single port
In Ping, adding acetonitrile 20ml, ethyl acetate 20ml, temperature rising reflux is to being completely dissolved.
(2) in the solution in step (1), diisopropyl ether about 55ml it is slowly added dropwise at a reflux temperature, to described clear liquid
Slightly muddy.Stop heating, by gained solution slow cooling to room temperature；It is stirred overnight under ice bath to there being crystal to separate out.Filter, 40
DEG C forced air drying, to constant weight, obtains white solid 5.3g, yield 68%, HPLC purity-99.2%.
Embodiment two
(1) hydrochloric acid Vernakalant (grease, HPLC purity 78%) the most purified for 10g is placed in the reaction of 250ml single port
In Ping, add acetonitrile 10ml, ethyl acetate 30ml, be warming up to backflow, be heated to being completely dissolved.
(2) in the backflow of step (1), diisopropyl ether about 75ml it is slowly added dropwise at a reflux temperature, to described clear liquid slightly
There is muddiness.Stopping heating, gained solution slow cooling is to room temperature；It is stirred overnight crystallize under ice bath.Filtering, 40 DEG C of forced air dryings are extremely
Constant weight, obtains white solid 5.1g, yield 65.4% (in terms of the most purified middle product content), HPLC purity-99.0%.
Embodiment three
(1) hydrochloric acid Vernakalant (grease, HPLC purity 78%) the most purified for 10g is placed in the reaction of 250ml single port
In Ping, adding acetonitrile 30ml, be warming up to backflow, the most purified hydrochloric acid Vernakalant is completely dissolved.
(2) it is slowly added dropwise diisopropyl ether about 100ml under backflow, has somewhat muddy to clear liquid.Stopping heating, slow cooling is extremely
Room temperature；It is stirred overnight under ice bath.Filtering, 40 DEG C of forced air dryings, to constant weight, obtain white solid 5.5g, and yield 70% is (with without pure
The middle product content meter changed), HPLC purity-98.7%.
The selection of good solvent and the atent solvent impact on purification result in experimental example one step
Hydrochloric acid Vernakalant (grease, HPLC purity 78%) the most purified for 10g is placed in 250ml single port reaction bulb
In, adding good solvent, temperature rising reflux is to being completely dissolved.It is slowly added dropwise at a reflux temperature in atent solvent extremely described clear liquid slightly
There is muddiness.Stop heating, by gained solution slow cooling to room temperature；It is stirred overnight under ice bath to there being crystal to separate out.Filter, 40 DEG C
Forced air drying, to constant weight, obtains white solid, calculates yield and the purity of product.Its result is as shown in table 1.
Selecting product yield and the impact of purity of table 1 solvent
Conclusion: as it can be seen from table 1 when good solvent selects the mixed solvent of acetonitrile or acetonitrile and ethyl acetate, atent solvent
When selecting diisopropyl ether, the yield of product is higher.
The impact on experimental result of the ratio of experimental example two solvent
Further being screened the consumption of good solvent preferred in experimental example 1 and atent solvent, it screens structure
As shown in table 2 below and table 3.
The impact on experimental result of the volume ratio of table 2 solvent
Conclusion: when the volume ratio of acetonitrile Yu diisopropyl ether is 1: 1-1: 5, the yield of hydrochloric acid Vernakalant product is 60%
Above, more than or less than should in the range of time, its yield substantially reduces, and when its volume ratio is 1: 3, and the yield of product is
Height, is 72%.
The impact on experimental result of the volume ratio of table 3 solvent
Conclusion: when the volume ratio of acetonitrile, ethyl acetate and diisopropyl ether is between 1: 1: 1-1: 5: 5, the yield of product is relatively
Height, is more than 60%, and after this scope, the yield of product significantly reduces；Its optimum proportioning is 1: 1: 2.
The experimental data impact on product yield in experimental example three purification step
The factor affecting product yield in this experiment step each on purification process is investigated, and it investigates factor and result
Being shown in Table 4. wherein, the acetonitrile with good solvent as 30ml, atent solvent is to investigate as a example by 100ml diisopropyl ether.
The impact on product yield of table 4 empirical factor
Conclusion: by above experiment it can be seen that experimentation affects product yield because have adding of atent solvent
Entering speed, temperature of lowering the temperature, if stirring and temperature fall time etc., is 3d/5s when atent solvent adds speed, temperature of lowering the temperature
Less than 0 DEG C, and in temperature-fall period under conditions of continuously stirred 24h, the yield of product is the highest, and its character is optimum.
Experimental example four zoopery
4.1 pairs of ventricular tachycardia and the not normal therapeutic effect of ventricular fibrillation
The overall heart selecting rabbit is tested, with aconitine 100～150 μ g/kg slow intravenous injection moulding.Cause
Animal polyphyly premature beat, short battle array ventricular tachycardia etc..
The successful rabbit of modeling is given and the hydrochloric acid Vernakalant sterling of gained in embodiment 1-3, observes the most not normal extensive
Answer and duration.It is zooperal the results are shown in Table 5.
Table 5 zoopery
Conclusion；Compared with purifying pharmaceutical administration group non-with non-administered group, hydrochloric acid wiener prepared by purification process of the present invention
The cure rate original text that card is blue, therapeutic effect is rapid, and the therapeutic effect persistent period is long, has good clinical value.
Last it is noted that above-described each embodiment is merely to illustrate technical scheme, rather than to it
Limit；Although the present invention being described in detail with reference to previous embodiment, it will be understood by those within the art that:
Technical scheme described in previous embodiment still can be modified by it, or enters wherein part or all of technical characteristic
Row equivalent；And these amendments or replacement, do not make the essence of appropriate technical solution depart from various embodiments of the present invention technical side
The scope of case.
Claims (9)
1. the purification process of a hydrochloric acid Vernakalant, it is characterised in that: its method includes to the most purified hydrochloric acid wiener card
Blue add good solvent and atent solvent mix after crystallization purifying, wherein, described good solvent includes acetonitrile, acetic acid second
One or more in ester, isopropanol, isopropyl acetate, oxolane, described atent solvent include diisopropyl ether or diisopropyl ether with
The mixed solvent of one or more that methyl tertiary butyl ether(MTBE), ether, normal hexane, normal heptane, pentane are many.
The purification process of hydrochloric acid Vernakalant the most according to claim 1, it is characterised in that: described method is optimum for using
The most purified Vernakalant hydrochloride salt to dissolving completely, is then added atent solvent to muddiness and does not continues to molten by solvent
Till Qing, after being down to room temperature, carry out cooling crystallize and filter to obtain purified product.
The purification process of hydrochloric acid Vernakalant the most according to claim 2, it is characterised in that: use the good solvent will be without
The Vernakalant hydrochloride salt of purification is 40-80 DEG C to the temperature dissolved.
The purification process of hydrochloric acid Vernakalant the most according to claim 2, it is characterised in that: the temperature of cooling crystallize is 0
Below DEG C.
The purification process of hydrochloric acid Vernakalant the most according to claim 2, it is characterised in that: cooling Crystallization Process needs not
Disconnected stirring, mixing time is 24h.
The purification process of hydrochloric acid Vernakalant the most according to claim 2, it is characterised in that: the most purified described hydrochloric acid
The consumption of Vernakalant is 10g, and described good solvent is acetonitrile, and atent solvent is diisopropyl ether, acetonitrile and the volume ratio of diisopropyl ether
It is 1: 1-1: 5.
The purification process of hydrochloric acid Vernakalant the most according to claim 2, it is characterised in that: the most purified described hydrochloric acid
The consumption of Vernakalant is 10g, and described good solvent is acetonitrile and ethyl acetate, and atent solvent is diisopropyl ether, acetonitrile, acetic acid second
Ester is 1: 1: 1-1: 5: 5 with the volume ratio of diisopropyl ether.
The purification process of hydrochloric acid Vernakalant the most according to claim 6, it is characterised in that: acetonitrile and the volume of diisopropyl ether
Ratio is 1: 3.
The purification process of hydrochloric acid Vernakalant the most according to claim 7, it is characterised in that: acetonitrile, ethyl acetate are with different
The volume ratio of propyl ether is 1: 1: 2.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610626735.4A CN106220544A (en) | 2016-08-03 | 2016-08-03 | A kind of purification process of hydrochloric acid Vernakalant |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105847A (en) * | 2021-12-02 | 2022-03-01 | 上海旭东海普药业有限公司 | Refining method of Vernakalant hydrochloride |
| CN114200034A (en) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | Analysis method of vernakalant related substances |
| CN114436928A (en) * | 2022-01-21 | 2022-05-06 | 上海旭东海普药业有限公司 | Crystalline form A of Vernakalant hydrochloride and preparation method thereof |
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| WO2006075778A1 (en) * | 2005-01-12 | 2006-07-20 | Astellas Pharma Inc. | Production method of optically active cyclohexane ether compounds |
| CN103819385A (en) * | 2014-03-03 | 2014-05-28 | 上海博志研新药物技术有限公司 | Preparing method for (3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxy phenyl) ethyoxyl] cyclohexyl]-3-pyrrolidinol |
| CN104610121A (en) * | 2015-01-07 | 2015-05-13 | 北京哈三联科技有限责任公司 | Preparation method for Vernakalant hydrochloride |
| CN105294530A (en) * | 2015-11-30 | 2016-02-03 | 北京哈三联科技有限责任公司 | Purification method of vernakalant hydrochloride |
| CN105646320A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Stable Vernakalant compound |
-
2016
- 2016-08-03 CN CN201610626735.4A patent/CN106220544A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006075778A1 (en) * | 2005-01-12 | 2006-07-20 | Astellas Pharma Inc. | Production method of optically active cyclohexane ether compounds |
| CN103819385A (en) * | 2014-03-03 | 2014-05-28 | 上海博志研新药物技术有限公司 | Preparing method for (3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxy phenyl) ethyoxyl] cyclohexyl]-3-pyrrolidinol |
| CN105646320A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Stable Vernakalant compound |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114200034A (en) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | Analysis method of vernakalant related substances |
| CN114105847A (en) * | 2021-12-02 | 2022-03-01 | 上海旭东海普药业有限公司 | Refining method of Vernakalant hydrochloride |
| CN114436928A (en) * | 2022-01-21 | 2022-05-06 | 上海旭东海普药业有限公司 | Crystalline form A of Vernakalant hydrochloride and preparation method thereof |
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