CN106588736A - Preparation method of azelnidipine intermediate amidine acetate - Google Patents
Preparation method of azelnidipine intermediate amidine acetate Download PDFInfo
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- CN106588736A CN106588736A CN201611142216.7A CN201611142216A CN106588736A CN 106588736 A CN106588736 A CN 106588736A CN 201611142216 A CN201611142216 A CN 201611142216A CN 106588736 A CN106588736 A CN 106588736A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
Abstract
The invention relates to a preparation method of azelnidipine intermediate amidine acetate, in particular to a modified preparation method of azelnidipine intermediate amidine acetate; the method replaces traditional introduced HCl gas with HCl gas prepared in situ, so that the feeding ratio of starting materials is fully controllable, hydrogen chloride in each batch of reaction liquid is accurately quantitated, and mass reproducibility is good; in addition, only industrial standard materials are used, and advanced water-free treatment is not required; the modified process has greatly lessened operation steps, such as solvent pre-drying, vent pipeline and ventilation regulation and monitoring, ventilation moisture regular monitoring, long ventilation time and the like, and production efficiency is improved; furthermore, the yield and quality of amidine acetate acquired by modification are greatly increased, the yield is up to 75% and above, and the purity of HPLC (high performance liquid chromatography) is up to 99.0% and above.
Description
Technical field
The present invention relates to a kind of preparation method of azelnidipine intermediate acetic acid amidine, belongs to pharmaceutical technology field.
Background technology
Azelnidipine belongs to dihydropyridine calcium channel blocker（CCB）, CCB as a line hypertension therapeutic medicine, due to
Antihypertensive effect reliability and be widely used.The preparation of azelnidipine crude drug needs to use key intermediate amidino groups acetic acid
（N- benzhydryl ring fourth heterocycle -3- alcohol）Ester acetate, abbreviation acetic acid amidine（Compound III）, at present about its preparation, commonly use
Route it is as follows with method：
（One）It is passed through hydrogen chloride gas method
The route adds the ethanol of basic equimolar amountss, in solvent with compound I as starting material（Dichloromethane or chloroform）Sternly
Under the conditions of lattice are anhydrous, dry hydrogen chloride gas are passed through, first generate the hydrochlorate of intermediate state II, it is neutralized to obtain intermediate
II, not purification be directly added into ammonium acetate, obtain acetic acid amidine by solvent reaction of acetonitrile：
Nearly all at present report adopt this route, such as Chemical and Pharmaceutical Bulletin,
1995 , 43（5）：797-817、CN103183663、CN103509003、CN101475521、CN102453023、
CN103130700, CN87107150A, EP0266922, JP2011201804 etc..The problem that the route is present is, to reactant liquor
In be passed through the production operation that hydrogen chloride gas are an extremely difficult control, reason is as follows：
（1）Industrial gas hydrogen chloride must pass through decompressor and various pipelines are connected in reactor, due to hydrogen chloride gas
Corrosivity are very strong, are easily caused equipment valve invalidation and pipeline leakage, cause workshop security incident.
（2）Jing is tested, and the concentration of hydrogen chloride has very big impact to the effect that intermediate II is reacted, and concentration gets over low reaction
Effect is poorer.And be passed through the hydrogen chloride gas in reactant liquor and be dissolved into the efficiency of reactant liquor and affected by many factors, such as liquid level
Lower breather, liquid level, mixing speed, liquid temperature etc., even if causing the dry hydrogen chloride gas for being passed through same amount, after absorption
Hydrogen cloride concentration in reactant liquor is also differed.
（3）The amount for being passed through hydrogen chloride gas is difficult to grasp.Although can be converted by gas flowmeter, accurate amount
On-line monitoring is unable to, needs to disconnect gas cylinder weighing, with the method for loss of weight accurate intake is determined, it is cumbersome.
（4）The rate request for being passed through hydrogen chloride is uniform and can not be too fast, and it is long to cause to be passed through the time, affects production efficiency.
（5）Industrial gas hydrogen chloride contains a certain amount of moisture, and during prepare compound II, solvent for use is aqueous
Or the hydrogen chloride being passed through brings aqueous vapor into and is readily formed side reaction, affects product yield and quality, concrete side reaction is through as follows：
Therefore the strict moisture for controlling first step reaction material used is very crucial to reacting success or failure, big to produce logical industrial chlorinations hydrogen
Need to use concentrated sulphuric acid drying device, but after concentrated sulphuric acid water suction reaches to a certain degree, soaking effect and deterioration of efficiency, or no longer inhale
Water, needs the moisture in frequently monitoring hydrogen chloride gas, changes desiccant, operates and processes trouble.
In sum, be passed through hydrogen chloride gas method due to material moisture difference, be passed through chlorination hydrogen amount it is not equal because
The impact of element, can cause the yield of every batch of intermediate II unstable with quality, and ultimately results in the quality of acetic acid product amidine and receive
Rate is unstable.
（Two）Hydroxylamine reduction method
《Chinese Journal of Pharmaceuticals》, 2012, 43（11）:885-887 prepares acetic acid amidine using innovative technology：
Through the repeated authentication to testing, target product VI is not obtained, but the azanol amine solution for obtaining compound I is produced
Thing：
。
The content of the invention
It is an object of the invention to provide a kind of preparation method of azelnidipine intermediate acetic acid amidine.
The technical scheme is that a kind of preparation method of azelnidipine intermediate acetic acid amidine, it is characterised in that chemical combination
Post-treated to obtain compound II under the HCl effects that thing I and alcohol R ' OH are prepared at the scene, compound II reacts again with ammonium acetate
Obtain the acetic acid amidine shown in formula III：
Wherein, R ' is methyl or ethyl；The HCl being prepared in situ, refers in same reaction system, is produced by chemical reaction
Raw HCl.
, according to the invention it is preferred to, the HCl being prepared in situ can be by chloride compounds VII and alcoholic compound
VIII reactions are obtained：
Wherein, R is alkyl or (CH in compound VII2)mCOCl, m=0 or 1；R ' is as defined above in compound VIII.
According to the present invention, when acyl chlorides and alcohol are prepared in situ HCl, the chloride compounds VII selected from chloroacetic chloride, propionyl chloride,
Oxalyl chloride, malonyl chloride；The preferred technical grade absolute methanols of alcoholic compound VIII, dehydrated alcohol.
According to the present invention, when acyl chlorides is prepared in situ HCl with alcohol, reacting the organic acid esters IX for generating can be used as reaction dissolvent.
According to the present invention, when acyl chlorides is prepared in situ HCl with alcohol, reaction system needs to add appropriate retarder thinner, this molten
Agent can not participate in reacting and the material to reacting has reasonable dissolubility, preferred dichloromethane, chloroform.
According to the present invention, when acyl chlorides is prepared in situ HCl with alcohol, as chloride compounds VII only one of which acid chloride groups, i.e. R
For alkyl when, each material rate of charge be I：VII：VIII = 1：N：（N+1）, wherein, N is the number more than 1, preferably 8 ~ 13；Work as acyl
Chlorine compound VII has two acid chloride groups, i.e. R is (CH2)mCOCl, m=0 or when 1, each material rate of charge is I：VII：VIII =
1：N/2：（N+1）, N is the number more than 1, preferably 8 ~ 13.
According to the present invention, during HCl prepare compounds II being prepared in situ using acyl chlorides and alcohol, operating process is as follows：
Acyl chlorides VII is added in retarder thinner, alcohol VIII, or the addition of acyl chlorides VII and alcohol VIII are slowly added at 10 DEG C of temperature control
Order is exchanged, completion of dropping, adds compound I, is controlled less than 10 DEG C and is continued to react to complete, post-treated to be changed
Compound II.
According to the present invention, compound II prepares the acetic acid amidine shown in formula III with ammonium acetate reaction, " logical according to background information
Enter hydrogen chloride gas method " obtain by method disclosed in pertinent literature.
The invention has the beneficial effects as follows using be prepared in situ HCl gases replace it is traditional be passed through HCl gases, can be with：
（1）By the ingredient proportion for controlling each starting material, it is ensured that the hydrogen chloride produced in per batch reaction liquid is accurate quantitative analysis,
So that it is guaranteed that the effect per batch reaction is consistent, big production technology is reappeared；
（2）Using the material of industrial standard, it is not necessary to carry out Non-aqueous processing in advance；
（3）Reduce many operation sequences, such as solvent is predrying, debugging and monitoring, the moisture of ventilation of vent line and ventilation
Periodic monitor, ventilation take longer etc., improve production efficiency；
（4）Gained acetic acid amidine product yield is set to be greatly improved with quality, yield reaches more than 75%, HPLC purity and reaches
More than 99.0%.
Specific embodiment：
For a better understanding of the present invention content, is described further with reference to specific embodiment, but the present invention is not only limited to
This.
Embodiment 1
By 500ml dichloromethane and 628g（8mol）In chloroacetic chloride input reaction bulb, below 0 DEG C of temperature control, then slow Deca 414g
（9mol）Dehydrated alcohol, completion of dropping adds material I 306g（1mol）, overnight, HPLC monitoring reactions are complete for temperature control reaction.Will
Reaction system is slowly added in strong aqua ammonia, keeps system in alkalescence.Organic layer is separated, anhydrous sodium sulfate drying, concentration adds second
Nitrile, adds ammonium acetate 77g, and 50 DEG C of temperature control is finished to reaction, separates out solid, is filtered, and obtains white crystals acetic acid amidine 289.5g,
Yield 75.6%, HPLC purity 99.2%.
Embodiment 2
By 500ml chloroform and 414g（9mol）In dehydrated alcohol input reaction bulb, below 0 DEG C of temperature control, then slow Deca 628g
（8mol）Chloroacetic chloride, completion of dropping adds material I 306g（1mol）, overnight, HPLC monitoring reactions are complete for temperature control reaction.Will be anti-
Answer system to be slowly added in strong aqua ammonia, keep system in alkalescence.Organic layer is separated, anhydrous sodium sulfate drying, concentration adds second
Nitrile, adds ammonium acetate 77g, and 50 DEG C of temperature control is finished to reaction, separates out solid, is filtered, and obtains white crystals acetic acid amidine 292.2g,
Yield 76.3%, HPLC purity 99.4%.
Embodiment 3
By 800ml chloroform and 506g（11mol）In dehydrated alcohol input reaction bulb, below 10 DEG C of temperature control, then slow Deca
635g（5mol）Oxalyl chloride, completion of dropping adds material I 306g（1mol）, overnight, HPLC monitoring reactions are complete for temperature control reaction.
Reaction system is slowly added in strong aqua ammonia, system is kept in alkalescence.Organic layer is separated, anhydrous sodium sulfate drying, concentration is added
Acetonitrile, adds ammonium acetate 77g, and 50 DEG C of temperature control is finished to reaction, separates out solid, is filtered, and obtains white crystals acetic acid amidine 301g,
Yield 78.6%, HPLC purity 99.6%.
Embodiment 4
By 800ml dichloromethane and 416g（13mol）In absolute methanol input reaction bulb, below 10 DEG C of temperature control, then slow Deca
1110（12mol）Propionyl chloride, completion of dropping adds material I 306g（1mol）, overnight, HPLC monitorings have been reacted for temperature control reaction
Entirely.Reaction system is slowly added in strong aqua ammonia, system is kept in alkalescence.Organic layer is separated, anhydrous sodium sulfate drying is concentrated,
Acetonitrile is added, ammonium acetate 77g is added, 50 DEG C of temperature control is finished to reaction, separates out solid, is filtered, and obtains white crystals acetic acid amidine
307.5g, yield 80.3%, HPLC purity 99.6%.
Embodiment 5
By 800ml dichloromethane and 644g（14mol）In ethanol input reaction bulb, below 0 DEG C of temperature control, then slow Deca 1020g
（13mol）Chloroacetic chloride, completion of dropping adds material I 306g（1mol）, overnight, HPLC monitoring reactions are complete for temperature control reaction.Will
Reaction system is slowly added in strong aqua ammonia, keeps system in alkalescence.Organic layer is separated, anhydrous sodium sulfate drying, concentration adds second
Nitrile, adds ammonium acetate 77g, and 50 DEG C of temperature control is finished to reaction, separates out solid, is filtered, and obtains white crystals acetic acid amidine 315.2g,
Yield 82.3%, HPLC purity 99.7%.
Claims (4)
1. a kind of preparation method of azelnidipine intermediate acetic acid amidine, it is characterised in that compound I is prepared at the scene with alcohol R ' OH
The lower reaction of HCl effects, post processing obtains compound II, and compound II obtains again the acetic acid shown in formula III with ammonium acetate reaction
Amidine：
,
Wherein, R ' is methyl or ethyl in alcohol R ' OH；The HCl being prepared in situ, refers in same reaction system, by changing
Learn the HCl that reaction is produced.
2. preparation method according to claim 1, it is characterised in that the HCl being prepared in situ can pass through chloride
Compound VII and alcohol R ' OH reactions are obtained：
,
Wherein, R is alkyl or (CH in compound VII2)mCOCl, m=0 or 1；R ' is as defined above in alcohol R ' OH.
3. preparation method according to claim 2, it is characterised in that the acyl chlorides is selected from chloroacetic chloride, propionyl chloride, oxalyl
Chlorine, malonyl chloride；The preferred technical grade absolute methanol of the alcohol, dehydrated alcohol.
4. according to the arbitrary described preparation method of claim 1-3, it is characterised in that during compound I prepare compounds II,
Reaction solvent for use can not participate in reacting and the material to reacting will have reasonable dissolubility, preferred dichloromethane, chloroform.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183663A (en) * | 2013-03-25 | 2013-07-03 | 威海迪素制药有限公司 | Preparation method for azelnidipine |
| CN104529809A (en) * | 2014-10-10 | 2015-04-22 | 浙江大学 | Preparation method polysubstituted imidazole derivatives |
| CN105377819A (en) * | 2013-07-09 | 2016-03-02 | Cj医药健康株式会社 | Method for preparation of benzimidazole derivatives |
| CN105461691A (en) * | 2015-12-31 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of azelnidipine |
-
2016
- 2016-12-13 CN CN201611142216.7A patent/CN106588736A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183663A (en) * | 2013-03-25 | 2013-07-03 | 威海迪素制药有限公司 | Preparation method for azelnidipine |
| CN105377819A (en) * | 2013-07-09 | 2016-03-02 | Cj医药健康株式会社 | Method for preparation of benzimidazole derivatives |
| CN104529809A (en) * | 2014-10-10 | 2015-04-22 | 浙江大学 | Preparation method polysubstituted imidazole derivatives |
| CN105461691A (en) * | 2015-12-31 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of azelnidipine |
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