CN105153169B - A kind of synthetic method of epinastine hydrochloride - Google Patents
A kind of synthetic method of epinastine hydrochloride Download PDFInfo
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- CN105153169B CN105153169B CN201510641046.6A CN201510641046A CN105153169B CN 105153169 B CN105153169 B CN 105153169B CN 201510641046 A CN201510641046 A CN 201510641046A CN 105153169 B CN105153169 B CN 105153169B
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- 0 CCC[C@@](C)(*C([C@](C)*ICCC1CCCCC1)=IC)[C@@](C)C=CC Chemical compound CCC[C@@](C)(*C([C@](C)*ICCC1CCCCC1)=IC)[C@@](C)C=CC 0.000 description 3
- DROVWXGPQRYEGB-UHFFFAOYSA-N CC(C)c1ccccc1C1N(C)C(N)=NC1 Chemical compound CC(C)c1ccccc1C1N(C)C(N)=NC1 DROVWXGPQRYEGB-UHFFFAOYSA-N 0.000 description 1
- YUTIUWLTFNPGKN-UHFFFAOYSA-N O=CNC1SC1 Chemical compound O=CNC1SC1 YUTIUWLTFNPGKN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of synthetic method of epinastine hydrochloride, this method is that starting material carrys out synthetic hydrochloric acid epinastine with compound shown in Formula II (6- aminomethyl -6,11- dihydro -5H- dibenzo [b, e] azatropylidene maleate).Epinastine hydrochloride can be not only effectively synthesized using the synthetic method of epinastine hydrochloride of the invention, and have many advantages, such as that combined coefficient height, production safety, technological operation are simple, with short production cycle, thus more suitable for extensive, industrialized production epinastine hydrochloride.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly, to a kind of synthetic method of epinastine hydrochloride.
Background technique
The entitled epinastine hydrochloride of epinastine hydrochloride English, the entitled 3- amino -9,13- bis- of chemistry
Hydrogen -1H- dibenzo [c, f]-imidazo [1,5-a] azacyclonol hydrochloride salt, structural formula are as follows：
Epinastine hydrochloride is for treating bronchial asthma, allergic dermatitis, nettle rash, eczema, dermatitis and common silver bits
Sick (psoriasis) uses the bronchoconstriction as caused by histamine and bradykinin with very strong inhibition, and to by other changes
Bronchoconstriction caused by medium is learned then without inhibiting effect, is the most effective histamine for acting on perineural no sedation
One of H1 receptor antagonist.D- epinastine, L- epinastine and racemization the epinastine no significant difference in terms of pharmacological activity.
Epinastine hydrochloride is developed by German Boehringer Ingelheim company, is total to the further joint development markets of pharmacy cooperation with Japan three,
1994 in Japanese Initial Public Offering, China's approval epinastine hydrochloride tablets import in 2000, trade name：Alesion (love reason
Victory).
Currently, the synthetic method of epinastine hydrochloride mainly has：
If Chinese patent CN101130544 reports a kind of method for synthesizing epinastine, this method with chloromethyl -6 6-,
11- dihydro-dibenzo [b, e] azatropylidene is starting material, and synthesis 6- aminomethyl -11- hydrogen-dibenzo is directly reacted with ammonia
Then [b, e] azatropylidene synthesizes epinastine with sodium borohydride reduction, cyanogen bromide cyclization again, process route is as follows：
The route uses extremely toxic substance cyanogen bromide in the reaction, and concentration contacts 30 minutes under the conditions of reaching 120mg/m3
It is i.e. dead, therefore not only need to prevent cyanogen bromide from leaking in the synthesis process using above method synthetic hydrochloric acid epinastine, it threatens
Operator's safety, and not can guarantee cyanogen bromide and will not remain in epinastine hydrochloride obtained, influence drug safety.It is Chinese special
Sharp CN105172658 recently discloses the method for another synthesis epinastine, with 6- aminomethyl -6,11- dihydro -5H- hexichol
And [b, e] azatropylidene synthesizes epinastine, the process route is as follows：
Route synthesis difficulty is big, is 7 days the time required to synthesis, and the reaction time is extremely long, is unfavorable for industrialized production.It is another
Kind method Chinese patent CN103012408, obtains 2- benzyl by reacting with silane reagent using 2- aminobenzophenone as raw material
Aniline, then N- (2- benzyl phenyl) -2- chloroacetamide is obtained through acylation reaction with 2- chloracetyl chloride, then under the action of dehydrating agent
Dehydration of amide cyclization obtains 6- (chloromethyl) -11H- dibenzo [b, e] azatropylidene, obtains 6- (nitrine first through azido reaction
Base) -11H- dibenzo [b, e] azatropylidene, then 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] is obtained through reduction
Azatropylidene, finally generates epinastine with cyanogen bromide cyclization again, and the process route is as follows：
The route can carry out azido reaction using azido compound in the reaction, and compound stability is bad, easily
Explosion, due to largely using in industrialized production, risk is high；Secondly extremely toxic substance cyanogen bromide can be used in the reaction,
Operator's safety is threatened, and not can guarantee cyanogen bromide to remain in epinastine hydrochloride obtained.
Therefore, the synthetic method of current epinastine hydrochloride is further improved.
Summary of the invention
In order to solve the above technical problems, the invention discloses a kind of synthetic methods of epinastine hydrochloride.
The invention discloses a kind of synthetic method of epinastine hydrochloride, this method includes：
1) willDecarboxylic reaction occurs with alkali, to obtain
2) willWithSubstitution reaction occurs, to obtain
3) makeCyclization reaction occurs, to obtain
4) makeHydrolysis occurs, to obtain
And
5) makeSalt-forming reaction occurs, to obtain
Preferably, step 1)~4) in an at least step carry out in organic solvent；
In step 1), the alkali used is monoacidic base.
Preferably, if step 1) carries out in organic solvent, the organic solvent used is the ether of C atomicity 1~6, halogenated
At least one of hydrocarbon；
If step 2) carries out in organic solvent, the organic solvent used in the ketone of C atomicity 1~6, halogenated hydrocarbons extremely
Few one kind；
If step 3) carries out in organic solvent, the organic solvent used is n,N-Dimethylformamide, N, N- dimethyl
At least one of acetamide；
If step 4) carries out in organic solvent, the organic solvent used is the monohydric alcohol of C atomicity 1~6, tetrahydro furan
It mutters, at least one of methylfuran and acetonitrile.
Preferably, in step 2), reaction temperature -30~10 DEG C of substitution reaction are carried out.
Preferably, in step 2), the molar ratio of compound shown in compound shown in formula III and formula IV is 1：0.9~3.
Preferably, in step 3), occur under the conditions of the cyclization reaction is existing for the condensing agent or/and acid binding agent.
Preferably, the condensing agent is the chloro- 1- picoline of iodo 2-；
The acid binding agent is at least one of triethylamine, pyridine, methylamine, dimethylamine, positive di-n-propylamine.
Preferably, in step 3), the molar ratio of compound and condensing agent shown in Formula V is 1：0.9~2；
The molar ratio 1 of compound and acid binding agent shown in Formula V：2~6.
Preferably, in step 3), 10~40 DEG C of the reaction temperature of cyclization reaction.
Preferably, in step 4), the reaction temperature of hydrolysis is 40~100 DEG C.
Preferably, in step 5), salt-forming reaction occurs under the conditions of pH value is 0~6；
The reaction temperature of the salt-forming reaction is 0~40 DEG C.
Preferably, in step 1)~5) in either step in, further include utilize：It filters, centrifugation, washing, recrystallization, mistake
At least one of filter, drying, stirring carry out purification process.
Preferably, in step 5), recrystallize recrystallisation solvent used be the monohydric alcohol of C atomicity 1~6, in ether extremely
Few one kind.
The synthetic method of epinastine hydrochloride according to the present invention can obtain beneficial effect at least as described below：
1, the synthetic method of epinastine hydrochloride according to the present invention, the bromine that entire synthesis process does not use toxicity strong
Change cyanogen, reduce toxicity, is conducive to environmental protection, and residual of the epinastine hydrochloride synthesized due to not having cyanogen bromide,
Drug safety is improved, to be easy to industrialization large-scale production.In addition, also without using azido compound when synthesis,
It can be effectively prevented and explode, safety is high, operator will not be threatened safe, to be conducive to keep the safety in production.
2, the synthetic method of epinastine hydrochloride according to the present invention, reaction condition is mild, and setting without special reaction
Standby, the scope of application is more extensive.
3, the synthetic method of epinastine hydrochloride according to the present invention, raw materials used and reagent are easy to buy from market, from
And advantageously reduce production cost.
4, the synthetic method of epinastine hydrochloride according to the present invention, technological operation is simple, and synthesis cycle is short, thus more suitable
Carry out epinastine hydrochloride together in extensive, industrialized production.
5, the synthetic method of epinastine hydrochloride according to the present invention, not only combined coefficient is high, and synthesized hydrochloric acid according to
The purity of sting is also very high, complies fully with medicine quality requirement.
6, the synthetic method of epinastine hydrochloride according to the present invention, synthesized epinastine hydrochloride can be used for treating branch
San bronchial asthma, allergic dermatitis, nettle rash, eczema, dermatitis and Psoriasis vulgaris etc., to make epinastine hydrochloride of the invention
Synthetic method have huge medical application value and market popularization value.
Additional aspect and advantage of the invention will be set forth in part in the description, and will partially become from the following description
It is more obvious, or practice through the invention recognizes.
Detailed description of the invention
Above-mentioned and/or additional aspect of the invention and advantage will become from the description of the embodiment in conjunction with the following figures
Obviously and it is readily appreciated that, wherein：
Fig. 1 is the high-efficient liquid phase chromatogram using epinastine hydrochloride synthesized by the present invention；
Fig. 2 is the high-efficient liquid phase chromatogram of epinastine hydrochloride standard items.
Specific embodiment
The present invention is described in further detail below by specific embodiment, and in conjunction with attached drawing.It needs to illustrate
It is that in the absence of conflict, the features in the embodiments and the embodiments of the present application can be combined with each other.Embodiment is example
Property, for explaining only the invention, and it is not considered as limiting the invention.In addition, if do not clearly stated, below
Embodiment employed in all reagents be commercially available in the market, or can according to herein or known method close
At, it is also what those skilled in the art were easy to get for the reaction condition that do not list.
Conventional method：
Referring to following formula, in the examples below that, the method for synthetic hydrochloric acid epinastine is mainly included the following steps that：
1) by compound shown in Formula II (6- aminomethyl -6,11- dihydro -5H- dibenzo [b, e] azatropylidene maleate) with
Decarboxylic reaction occurs for alkali, to obtain compound shown in formula III；
2) substitution reaction is occurred into for compound shown in compound shown in formula III and formula IV, to obtain chemical combination shown in Formula V
Object；
3) make compound shown in Formula V that cyclization reaction occur, to obtain compound shown in Formula IV；
4) make compound shown in Formula IV that hydrolysis occur, to obtain compound shown in Formula VII；And
5) make compound shown in Formula VII that salt-forming reaction occur, to obtain compound shown in Formulas I,
Embodiment 1：The synthesis of compound shown in formula III
Reaction equation is as follows：
In 20L reaction kettle, (6- aminomethyl -6,11- dihydro -5H- dibenzo [b, the e] nitrogen of compound shown in throw-in type II
Miscellaneous Zhuo maleate) 1Kg, t-butyl methyl ether 6L, 30% sodium hydrate aqueous solution 8L, it is stirred at room temperature 2 hours, after completion of the reaction,
Stratification is concentrated under reduced pressure after taking organic phase, sodium sulphate to dry, filter, and obtains compound 650g (mass yield shown in formula III
65%).
Embodiment 2：The synthesis of compound shown in formula III
Reaction equation is as follows：
In 20L reaction kettle, compound 1Kg shown in throw-in type II, methylene chloride 6L, 30% sodium hydrate aqueous solution 8L,
It is stirred at room temperature 2 hours, after completion of the reaction, stratification is concentrated under reduced pressure after taking organic phase, sodium sulphate to dry, filter, and obtains formula
Compound 570g shown in III (mass yield 57%).
Embodiment 3：The synthesis (substitution reaction) of compound shown in Formula V
Reaction equation is as follows：
Compound 650g shown in formula III is dissolved in acetone 1.5L, is slowly added dropwise containing the anhydrous of compound 575g shown in formula IV
Acetone soln stirs 3 hours at 0 DEG C, a large amount of faint yellow solids is precipitated, are filtered under diminished pressure, filter cake acetone washing, and vacuum is dry
It is dry, obtain compound 292g (light yellow solid, mass yield 45%) shown in Formula V.
Embodiment 4：The synthesis (substitution reaction) of compound shown in Formula V
Reaction equation is as follows：
Compound 630g shown in formula III is dissolved in methylene chloride 1.5L, is slowly added dropwise containing compound 555g shown in formula IV
Dichloromethane solution stirs 3 hours at 0 DEG C, a large amount of faint yellow solids is precipitated, are filtered under diminished pressure, filter cake acetone washing, vacuum
It is dry, obtain compound 202g (light yellow solid, mass yield 32%) shown in Formula V.
Embodiment 5：The synthesis (substitution reaction) of compound shown in Formula V
Reaction equation：
Compound 650g shown in formula III is dissolved in acetone 1.5L, and the acetone containing compound 1150g shown in formula IV is slowly added dropwise
Solution stirs 3 hours at 0 DEG C, a large amount of faint yellow solids is precipitated, are filtered under diminished pressure, filter cake acetone washing, and vacuum drying obtains
Obtain compound 242g (light yellow solid, mass yield 37%) shown in Formula V.
Embodiment 6：The synthesis (substitution reaction) of compound shown in Formula V
Reaction equation：
Compound 650g shown in formula III is dissolved in acetone 1.5L, and the acetone containing compound 575g shown in formula IV is slowly added dropwise
Solution stirs 3 hours at -30 DEG C, a large amount of faint yellow solids is precipitated, are filtered under diminished pressure, filter cake acetone washing, vacuum drying,
Obtain compound 282g (light yellow solid, mass yield 43%) shown in Formula V.
Embodiment 7：The synthesis (cyclization reaction) of structural compounds shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in N,N-dimethylformamide
1.8L, in 25 DEG C of dropwise addition triethylamine 352g, 25 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, are precipitated light yellow solid
Body, centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 337g (light yellow solid, matter shown in Formula IV
Measure yield 75%).
Embodiment 8：The synthesis (cyclization reaction) of structural compounds shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in DMAC N,N' dimethyl acetamide
1.8L, in 25 DEG C of dropwise addition triethylamine 352g, 25 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, are precipitated light yellow solid
Body, centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 310g (light yellow solid, matter shown in Formula IV
Measure yield 69%).
Embodiment 9：The synthesis (cyclization reaction) of structural compounds shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in N,N-dimethylformamide
1.8L, in 25 DEG C of dropwise addition triethylamine 352g, 40 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, are precipitated light yellow solid
Body, centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 320g (light yellow solid, matter shown in Formula IV
Measure yield 71.1%).
Embodiment 10：The synthesis (cyclization reaction) of compound shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in N,N-dimethylformamide
1.8L, in 25 DEG C of dropwise addition triethylamine 700g, 25 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, are precipitated light yellow solid
Body, centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 300g (light yellow solid, matter shown in Formula IV
Measure yield 66.7%).
Embodiment 11：The synthesis (cyclization reaction) of compound shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in N,N-dimethylformamide
1.8L, in 25 DEG C of dropwise addition methylamine 64g, 25 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, light yellow solid is precipitated,
Centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 260g (light yellow solid, quality shown in Formula IV
Yield 57.8%).
Embodiment 12：The synthesis (cyclization reaction) of compound shown in Formula IV
Reaction equation：
Compound 450g shown in Formula V and the chloro- 1- picoline 356g of condensing agent iodo 2- are dissolved in N,N-dimethylformamide
1.8L, in 25 DEG C of dropwise addition pyridine 352g, 25 DEG C are reacted 10 hours, after completion of the reaction, water are added at room temperature, are precipitated light yellow solid
Body, centrifugation, adds water.Mashing 5 hours.Filtering, filtration cakes torrefaction obtain compound 283g (light yellow solid, matter shown in Formula IV
Measure yield 62.9%).
Embodiment 13：The synthesis (hydrolysis) of structural compounds shown in Formula VII
Reaction equation：
Compound 335g shown in Formula IV is suspended in concentrated hydrochloric acid, is slowly heated to 100 DEG C, and solution gradually becomes to clarify, and 100
DEG C reaction 2 hours, TLC monitor reaction process.
After completion of the reaction, it is cooled to room temperature, sodium hydrate aqueous solution alkali tune to pH >=12, ethyl acetate aqueous layer extracted 3 times,
Merge organic phase, saturated common salt water washing is concentrated under reduced pressure, and obtaining compound 235g shown in Formula VII, (light yellow solid, quality are received
Rate 70.1%).
Embodiment 14：The synthesis (hydrolysis) of compound shown in Formula VII
Reaction equation：
Compound 335g shown in Formula IV is suspended in concentrated hydrochloric acid 2L, is heated to 40 DEG C, and solution gradually becomes to clarify, and 40 DEG C anti-
It answers 20 hours.
After completion of the reaction, it is cooled to room temperature, sodium hydrate aqueous solution alkali tune to pH >=12, ethyl acetate aqueous layer extracted 3 times,
Merge organic phase, saturated common salt water washing is concentrated under reduced pressure, and obtaining compound 183g shown in Formula VII, (light yellow solid, quality are received
Rate 54.6%).
Embodiment 15：The synthesis (salt-forming reaction) of compound shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in tetrahydrofuran 2L, and it is 3.6 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls it
Reaction temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Filtering obtains compound 210g (mass yield 89.4%) shown in Formulas I.
Embodiment 16：The synthesis (salt-forming reaction) of structural compounds shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in methanol 2L, and it is 3.1 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls its reaction
Temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Obtain compound 198g (mass yield 84.3%) shown in Formulas I.
Embodiment 17：The synthesis (salt-forming reaction) of compound shown in Formula VIII
Reaction equation：
Compound 235g shown in Formula VII is dissolved in methylfuran 2L, and it is 3.7 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls it
Reaction temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Filtering obtains compound 180g (mass yield 76.6%) shown in Formulas I.
Embodiment 18：The synthesis (salt-forming reaction) of compound shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in acetonitrile 2L, and it is 3.3 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls its reaction
Temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Filtering obtains compound 151g (mass yield 64.3%) shown in Formulas I.
Embodiment 19：The synthesis (salt-forming reaction) of compound shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in tetrahydrofuran 2L, and it is 3.6 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls it
Reaction temperature is 40 DEG C.40 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Filtering obtains compound 211g (mass yield 89.7%) shown in Formulas I.
Embodiment 20：The synthesis (salt-forming reaction) of compound shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in tetrahydrofuran 2L, and it is 6 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, and it is anti-to control it
Answering temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is added dropwise in filtrate
Isopropyl ether, room temperature crystallization 2 hours.Filtering obtains compound 186g (mass yield 79.1%) shown in Formulas I.
Embodiment 21：The synthesis (salt-forming reaction) of compound shown in Formulas I
Reaction equation：
Compound 235g shown in Formula VII is dissolved in tetrahydrofuran 2L, and it is 3.4 that concentrated hydrochloric acid, which is added dropwise, and adjusts its pH value, controls it
Reaction temperature is 10 DEG C.25 DEG C are stirred 4 hours, filtering, and filter cake vacuum drying obtains off-white powder epinastine hydrochloride crude product.
Epinastine hydrochloride crude product is dissolved in methanol, active carbon is added, is heated to reflux 1 hour, is filtered, is dripped in filtrate
Add t-butyl methyl ether, room temperature crystallization 2 hours.Filtering obtains compound 166g (mass yield 70.6%) shown in Formulas I.
Embodiment 22：The detection of compound shown in the Formulas I that the present invention synthesizes
Using high performance liquid chromatography, compound (epinastine hydrochloride) shown in the Formulas I to synthesis of the embodiment of the present invention is carried out
Detection, and commercial standard is taken to carry out detection as control map using same chromatographic condition, detection uses European Pharmacopoeia hydrochloric acid
Method provided by epinastine bulk pharmaceutical chemicals.Wherein, the testing result of compound shown in the Formulas I synthesized to the embodiment of the present invention 15
As shown in Figure 1, control map is as shown in Figure 2.
Show the test map of compound shown in the Formulas I of the synthesis of the embodiment of the present invention 15 by the testing result of Fig. 1 and Fig. 2
With control map in the appearance time of epinastine hydrochloride it is consistent, thus prove the embodiment of the present invention successfully synthesized hydrochloric acid according to
Sting, and be not detected in standard items and contain in the detection process of the compound shown in the Formulas I synthesized to the embodiment of the present invention
Impurity.The testing result of compound shown in the Formulas I of other embodiments synthesis of the present invention is similarly, it was demonstrated that provided by the invention
Method can successfully synthesize qualified epinastine hydrochloride.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (12)
1. a kind of synthetic method of epinastine hydrochloride, which is characterized in that this method includes：
1) willDecarboxylic reaction occurs with alkali, to obtain
2) willWithSubstitution reaction occurs, to obtain
Compound shown in formula III is dissolved in acetone, the anhydrous propanone solution containing compound shown in formula IV, reaction analysis is slowly added dropwise
Faint yellow solid out uses acetone washing, obtains compound shown in Formula V after filtering；
3) makeCyclization reaction occurs, to obtain
4) makeHydrolysis occurs, to obtain
In step 4), the reaction temperature of hydrolysis is 40~100 DEG C, after completion of the reaction, is cooled to room temperature, sodium hydroxide water
Solution is adjusted to PH >=12, and extracting and washing is concentrated under reduced pressure, and obtains formula VII；
5) makeSalt-forming reaction occurs, to obtain
2. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that step 1)~4) at least
One step carries out in organic solvent；
In step 1), the alkali used is monoacidic base.
3. the synthetic method of epinastine hydrochloride according to claim 2, which is characterized in that if step 1) is in organic solvent
Middle progress, the organic solvent used is at least one of the ether of C atomicity 1~6, halogenated hydrocarbons；
If step 2) carries out in organic solvent, the organic solvent used is acetone；
If step 3) carries out in organic solvent, the organic solvent used is n,N-Dimethylformamide, N, N- dimethylacetamide
At least one of amine；
If step 4) carries out in organic solvent, the organic solvent used is the monohydric alcohol of C atomicity 1~6, tetrahydrofuran, first
At least one of base furans and acetonitrile.
4. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that in step 2), taken
Reaction temperature -30~10 DEG C of generation reaction.
5. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that in step 2), formula III institute
The molar ratio for showing compound shown in compound and formula IV is 1：0.9~3.
6. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that in step 3), the ring
Occur under the conditions of reaction is closed existing for the condensing agent or/and acid binding agent.
7. the synthetic method of epinastine hydrochloride according to claim 6, which is characterized in that the condensing agent is iodo 2-
Chloro- 1- picoline；
The acid binding agent is at least one of triethylamine, pyridine, methylamine, dimethylamine, positive di-n-propylamine.
8. the synthetic method of epinastine hydrochloride according to claim 6, which is characterized in that in step 3), shown in Formula V
The molar ratio of compound and condensing agent is 1：0.9~2；
The molar ratio 1 of compound and acid binding agent shown in Formula V：2~6.
9. the synthetic method of epinastine hydrochloride according to claim 6, which is characterized in that in step 3), cyclization is anti-
10~40 DEG C of the reaction temperature answered.
10. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that anti-at salt in step 5)
It should occur under the conditions of pH value is 0~6；
The reaction temperature of the salt-forming reaction is 0~40 DEG C.
11. the synthetic method of epinastine hydrochloride described according to claim 1~any one of 10, which is characterized in that in step
It is rapid 1)~5) in either step in, further include utilize：Filter, centrifugation, washing, recrystallization, filtering, drying, stirring in extremely
A kind of few carry out purification process.
12. the synthetic method of epinastine hydrochloride according to claim 11 again, which is characterized in that in step 5), tie
Recrystallisation solvent used in crystalline substance is at least one of the monohydric alcohol of C atomicity 1~6, ether.
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| CN201510641046.6A CN105153169B (en) | 2014-11-27 | 2015-09-29 | A kind of synthetic method of epinastine hydrochloride |
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| CN108341821B (en) * | 2018-04-10 | 2020-10-27 | 千辉药业（安徽）有限责任公司 | Synthesis method of epinastine hydrochloride |
| CN111423442B (en) * | 2020-04-03 | 2022-09-27 | 重庆美莱德生物医药有限公司 | Epinastine hydrochloride intermediate and synthesis method thereof |
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| US5312916A (en) * | 1991-01-25 | 1994-05-17 | Boehringer Ingelheim Kg | Process for preparing 3-amino-9,13b-dihydro-1H-dibenz(c,f)imidazo(1,5-a)azepine-hydrochloride |
| CN101036659A (en) * | 2006-03-13 | 2007-09-19 | 张文静 | A group of epinastine hydrochloride agent and the method for preparing the same |
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| WO2009063504A2 (en) * | 2007-09-24 | 2009-05-22 | Usv Limited | Novel crystal modification of epinastine or salts thereof and process for preparation thereof |
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| US5312916A (en) * | 1991-01-25 | 1994-05-17 | Boehringer Ingelheim Kg | Process for preparing 3-amino-9,13b-dihydro-1H-dibenz(c,f)imidazo(1,5-a)azepine-hydrochloride |
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