CN105153169A - Synthesis method for epinastine hydrochloride - Google Patents
Synthesis method for epinastine hydrochloride Download PDFInfo
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Abstract
The invention discloses a synthesis method for epinastine hydrochloride. With a compound (6-aminomethyl-6,11-dihydro-5H-dibenzo [b, e] azepine maleate), shown in the formula II, being the initial raw material, epinastine hydrochloride is synthesized. By the utilization of the synthesis method for epinastine hydrochloride, epinsastine hydrochloride can be effectively synthesized, and the method has the advantages of being high in synthesis efficiency, safe in production, simple in technology operation, short in production period and the like and is more suitable for large-scale and industrialized production of epinastine hydrochloride.
Description
Technical field
The present invention relates to medical art, especially relate to a kind of synthetic method of Epinastine Hydrochloride.
Background technology
Amino-9,13-dihydro-1H-dibenzo [c, f]-imidazo [1,5-a] the azacyclonol hydrochloride salt of Epinastine Hydrochloride English epinastinehydrochloride by name, chemistry 3-by name, its structural formula is as follows:
Epinastine Hydrochloride is used for the treatment of bronchial asthma, allergic dermatitis, urticaria, eczema, dermatitis and Psoriasis vulgaris (psoriasis), for the bronchoconstriction caused by histamine and bradykinin, there is very strong suppression to use, then not having restraining effect to the bronchoconstriction caused by other chemical mediators, is that most useful effect is in one of perineural histamine H 1 receptor antagonist without sedative effect.D-epinastine, L-epinastine and racemization epinastine no significant difference in pharmacologically active.Epinastine Hydrochloride is developed by German Boehringer Ingelheim company, with the Japan three further joint development market of pharmacy cooperation altogether, within 1994, in Japanese Initial Public Offering, China's approval epinastine hydrochloride tablets import in 2000, commodity are called: Alesion (WAL-801).
At present, the synthetic method of Epinastine Hydrochloride mainly contains:
As Chinese patent CN101130544 reports a kind of method of synthesizing epinastine, the method is with 6-chloromethyl-6,11-dihydro-dibenzo [b, e] azatropylidene is starting material, direct and ammonia gas react synthesizes 6-aminomethyl-11-hydrogen-dibenzo [b, e] azatropylidene, and then synthesize epinastine with sodium borohydride reduction, cyanogen bromide cyclization, its operational path is as follows:
This route have employed highly toxic substance cyanogen bromide in the reaction, it is namely dead that its concentration contacts 30 minutes under reaching 120mg/m3 condition, therefore aforesaid method synthetic hydrochloric acid epinastine is adopted not only to need to prevent cyanogen bromide from leaking in building-up process, threaten operator safety, and cannot ensure that cyanogen bromide can not remain in obtained Epinastine Hydrochloride, affect drug safety.Chinese patent CN105172658 recently discloses the method for another kind of synthesis epinastine, and with 6-aminomethyl-6,11-dihydro-5H-dibenzo [b, e] azatropylidene synthesizes epinastine, and this operational path is as follows:
This route synthesis difficulty is large, and synthesis required time is 7 days, and the reaction times is extremely long, is unfavorable for suitability for industrialized production.Another kind method Chinese patent CN103012408, with 2-aminobenzophenone for raw material is by being obtained by reacting 2-benzylaniline with silane reagent, N-(2-benzyl phenyl)-2-chlor(o)acetamide is obtained through acylation reaction again with 2-chloroacetyl chloride, under the effect of dewatering agent, dehydration of amide cyclization obtains 6-(chloromethyl)-11H-dibenzo [b again, e] azatropylidene, 6-(azido-methyl)-11H-dibenzo [b is obtained through azido reaction, e] azatropylidene, 6-(amino methyl)-6 is obtained again through reduction, 11-dihydro-1H-dibenzo [b, e] azatropylidene, finally generate epinastine with cyanogen bromide cyclization again, this operational path is as follows:
This route can adopt triazo-compound to carry out azido reaction in the reaction, and its compound stability is bad, very easily explodes, due to a large amount of use in suitability for industrialized production, dangerous high; Secondly can adopt highly toxic substance cyanogen bromide in the reaction, threaten operator safety, and cannot ensure that cyanogen bromide can not remain in obtained Epinastine Hydrochloride.
Therefore, the synthetic method of current Epinastine Hydrochloride is further improved.
Summary of the invention
For solving the problems of the technologies described above, the invention discloses a kind of synthetic method of Epinastine Hydrochloride.
The invention discloses a kind of synthetic method of Epinastine Hydrochloride, the method comprises:
1) will
with alkali generation decarboxylic reaction, to obtain
2) will
with
there is substitution reaction, to obtain
3) make
there is ring-closure reaction, to obtain
4) make
there is hydrolysis reaction, to obtain
And
5) make
there is salt-forming reaction, to obtain
Preferably, step 1) ~ 4) at least one step carry out in organic solvent;
In step 1) in, the alkali of employing is monoatomic base.
Preferably, if step 1) carry out in organic solvent, the organic solvent of employing is at least one in the ether of C atomicity 1 ~ 6, halohydrocarbon;
If step 2) carry out in organic solvent, the organic solvent of employing is at least one in the ketone of C atomicity 1 ~ 6, halohydrocarbon;
If step 3) carry out in organic solvent, the organic solvent of employing is at least one in DMF, N,N-dimethylacetamide;
If step 4) carry out in organic solvent, the organic solvent of employing is at least one in the monohydroxy-alcohol of C atomicity 1 ~ 6, tetrahydrofuran (THF), methyl furan and acetonitrile.
Preferably, in step 2) in, carry out the temperature of reaction-30 ~ 10 DEG C of substitution reaction.
Preferably, in step 2) in, the mol ratio of compound shown in compound and formula IV shown in formula III is 1:0.9 ~ 3.
Preferably, in step 3) in, described ring-closure reaction at condensing agent or/and occur under acid binding agent existent condition.
Preferably, described condensing agent is the chloro-1-picoline of iodo 2-;
Described acid binding agent is at least one in triethylamine, pyridine, methylamine, dimethylamine, positive dipropyl amine.
Preferably, in step 3) in, the mol ratio of compound shown in formula V and condensing agent is 1:0.9 ~ 2;
Mol ratio 1:2 ~ 6 of compound shown in formula V and acid binding agent.
Preferably, in step 3) in, the temperature of reaction of ring-closure reaction 10 ~ 40 DEG C.
Preferably, in step 4) in, the temperature of reaction of hydrolysis reaction is 40 ~ 100 DEG C.
Preferably, in step 5) in, salt-forming reaction occurs under pH value is 0 ~ 6 condition;
The temperature of reaction of described salt-forming reaction is 0 ~ 40 DEG C.
Preferably, in step 1) ~ 5) in arbitrary step in, also comprise utilization: at least one in suction filtration, centrifugal, washing, recrystallization, filtration, oven dry, stirring carries out purification process.
Preferably, in step 5) in, recrystallization recrystallisation solvent used is at least one in the monohydroxy-alcohol of C atomicity 1 ~ 6, ether.
According to the synthetic method of Epinastine Hydrochloride of the present invention, beneficial effect at least as described below can be obtained:
1, according to the synthetic method of Epinastine Hydrochloride of the present invention; whole building-up process does not use the cyanogen bromide that toxicity is strong; reduce toxicity; be conducive to environment protection; and the Epinastine Hydrochloride of synthesis is not owing to having the residual of cyanogen bromide; improve Drug safety, thus be easy to industrialization scale operation.In addition, also do not adopt triazo-compound during synthesis, effectively can prevent blast, security is high, can not threaten operator safety, thus is conducive to safety in production.
2, according to the synthetic method of Epinastine Hydrochloride of the present invention, reaction conditions is gentle, and without the need to the equipment of special reaction, the scope of application is more extensive.
3, according to the synthetic method of Epinastine Hydrochloride of the present invention, raw materials used and reagent is easily buied from market, thus is conducive to reducing production cost.
4, according to the synthetic method of Epinastine Hydrochloride of the present invention, technological operation is simple, and synthesis cycle is short, thus is more suitable for extensive, suitability for industrialized production and carrys out Epinastine Hydrochloride.
5, according to the synthetic method of Epinastine Hydrochloride of the present invention, not only combined coefficient is high, and the purity of synthesized Epinastine Hydrochloride is also very high, meets medicine quality requirement completely.
6, according to the synthetic method of Epinastine Hydrochloride of the present invention, synthesized Epinastine Hydrochloride may be used for treatment bronchial asthma, allergic dermatitis, urticaria, eczema, dermatitis and Psoriasis vulgaris etc., thus makes the synthetic method of Epinastine Hydrochloride of the present invention have huge medical use value and market popularization value.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become more obvious from the following description, or be recognized by practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or additional aspect of the present invention and advantage will become obvious and easy understand from accompanying drawing below combining to the description of embodiment, wherein:
Fig. 1 is the high-efficient liquid phase chromatogram of the Epinastine Hydrochloride utilized synthesized by the present invention;
Fig. 2 is the high-efficient liquid phase chromatogram of Epinastine Hydrochloride standard substance.
Embodiment
Below by specific embodiment, and by reference to the accompanying drawings the present invention is described in further detail.It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Embodiment is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to herein or known method synthesis, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
General method:
With reference to following formula, in the examples below that, the method for synthetic hydrochloric acid epinastine mainly comprises the following steps:
1) by compound shown in formula II (6-aminomethyl-6,11-dihydro-5H-dibenzo [b, e] azatropylidene maleate) and alkali generation decarboxylic reaction, to obtain compound shown in formula III;
2) by the substitution reaction of compound generation shown in compound and formula IV shown in formula III, to obtain compound shown in formula V;
3) generation of compound shown in formula V ring-closure reaction is made, to obtain compound shown in formula VI;
4) compound hydro lyses shown in formula VI is made to react, to obtain compound shown in formula VII; And
5) generation of compound shown in formula VII salt-forming reaction is made, to obtain compound shown in formula I,
Embodiment 1: the synthesis of compound shown in formula III
Reaction equation is as follows:
In 20L reactor, compound shown in throw-in type II (6-aminomethyl-6,11-dihydro-5H-dibenzo [b, e] azatropylidene maleate) 1Kg, t-butyl methyl ether 6L, 30% aqueous sodium hydroxide solution 8L, stirring at room temperature 2 hours, after completion of the reaction, stratification, gets organic phase, dried over sodium sulfate, concentrating under reduced pressure after filtering, obtains compound 650g (mass yield 65%) shown in formula III.
Embodiment 2: the synthesis of compound shown in formula III
Reaction equation is as follows:
In 20L reactor, compound 1Kg shown in throw-in type II, methylene dichloride 6L, 30% aqueous sodium hydroxide solution 8L, stirring at room temperature 2 hours, after completion of the reaction, stratification, gets organic phase, dried over sodium sulfate, concentrating under reduced pressure after filtering, obtains compound 570g (mass yield 57%) shown in formula III.
Embodiment 3: the synthesis (substitution reaction) of compound shown in formula V
Reaction equation is as follows:
The 650g of compound shown in formula III is dissolved in acetone 1.5L, slow dropping contains the anhydrous propanone solution of the 575g of compound shown in formula IV, stir 3 hours at 0 DEG C, separate out a large amount of faint yellow solid, filtration under diminished pressure, filter cake washing with acetone, vacuum-drying, compound 292g shown in acquisition formula V (light yellow solid, mass yield 45%).
Embodiment 4: the synthesis (substitution reaction) of compound shown in formula V
Reaction equation is as follows:
The 630g of compound shown in formula III is dissolved in methylene dichloride 1.5L, slow dropping contains the dichloromethane solution of the 555g of compound shown in formula IV, stir 3 hours at 0 DEG C, separate out a large amount of faint yellow solid, filtration under diminished pressure, filter cake washing with acetone, vacuum-drying, compound 202g shown in acquisition formula V (light yellow solid, mass yield 32%).
Embodiment 5: the synthesis (substitution reaction) of compound shown in formula V
Reaction equation:
The 650g of compound shown in formula III is dissolved in acetone 1.5L, slow dropping contains the acetone soln of the 1150g of compound shown in formula IV, stir 3 hours at 0 DEG C, separate out a large amount of faint yellow solid, filtration under diminished pressure, filter cake washing with acetone, vacuum-drying, compound 242g shown in acquisition formula V (light yellow solid, mass yield 37%).
Embodiment 6: the synthesis (substitution reaction) of compound shown in formula V
Reaction equation:
The 650g of compound shown in formula III is dissolved in acetone 1.5L, slow dropping contains the acetone soln of the 575g of compound shown in formula IV, stir 3 hours at-30 DEG C, separate out a large amount of faint yellow solid, filtration under diminished pressure, filter cake washing with acetone, vacuum-drying, compound 282g shown in acquisition formula V (light yellow solid, mass yield 43%).
Embodiment 7: the synthesis (ring-closure reaction) of structural compounds shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in DMF 1.8L, drips triethylamine 352g in 25 DEG C, 25 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 337g (light yellow solid, mass yield 75%) shown in formula VI.
Embodiment 8: the synthesis (ring-closure reaction) of structural compounds shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in N,N-dimethylacetamide 1.8L, drips triethylamine 352g in 25 DEG C, 25 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 310g (light yellow solid, mass yield 69%) shown in formula VI.
Embodiment 9: the synthesis (ring-closure reaction) of structural compounds shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in DMF 1.8L, drips triethylamine 352g in 25 DEG C, 40 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 320g (light yellow solid, mass yield 71.1%) shown in formula VI.
Embodiment 10: the synthesis (ring-closure reaction) of compound shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in DMF 1.8L, drips triethylamine 700g in 25 DEG C, 25 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 300g (light yellow solid, mass yield 66.7%) shown in formula VI.
Embodiment 11: the synthesis (ring-closure reaction) of compound shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in DMF 1.8L, drips methylamine 64g in 25 DEG C, 25 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 260g (light yellow solid, mass yield 57.8%) shown in formula VI.
Embodiment 12: the synthesis (ring-closure reaction) of compound shown in formula VI
Reaction equation:
The 450g of compound shown in formula V and condensing agent iodo 2-chloro-1-picoline 356g is dissolved in DMF 1.8L, drips pyridine 352g in 25 DEG C, 25 DEG C are reacted 10 hours, after completion of the reaction, add water under room temperature, separate out light yellow solid, centrifugal, then add water.Pull an oar 5 hours.Filter, filtration cakes torrefaction, obtain compound 283g (light yellow solid, mass yield 62.9%) shown in formula VI.
Embodiment 13: the synthesis (hydrolysis reaction) of structural compounds shown in formula VII
Reaction equation:
The 335g of compound shown in formula VI is suspended in concentrated hydrochloric acid, and be slowly heated to 100 DEG C, solution becomes clarification gradually, and 100 DEG C are reacted 2 hours, and TLC monitors reaction process.
After completion of the reaction, be cooled to room temperature, aqueous sodium hydroxide solution alkali tune is to pH >=12, extraction into ethyl acetate water layer 3 times, merges organic phase, saturated common salt water washing, concentrating under reduced pressure, obtains compound 235g (light yellow solid, mass yield 70.1%) shown in formula VII.
Embodiment 14: the synthesis (hydrolysis reaction) of compound shown in formula VII
Reaction equation:
The 335g of compound shown in formula VI is suspended in concentrated hydrochloric acid 2L, and be heated to 40 DEG C, solution becomes clarification gradually, and 40 DEG C are reacted 20 hours.
After completion of the reaction, be cooled to room temperature, aqueous sodium hydroxide solution alkali tune is to pH >=12, extraction into ethyl acetate water layer 3 times, merges organic phase, saturated common salt water washing, concentrating under reduced pressure, obtains compound 183g (light yellow solid, mass yield 54.6%) shown in formula VII.
Embodiment 15: the synthesis (salt-forming reaction) of compound shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in tetrahydrofuran (THF) 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.6, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 210g (mass yield 89.4%) shown in formula I.
Embodiment 16: the synthesis (salt-forming reaction) of structural compounds shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in methyl alcohol 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.1, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Obtain compound 198g (mass yield 84.3%) shown in formula I.
Embodiment 17: the synthesis (salt-forming reaction) of compound shown in formula VIII
Reaction equation:
The 235g of compound shown in formula VII is dissolved in methyl furan 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.7, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 180g (mass yield 76.6%) shown in formula I.
Embodiment 18: the synthesis (salt-forming reaction) of compound shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in acetonitrile 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.3, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 151g (mass yield 64.3%) shown in formula I.
Embodiment 19: the synthesis (salt-forming reaction) of compound shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in tetrahydrofuran (THF) 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.6, controlling its temperature of reaction is 40 DEG C.40 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 211g (mass yield 89.7%) shown in formula I.
Embodiment 20: the synthesis (salt-forming reaction) of compound shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in tetrahydrofuran (THF) 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 6, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip isopropyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 186g (mass yield 79.1%) shown in formula I.
Embodiment 21: the synthesis (salt-forming reaction) of compound shown in formula I
Reaction equation:
The 235g of compound shown in formula VII is dissolved in tetrahydrofuran (THF) 2L, and drip concentrated hydrochloric acid and regulate its pH value to be 3.4, controlling its temperature of reaction is 10 DEG C.25 DEG C are stirred 4 hours, and filter, filter cake vacuum-drying, obtains off-white color solid Epinastine Hydrochloride crude product.
Epinastine Hydrochloride crude product is dissolved in methyl alcohol, adds gac, reflux 1 hour, filter, drip t-butyl methyl ether in filtrate, room temperature crystallization 2 hours.Filter, obtain compound 166g (mass yield 70.6%) shown in formula I.
Embodiment 22: the detection of compound shown in the formula I of the present invention's synthesis
Adopt high performance liquid chromatography, shown in the formula I synthesize the embodiment of the present invention, compound (Epinastine Hydrochloride) detects, and get commercial standard and carry out detecting collection of illustrative plates in contrast with same chromatographic condition, detect the method adopting European Pharmacopoeia Epinastine Hydrochloride bulk drug to provide.Wherein, as shown in Figure 1, contrast collection of illustrative plates as shown in Figure 2 for the detected result of compound shown in the formula I synthesize the embodiment of the present invention 15.
Shown by the detected result of Fig. 1 and Fig. 2, the detection collection of illustrative plates of compound shown in the formula I that the embodiment of the present invention 15 is synthesized is consistent with the appearance time of Epinastine Hydrochloride in contrast collection of illustrative plates, thus prove that the embodiment of the present invention has successfully synthesized Epinastine Hydrochloride, and the impurity contained in standard substance do not detected in the testing process of compound shown in the formula I that the embodiment of the present invention is synthesized.Shown in the formula I of other embodiment of the present invention synthesis, the detected result of compound similarly, proves that method provided by the invention can successfully synthesize qualified Epinastine Hydrochloride.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (13)
1. a synthetic method for Epinastine Hydrochloride, is characterized in that, the method comprises:
1) will
with alkali generation decarboxylic reaction, to obtain
2) will
with
there is substitution reaction, to obtain
3) make
there is ring-closure reaction, to obtain
4) make
there is hydrolysis reaction, to obtain
And
5) make
there is salt-forming reaction, to obtain
2. the synthetic method of Epinastine Hydrochloride according to claim 1, is characterized in that, step 1) ~ 4) at least one step carry out in organic solvent;
In step 1) in, the alkali of employing is monoatomic base.
3. the synthetic method of Epinastine Hydrochloride according to claim 2, is characterized in that, if step 1) carry out in organic solvent, the organic solvent of employing is at least one in the ether of C atomicity 1 ~ 6, halohydrocarbon;
If step 2) carry out in organic solvent, the organic solvent of employing is at least one in the ketone of C atomicity 1 ~ 6, halohydrocarbon;
If step 3) carry out in organic solvent, the organic solvent of employing is at least one in DMF, N,N-dimethylacetamide;
If step 4) carry out in organic solvent, the organic solvent of employing is at least one in the monohydroxy-alcohol of C atomicity 1 ~ 6, tetrahydrofuran (THF), methyl furan and acetonitrile.
4. the synthetic method of Epinastine Hydrochloride according to claim 1, is characterized in that, in step 2) in, carry out the temperature of reaction-30 ~ 10 DEG C of substitution reaction.
5. the synthetic method of Epinastine Hydrochloride according to claim 1, is characterized in that, in step 2) in, the mol ratio of compound shown in compound and formula IV shown in formula III is 1:0.9 ~ 3.
6. the synthetic method of Epinastine Hydrochloride according to claim 1, is characterized in that, in step 3) in, described ring-closure reaction at condensing agent or/and occur under acid binding agent existent condition.
7. the synthetic method of Epinastine Hydrochloride according to claim 6, is characterized in that, described condensing agent is the chloro-1-picoline of iodo 2-;
Described acid binding agent is at least one in triethylamine, pyridine, methylamine, dimethylamine, positive dipropyl amine.
8. the synthetic method of Epinastine Hydrochloride according to claim 6, is characterized in that, in step 3) in, the mol ratio of compound shown in formula V and condensing agent is 1:0.9 ~ 2;
Mol ratio 1:2 ~ 6 of compound shown in formula V and acid binding agent.
9. the synthetic method of Epinastine Hydrochloride according to claim 6, is characterized in that, in step 3) in, the temperature of reaction of ring-closure reaction 10 ~ 40 DEG C.
10. the synthetic method of Epinastine Hydrochloride according to claim 1, is characterized in that, in step 4) in, the temperature of reaction of hydrolysis reaction is 40 ~ 100 DEG C.
The synthetic method of 11. Epinastine Hydrochloride according to claim 1, is characterized in that, in step 5) in, salt-forming reaction occurs under pH value is 0 ~ 6 condition;
The temperature of reaction of described salt-forming reaction is 0 ~ 40 DEG C.
The synthetic method of 12. Epinastine Hydrochloride according to any one of claim 1 ~ 11, it is characterized in that, in step 1) ~ 5) in arbitrary step in, also comprise utilization: at least one in suction filtration, centrifugal, washing, recrystallization, filtration, oven dry, stirring carries out purification process.
The synthetic method of 13. Epinastine Hydrochloride according to claim 12, is characterized in that, in step 5) in, recrystallization recrystallisation solvent used is at least one in the monohydroxy-alcohol of C atomicity 1 ~ 6, ether.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108341821A (en) * | 2018-04-10 | 2018-07-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of epinastine hydrochloride |
| WO2019117592A1 (en) * | 2017-12-12 | 2019-06-20 | (주)프론트바이오 | Compound of n-(9,13b-dihydro-1h-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-hydroxybenzamide and 2-((9,13b-dihydro-1h-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl) carbamoyl)phenyl acetate, preparation method therefor, and anti-inflammatory and analgesic agent containing same |
| CN115504985A (en) * | 2020-04-03 | 2022-12-23 | 重庆美莱德生物医药有限公司 | Synthesis method of epinastine hydrochloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019117592A1 (en) * | 2017-12-12 | 2019-06-20 | (주)프론트바이오 | Compound of n-(9,13b-dihydro-1h-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-hydroxybenzamide and 2-((9,13b-dihydro-1h-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl) carbamoyl)phenyl acetate, preparation method therefor, and anti-inflammatory and analgesic agent containing same |
| CN108341821A (en) * | 2018-04-10 | 2018-07-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of epinastine hydrochloride |
| CN108341821B (en) * | 2018-04-10 | 2020-10-27 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of epilastine hydrochloride |
| CN115504985A (en) * | 2020-04-03 | 2022-12-23 | 重庆美莱德生物医药有限公司 | Synthesis method of epinastine hydrochloride |
| CN115504985B (en) * | 2020-04-03 | 2024-01-19 | 重庆美莱德生物医药有限公司 | Synthesis method of epinastine hydrochloride |
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Inventor after: Li Xiaoyi Inventor after: Dai Xiangrong Inventor after: Ren Jian Inventor before: Li Xiaoyi Inventor before: Zuo Congju Inventor before: Dai Xiangrong Inventor before: Xia Liang Inventor before: Chi Quan de Inventor before: Ren Jian |