CN108997349A - A kind of preparation method of the epinastine in relation to substance - Google Patents
A kind of preparation method of the epinastine in relation to substance Download PDFInfo
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- CN108997349A CN108997349A CN201810636995.9A CN201810636995A CN108997349A CN 108997349 A CN108997349 A CN 108997349A CN 201810636995 A CN201810636995 A CN 201810636995A CN 108997349 A CN108997349 A CN 108997349A
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- epinastine
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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
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Abstract
A kind of preparation method the invention discloses epinastine in relation to substance, is related to pharmaceutical technology field.Preparation method of the present invention includes using epinastine as raw material, and addition oxidant, catalyst and reaction system stirring solvent are uniform, after reaction successively added with solvent extraction, washing, dry, decompression suction filtration recycling organic solvent.The present invention obtains purity up to 97% epinastine impurity A by oxidation preparation and separating-purifying step, and this method preparation process is simple, at low cost, high income.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more particularly to a kind of 3- amino -9H- hexichol [c, f] imidazo [1,5-a]
AzepineThe preparation method of (epinastine impurity A).
Background technique
Epinastine hydrochloride (3- amino -9,13b- dihydro -1H- hexichol [c, f] imidazo [1,5-a] azepineHydrochloride,
Formula 1) be histamine H 1 receptor antagonist, have inhibiting effect to histamine, leukotriene C, PAF, serotonin, moreover it is possible to inhibit histamine,
The release of slow reacting substance A (SRS-A) chemical mediator, can be clinically used for allergic rhinitis, nettle rash, eczema, dermatitis, skin scabies
Itch disease, pruigo, with itch psoriasis vulgaris and allergic bronchial asthma prevention and treatment.Common adverse reaction had
Quick, drowsiness, gastrointestinal symptom and dysfunction of liver.
The standard of 8.7 editions epinastine hydrochlorides included of European Pharmacopoeia includes two known impurities: impurity A (3- amino-
9H- hexichol [c, f] imidazo [1,5-a] azepine, formula 2) and impurity B (bromo- 9, the 13b- dihydro -1H- of 13bRS-3- amino -7-
Hexichol [c, f] imidazo [1,5-a] azepine, formula 3).Find that the content of impurity A can be with keeping sample in epinastine stability experiment
Time extend and increase, to ensure that drug quality is controllable, it is necessary to detect, control it is miscellaneous in epinastine hydrochloride bulk pharmaceutical chemicals and preparation
The content of matter A meets drug and declares and clinical requirement.
Chinese application publication number CN106749281A discloses a kind of 3- amino -9H- hexichol [c, f] imidazo [1,5-a]
AzepineThe preparation method of (epinastine impurity A)；10-30% hydrogen peroxide oxidation is used first, and heating reaction 8-28h extracts repeatedly
The lower epinastine solution of purity is obtained, then obtains epinastine impurity through chromatography；But it is long there are the reaction time, it adopts
With post separation mode, different proportion washing and dehydrating integrated machine is purified by flash to obtain 95% or more product of purity, complex procedures, it is difficult to quantifying
It is standby.
Summary of the invention
A kind of preparation method the purpose of the present invention is to provide epinastine in relation to substance is prepared and is separated by oxidation
Purification step obtains purity up to 97% epinastine impurity A, and this method preparation process is simple, and at low cost, high income is prepared into
To epinastine impurity A can be used as the impurity A reference substance of epinastine hydrochloride related substance detection and use.
In order to solve the above technical problems, the present invention is achieved by the following technical solutions:
The present invention is a kind of preparation method of epinastine in relation to substance, including using epinastine as raw material, and oxidation is added
Agent reacts to form epinastine impurity A；Its reaction route are as follows:
A kind of preparation method of the epinastine in relation to substance, including using epinastine as raw material, oxidant, catalyst is added
It is uniform with reaction system stirring solvent, successively have after reaction added with solvent extraction, washing, dry, decompression suction filtration recycling
Solvent.
Further, the oxidant is selected in ammonium ceric nitrate, manganese dioxide, divalent copper ion compound and ferric trichloride
It is one or more.
Further, the divalent copper ion compound includes copper chloride, copper nitrate and copper bromide.
Further, the catalyst selects one of palladium charcoal, bismuth nitrate, DBU and acid medium.
Further, the acid medium includes aqueous hydrochloric acid solution, acetic acid solution.
Further, the reaction system solvent uses dimethyl sulfoxide (DMSO) or n,N-Dimethylformamide (DMF).
Further, when the oxidant selects ammonium ceric nitrate or manganese dioxide, the catalyst selects palladium charcoal or nitre
Sour bismuth；When the oxidant selects divalent copper ion compound, the catalyst selects DBU；When the oxidant selects trichlorine
When changing iron, the catalyst selects acid medium.
Further, the organic solvent includes ethyl acetate and carbon tetrachloride and carbon tetrachloride.
The invention has the following advantages:
The present invention obtains purity up to 97% epinastine impurity A, this method by oxidation preparation and separating-purifying step
Preparation process is simple, at low cost, high income, and the epinastine impurity A being prepared can be used as the related substance of epinastine hydrochloride
The impurity A reference substance of detection uses, for the application of the quality of epinastine hydrochloride and its related preparations control, control hydrochloric acid according to
The purity of sting bulk pharmaceutical chemicals or its preparation.
Certainly, it implements any of the products of the present invention and does not necessarily require achieving all the advantages described above at the same time.
Detailed description of the invention
Fig. 1 is 1 product mass spectra analysis of spectra of the embodiment of the present invention.
Specific embodiment
Embodiment 1
A kind of preparation method of the epinastine in relation to substance, includes the following steps:
Step 1, take 0.01mol epinastine, 12ml n,N-Dimethylformamide solution, 0.03mol DBU and
0.011mol CuCl2.2H2O mixed room temperature stirs 3 hours；
Step 2, TLC detect the extent of reaction, after reaction, sequentially add 30ml water, 60ml ethyl acetate, point take acetic acid
Methacrylate layer, aqueous layer with ethyl acetate extract 2 times, merge organic layer and with saturated common salt water washing three times；
Step 3, it is dry using anhydrous sodium sulfate, filter, ethyl acetate be recovered under reduced pressure；
Step 4 carries out recrystallization purification using n-hexane-ethyl acetate.
It is above-mentioned through n-hexane-ethyl acetate be recrystallized to give epinastine impurity A be 2.1g, the rate of recovery 85%, and according to
The purity of sting impurity A is 97.2%.
As shown in fig.1, Chemical Formula:C16H13N3Know that mass-to-charge ratio is 247.1；Found [M+H]+Matter lotus
Than being 248.1.
Embodiment 2
A kind of preparation method of the epinastine in relation to substance, includes the following steps:
Step 1 takes 0.01mol epinastine, 10ml dimethyl sulfoxide, 1ml aqueous hydrochloric acid solution and 0.011mol tri-chlorination
Iron mixed room temperature stirs 2 hours；
Step 2, TLC detect the extent of reaction, after reaction, sequentially add 30ml water, 60ml ethyl acetate, point take acetic acid
Methacrylate layer, aqueous layer with ethyl acetate extract 2 times, merge organic layer and with saturated common salt water washing three times；
Step 3, it is dry using anhydrous sodium sulfate, filter, ethyl acetate be recovered under reduced pressure；
Step 4 carries out recrystallization purification using n-hexane-ethyl acetate.
Wherein, it is 10% hydrochloric acid solution that aqueous hydrochloric acid solution, which selects concentration,.
It is above-mentioned through n-hexane-ethyl acetate be recrystallized to give epinastine impurity A be 2.05g, the rate of recovery 82%, and
The purity of epinastine impurity A is 98.5%.
Embodiment 3
Step 1, take 0.01mol epinastine, 20ml n,N-Dimethylformamide solution, 0.05mol DBU and
0.02mol CuCl2.2H2O mixed room temperature stirs 3 hours；
Step 2, TLC detect the extent of reaction, after reaction, sequentially add 40ml water, 80ml ethyl acetate, point take acetic acid
Methacrylate layer, aqueous layer with ethyl acetate extract 4 times, merge organic layer and with saturated common salt water washing three times；
Step 3, it is dry using anhydrous sodium sulfate, filter, ethyl acetate be recovered under reduced pressure；
Step 4 carries out recrystallization purification using n-hexane-ethyl acetate.
It is above-mentioned through n-hexane-ethyl acetate be recrystallized to give epinastine impurity A be 1.9g, the rate of recovery 76.9%, and
The purity of epinastine impurity A is 97.3%.
Embodiment 4
Step 1, take 0.01mol epinastine, 12ml n,N-Dimethylformamide solution, 0.03mol bismuth nitrate and
0.011mol manganese dioxide mixed room temperature stirs 4 hours；
Step 2, TLC detect the extent of reaction, after reaction, sequentially add 30ml water, 60ml ethyl acetate, point take acetic acid
Methacrylate layer, aqueous layer with ethyl acetate extract 3 times, merge organic layer and with saturated common salt water washing three times；
Step 3, it is dry using anhydrous sodium sulfate, filter, ethyl acetate be recovered under reduced pressure；
Step 4 carries out recrystallization purification using n-hexane-ethyl acetate.
It is above-mentioned through n-hexane-ethyl acetate be recrystallized to give epinastine impurity A be 2.15g, the rate of recovery 87%, and
The purity of epinastine impurity A is 98.1%.
Embodiment 5
Step 1, take 0.01mol epinastine, 6ml n,N-Dimethylformamide solution, 0.03mol palladium charcoal and
0.005mol ammonium ceric nitrate mixed room temperature stirs 5 hours；
Step 2, TLC detect the extent of reaction, after reaction, sequentially add 15ml water, 30ml ethyl acetate, point take acetic acid
Methacrylate layer, aqueous layer with ethyl acetate extract 3 times, merge organic layer and with saturated common salt water washing three times；
Step 3, it is dry using anhydrous sodium sulfate, filter, ethyl acetate be recovered under reduced pressure；
Step 4 carries out recrystallization purification using n-hexane-ethyl acetate.
It is above-mentioned through n-hexane-ethyl acetate be recrystallized to give epinastine impurity A be 1.05g, the rate of recovery 43.5%,
And the purity of epinastine impurity A is 97.1%.
In the description of this specification, the description of reference term " one embodiment ", " example ", " specific example " etc. means
Particular features, structures, materials, or characteristics described in conjunction with this embodiment or example are contained at least one implementation of the invention
In example or example.In the present specification, schematic expression of the above terms may not refer to the same embodiment or example.
Moreover, particular features, structures, materials, or characteristics described can be in any one or more of the embodiments or examples to close
Suitable mode combines.
Present invention disclosed above preferred embodiment is only intended to help to illustrate the present invention.There is no detailed for preferred embodiment
All details are described, are not limited the invention to the specific embodiments described.Obviously, according to the content of this specification,
It can make many modifications and variations.These embodiments are chosen and specifically described to this specification, is in order to better explain the present invention
Principle and practical application, so that skilled artisan be enable to better understand and utilize the present invention.The present invention is only
It is limited by claims and its full scope and equivalent.
Claims (9)
1. a kind of preparation method of epinastine in relation to substance, it is characterised in that: using epinastine as raw material, it is anti-that oxidant is added
Epinastine impurity A should be formed；Its reaction route are as follows:
2. preparation method of a kind of epinastine in relation to substance according to claim 1, which is characterized in that including with according to
Sting is raw material, and addition oxidant, catalyst and reaction system stirring solvent are uniform, is successively extracted after reaction added with solvent
It takes, wash, drying, depressurizing suction filtration recycling organic solvent.
3. preparation method of a kind of epinastine in relation to substance according to claim 2, which is characterized in that the oxidant
Select one of ammonium ceric nitrate, manganese dioxide, divalent copper ion compound and ferric trichloride or a variety of.
4. preparation method of a kind of epinastine in relation to substance according to claim 3, which is characterized in that the divalent copper
Ionic compound includes copper chloride, copper nitrate and copper bromide.
5. preparation method of a kind of epinastine in relation to substance according to claim 2, which is characterized in that the catalyst
Select one of palladium charcoal, bismuth nitrate, DBU and acid medium.
6. preparation method of a kind of epinastine in relation to substance according to claim 5, which is characterized in that acid Jie
Matter includes aqueous hydrochloric acid solution, acetic acid solution.
7. preparation method of a kind of epinastine in relation to substance according to claim 2, which is characterized in that the reactant
Series solvent uses dimethyl sulfoxide (DMSO) or n,N-Dimethylformamide (DMF).
8. preparation method of a kind of epinastine in relation to substance according to claim 2, which is characterized in that when the oxidation
When ammonium ceric nitrate or manganese dioxide are selected in agent, the catalyst selects palladium charcoal or bismuth nitrate；When the oxidant select divalent copper from
When sub- compound, the catalyst selects DBU；When the oxidant selects ferric trichloride, the catalyst selects acid be situated between
Matter.
9. preparation method of a kind of epinastine in relation to substance according to claim 2, which is characterized in that described organic molten
Agent includes ethyl acetate and carbon tetrachloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810636995.9A CN108997349B (en) | 2018-06-20 | 2018-06-20 | Preparation method of epinastine related substances |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810636995.9A CN108997349B (en) | 2018-06-20 | 2018-06-20 | Preparation method of epinastine related substances |
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| CN108997349A true CN108997349A (en) | 2018-12-14 |
| CN108997349B CN108997349B (en) | 2021-03-16 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102080239B1 (en) * | 2019-08-06 | 2020-02-21 | 한양대학교 에리카산학협력단 | Novel method of preparing Epinastine |
| CN112661762A (en) * | 2020-12-26 | 2021-04-16 | 广州艾格生物科技有限公司 | Preparation method of epinastine impurity A |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014164704A2 (en) * | 2013-03-11 | 2014-10-09 | The Broad Institute, Inc. | Compounds and compositions for the treatment of cancer |
| CN106749281A (en) * | 2017-01-21 | 2017-05-31 | 重庆药友制药有限责任公司 | A kind of preparation method of epinastine impurity A |
-
2018
- 2018-06-20 CN CN201810636995.9A patent/CN108997349B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014164704A2 (en) * | 2013-03-11 | 2014-10-09 | The Broad Institute, Inc. | Compounds and compositions for the treatment of cancer |
| CN106749281A (en) * | 2017-01-21 | 2017-05-31 | 重庆药友制药有限责任公司 | A kind of preparation method of epinastine impurity A |
Non-Patent Citations (8)
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102080239B1 (en) * | 2019-08-06 | 2020-02-21 | 한양대학교 에리카산학협력단 | Novel method of preparing Epinastine |
| WO2021025442A1 (en) * | 2019-08-06 | 2021-02-11 | 한양대학교 에리카산학협력단 | Novel method for producing epinastine |
| CN114206873A (en) * | 2019-08-06 | 2022-03-18 | 汉阳大学校Erica产学协力团 | Novel preparation method of epinastine |
| CN114206873B (en) * | 2019-08-06 | 2024-03-08 | 汉阳大学校Erica产学协力团 | Preparation method of epinastine |
| CN112661762A (en) * | 2020-12-26 | 2021-04-16 | 广州艾格生物科技有限公司 | Preparation method of epinastine impurity A |
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| CN108997349B (en) | 2021-03-16 |
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