CN115636790A - Synthetic refining process of naphazoline hydrochloride - Google Patents
Synthetic refining process of naphazoline hydrochloride Download PDFInfo
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- CN115636790A CN115636790A CN202211291059.1A CN202211291059A CN115636790A CN 115636790 A CN115636790 A CN 115636790A CN 202211291059 A CN202211291059 A CN 202211291059A CN 115636790 A CN115636790 A CN 115636790A
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- naphazoline
- naphazoline hydrochloride
- hydrochloride
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- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 title claims abstract description 290
- 229960004760 naphazoline hydrochloride Drugs 0.000 title claims abstract description 164
- 238000007670 refining Methods 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 129
- 229960005016 naphazoline Drugs 0.000 claims abstract description 125
- CNIIGCLFLJGOGP-UHFFFAOYSA-N SJ000285664 Natural products C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 claims abstract description 124
- 239000002904 solvent Substances 0.000 claims abstract description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 70
- 238000001914 filtration Methods 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 238000003756 stirring Methods 0.000 claims abstract description 46
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000012043 crude product Substances 0.000 claims abstract description 32
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 26
- OQRMWUNUKVUHQO-UHFFFAOYSA-N 2-naphthalen-1-ylacetonitrile Chemical compound C1=CC=C2C(CC#N)=CC=CC2=C1 OQRMWUNUKVUHQO-UHFFFAOYSA-N 0.000 claims abstract description 24
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 22
- 239000007789 gas Substances 0.000 claims abstract description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 57
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 238000001816 cooling Methods 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- 239000000706 filtrate Substances 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 22
- 235000013162 Cocos nucifera Nutrition 0.000 claims description 18
- 244000060011 Cocos nucifera Species 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 13
- 238000013329 compounding Methods 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 230000001376 precipitating effect Effects 0.000 description 6
- 238000007086 side reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- PRPINYUDVPFIRX-UHFFFAOYSA-N 1-naphthaleneacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=CC2=C1 PRPINYUDVPFIRX-UHFFFAOYSA-N 0.000 description 2
- 239000005971 1-naphthylacetic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 150000002463 imidates Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- 206010028748 Nasal obstruction Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- CAOOISJXWZMLBN-PPHPATTJSA-N htn0d03vrz Chemical compound Cl.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 CAOOISJXWZMLBN-PPHPATTJSA-N 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- -1 imine ester Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the technical field of drug synthesis, and particularly discloses a synthetic refining process of naphazoline hydrochloride, which comprises the following steps: s1, preparing a naphazoline intermediate: adding methanol, 1-naphthylacetonitrile and methyl tert-butyl ether into a reaction kettle, fully stirring, and introducing hydrogen chloride gas to obtain a naphazoline intermediate; s2, preparing naphazoline: adding ethylenediamine, a solvent A and a naphazoline intermediate into a reaction kettle to obtain naphazoline; s3, preparing a naphazoline hydrochloride crude product: adding concentrated hydrochloric acid into the naphazoline obtained in the step S2, decompressing and concentrating, and filtering to obtain a naphazoline hydrochloride crude product; s4, refining naphazoline hydrochloride: dissolving the crude naphazoline hydrochloride into a solvent B, and recrystallizing to obtain naphazoline hydrochloride; the process is simple to operate, low in cost, and high in yield and purity and excellent in quality of the obtained naphazoline hydrochloride.
Description
Technical Field
The application relates to the technical field of drug synthesis, in particular to a synthetic refining process of naphazoline hydrochloride.
Background
Naphazoline hydrochloride (naphazoline hcl), chemical name is 2- (1-naphthylmethyl) -4, 5-dihydro-1H-imidazole hydrochloride, the structural formula is shown below.
The existing naphazoline hydrochloride synthesis method is divided into two types according to the difference of starting materials, the first type method takes 1-naphthylacetic acid as the starting material, and the 1-naphthylacetic acid reacts with ethylenediamine in the presence of hydrochloric acid to obtain naphazoline hydrochloride, the synthesis method can cause incomplete condensation to form a large amount of impurities, and the yield of the naphazoline hydrochloride is low, so that the production cost is greatly increased; in the second method, 1-naphthylacetonitrile is used as a starting material, hydrogen sulfide or a sulfur-containing catalyst (including carbon disulfide, sodium sulfide or thiourea and the like) capable of generating hydrogen sulfide in situ is added in the reaction process of the 1-naphthylacetonitrile and ethylenediamine, and the naphazoline hydrochloride is finally obtained. Therefore, a synthesis and refining process of naphazoline hydrochloride is urgently needed to solve the problems of low yield and purity of the obtained naphazoline hydrochloride in the existing preparation process of naphazoline hydrochloride, so that the naphazoline hydrochloride with excellent quality is obtained, and the naphazoline hydrochloride has a wider application prospect.
Disclosure of Invention
In order to solve the problem that the yield and purity of the obtained naphazoline hydrochloride are low in the existing preparation process of naphazoline hydrochloride, the application provides a synthesis and refining process of naphazoline hydrochloride.
The application provides a synthetic refining process of naphazoline hydrochloride, which adopts the following technical scheme:
a synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding methanol, 1-naphthylacetonitrile and methyl tert-butyl ether into a reaction kettle, fully stirring, introducing hydrogen chloride gas at a certain temperature, cooling, crystallizing, filtering and drying to obtain a naphazoline intermediate;
s2, preparing naphazoline: adding ethylenediamine and a solvent A into a reaction kettle, fully stirring, adding a naphazoline intermediate at a certain temperature, and heating for reacting for a period of time to obtain naphazoline;
s3, preparing a naphazoline hydrochloride crude product: adding concentrated hydrochloric acid into the naphazoline obtained in the step S2, decompressing and concentrating, and filtering to obtain a naphazoline hydrochloride crude product;
s4, refining naphazoline hydrochloride: dissolving the crude naphazoline hydrochloride in the solvent B, heating, filtering while hot, and collecting filtrate; then cooling and crystallizing the filtrate, filtering and washing to obtain naphazoline hydrochloride;
the solvent A is methanol and/or N, N-dimethylformamide; the solvent B is prepared by mixing water, acetone and ethanol according to the mass ratio of (1-2) to (4-6) to (80-90).
By adopting the technical scheme, the process for synthesizing and refining the naphazoline hydrochloride mainly comprises four steps of preparing a naphazoline intermediate, preparing the naphazoline, preparing a crude naphazoline hydrochloride product and refining the naphazoline hydrochloride product, wherein 1-naphthylacetonitrile and methanol generate an imidoester active intermediate under the action of hydrogen chloride, namely the naphazoline intermediate, then the naphazoline intermediate reacts with ethylenediamine to generate the naphazoline, concentrated hydrochloric acid is added, reduced pressure distillation is carried out to obtain the crude naphazoline hydrochloride product, and recrystallization is carried out to obtain the naphazoline hydrochloride product, wherein the specific synthetic route is shown as follows. According to the synthesis and refining process of naphazoline hydrochloride, no catalyst is added, no impurity catalyst is required to be removed, the operation is simple, the production cost is low, the process is suitable for industrial production, and the obtained naphazoline hydrochloride has high purity, high yield and excellent product quality. In addition, the solvent A is methanol and/or N, N-dimethylformamide, and the solvent B is obtained by mixing water, acetone and ethanol according to a certain mass ratio, so that the finally obtained naphazoline hydrochloride is purer.
Preferably, the mass ratio of the methanol to the 1-naphthylacetonitrile to the methyl tert-butyl ether to the hydrogen chloride in the step S1 is (6-8) to 10 (2-3) to (1-4).
By adopting the technical scheme, the mass ratio of the methanol, the 1-naphthylacetonitrile, the methyl tert-butyl ether and the hydrogen chloride gas is controlled within a certain range, so that the methanol and the 1-naphthylacetonitrile fully react under the action of the hydrogen chloride to generate an imidoester active intermediate, namely a naphazoline intermediate; methyl tert-butyl ether is added to improve the selectivity of the reaction, and simultaneously, an anhydrous reaction system is formed to prevent the hydrolysis of the naphazoline intermediate imine ester, reduce the occurrence of side reactions and further improve the yield of the naphazoline intermediate.
Preferably, the specific operation of step S1 is:
adding methanol, 1-naphthylacetonitrile and methyl tert-butyl ether into a reaction kettle, fully stirring at the rotation speed of 600-800r/min for 20-30min, introducing hydrogen chloride gas at the temperature of 30-40 ℃, reacting for 60-90min, cooling to 0-2 ℃, crystallizing, filtering, and drying to obtain a naphazoline intermediate.
By adopting the technical scheme, in the process of preparing the naphazoline intermediate, technological parameters such as stirring speed, stirring time, temperature and the like are controlled, and meanwhile, a series of purification operations such as cooling crystallization, filtration and the like are carried out on the naphazoline intermediate, so that impurities of the naphazoline intermediate are effectively removed, and the purity of the obtained naphazoline intermediate is high.
Preferably, the mass ratio of the solvent A, the ethylenediamine and the naphazoline intermediate in the step S2 is 3 (12-16): 10.
By adopting the technical scheme, in the preparation process of the naphazoline, the mass ratio of the solvent A, the ethylenediamine and the naphazoline intermediate is controlled, so that the ethylenediamine and the naphazoline intermediate are fully reacted, the utilization rate of reactants is improved, resources are saved, unreacted impurities in the obtained naphazoline are reduced, and the purity of the naphazoline is improved.
Preferably, the solvent A is prepared by compounding methanol and N, N-dimethylformamide in a mass ratio of (2-4): 1.
By adopting the technical scheme, the methanol in the solvent A can fully dissolve the ethylenediamine and the naphazoline intermediate to form a uniform and stable reaction system and promote the reaction; the product of the reaction contains methanol, and the methanol can be recycled by distillation with the solvent after the reaction is finished, so that resources are saved; meanwhile, the reaction can be promoted, and the yield of the reaction is improved; the N, N-dimethylformamide can be used as a reaction solvent for reaction, and water can be added after the reaction is finished to quench the reaction, so that the occurrence of side reactions is reduced, and the purity of the product is improved. The compound of methanol and N, N-dimethylformamide is used as the solvent A, so that a good reaction system can be formed, the quenching reaction in the later stage is facilitated, the preparation cost is saved, and the product purity and yield are improved.
Preferably, the specific operation of step S2 is:
adding ethylenediamine and a solvent A into a reaction kettle, stirring at a rotation speed of 400-600r/min for 30-40min, adding a naphazoline intermediate at a temperature of 30-40 ℃, heating to 80-100 ℃, and continuously reacting at the same stirring speed for 1-2h to obtain naphazoline.
By adopting the technical scheme, in the preparation process of the naphazoline, all process parameters are strictly controlled, so that the prepared ethylenediamine and the naphazoline intermediate are fully reacted to generate the naphazoline, the side reaction is reduced, and the purity and the yield of the finally obtained naphazoline hydrochloride are greatly improved.
Preferably, the mass ratio of the naphazoline to the concentrated hydrochloric acid in the step S3 is 1 (1.1-1.5).
By adopting the technical scheme, the mass ratio of the naphazoline to the concentrated hydrochloric acid is controlled within a certain range, if the amount of the concentrated hydrochloric acid is too small, the naphazoline cannot be completely converted into the naphazoline hydrochloride, if the amount of the concentrated hydrochloric acid is too large, waste of raw materials can be caused, and the obtained naphazoline hydrochloride is yellow in color, is not easy to decolor, and seriously affects the product quality of the naphazoline hydrochloride.
Preferably, the specific operation of step S3 is:
and (3) adding concentrated hydrochloric acid with the mass fraction of 37-38% into the naphazoline obtained in the step (S2), reacting for 1-2h, concentrating under reduced pressure at the temperature of 30-40 ℃ and the pressure of 0.07-0.08Mpa, and filtering to obtain a crude naphazoline hydrochloride product.
By adopting the technical scheme, in the process of preparing the crude naphazoline hydrochloride product, the technological parameters are controlled, the reduced pressure concentration mode is adopted, the solution evaporation is carried out at a lower temperature, the energy is saved, the rapid precipitation of the naphazoline hydrochloride is facilitated, and the content of active ingredients in the crude naphazoline hydrochloride product is increased.
Preferably, coconut shell activated carbon is also added in the step S4, and the mass of the coconut shell activated carbon is 0.1-0.2 time of that of the naphazoline hydrochloride crude product.
Through adopting above-mentioned technical scheme, the coconut husk active carbon is added in this application, pigment and impurity in the effective absorption crude make the quality that finally obtains naphazoline hydrochloride more excellent.
Preferably, the mass ratio of the crude naphazoline hydrochloride to the solvent B in the step S4 is 1 (2-3).
By adopting the technical scheme, the mass ratio of the crude naphazoline hydrochloride product to the solvent B is controlled within a certain range, so that the naphazoline hydrochloride serving as an effective component in the crude product can be fully dissolved, and impurities are removed in a precipitation form to obtain pure naphazoline hydrochloride.
Preferably, the specific operation of step S4 is:
dissolving the naphazoline hydrochloride crude product in a solvent B, adding coconut shell activated carbon, heating to 50-60 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1-5 ℃, separating out crystals, filtering, washing and drying to obtain the naphazoline hydrochloride.
By adopting the technical scheme, the solvent B is added in the refining process of the naphazoline hydrochloride, so that the naphazoline hydrochloride in the crude naphazoline hydrochloride product is fully dissolved, the recrystallization crystallization rate is effectively improved, the purity of the naphazoline hydrochloride is higher, and the acetone and the ethanol have lower boiling points and are volatile and convenient to remove; meanwhile, various process parameters are controlled, and the product quality of the naphazoline hydrochloride is further improved.
In summary, the present application has the following beneficial effects:
1. the method comprises the following steps of taking 1-naphthylacetonitrile as a raw material, reacting with methanol under the action of hydrogen chloride, and adding methyl tert-butyl ether to generate a naphazoline intermediate; then, fully reacting ethylenediamine with a naphazoline intermediate in a solvent A to obtain naphazoline; adding concentrated hydrochloric acid into the naphazoline to obtain a crude naphazoline hydrochloride product; finally, dissolving the crude naphazoline hydrochloride product in a solvent B, and recrystallizing to obtain naphazoline hydrochloride; the synthesis and refining process of naphazoline hydrochloride effectively reduces the occurrence of side reactions, improves the product purity and yield, and has wider application prospect.
2. The synthetic refining process of naphazoline hydrochloride has the advantages of simple operation, high product yield and purity, low preparation cost, short reaction time and the like, and the solvent used in the reaction process can be recycled by distillation, so that the synthetic refining process has important significance in sustainable development and is suitable for industrial production.
Detailed Description
The present application will be described in further detail with reference to examples.
Examples 1-5 provide a synthetic refining process for naphazoline hydrochloride.
Example 1
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol, 10kg of 1-naphthylacetonitrile and 2kg of methyl tert-butyl ether into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.52kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.62kg of ethylenediamine and 3.16kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.52kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting at the same stirring speed for 2h to obtain 12.03kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 2;
s3, preparing a naphazoline hydrochloride crude product: adding 13.3kg of concentrated hydrochloric acid with the mass fraction of 36% into 12.03kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 14.13kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.13kg of a naphazoline hydrochloride crude product in 28.26kg of a solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain 13.97kg naphazoline hydrochloride
Wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
Example 2
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6.5kg of methanol, 10kg of 1-naphthylacetonitrile and 2.2kg of methyl tert-butyl ether into a reaction kettle, fully stirring at the rotating speed of 650r/min for 28min, introducing 2kg of hydrogen chloride gas at the temperature of 32 ℃, reacting for 85min, cooling to 0.5 ℃, crystallizing, filtering and drying to obtain 12.32kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 14.1kg of ethylenediamine and 3.25kg of solvent A into a reaction kettle, stirring at the rotation speed of 450r/min for 38min, adding 10.85kg of naphazoline intermediate at the temperature of 32 ℃, heating to 85 ℃, and continuously reacting at the same stirring speed for 1.8h to obtain 14.25kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 11;
s3, preparing a naphazoline hydrochloride crude product: adding 14.78kg of concentrated hydrochloric acid with the mass fraction of 36.5% into 12.32kg of naphazoline obtained in the step S2, reacting for 1.2h, and concentrating under reduced pressure at the temperature of 32 ℃ and the pressure of 0.072Mpa to obtain 14.25kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.25kg of a naphazoline hydrochloride crude product in 32.5kg of a solvent B, adding 1.71kg of coconut shell activated carbon, heating to 52 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 2 ℃, separating out crystals, filtering, washing and drying to obtain 14.16kg of naphazoline hydrochloride;
wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
Example 3
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 7kg of methanol, 10kg of 1-naphthylacetonitrile and 2.5kg of methyl tert-butyl ether into a reaction kettle, fully stirring at the rotating speed of 650r/min for 25min, introducing 3kg of hydrogen chloride gas at the temperature of 35 ℃, reacting for 80min, cooling to 1 ℃, crystallizing, filtering and drying to obtain 11.22kg of naphazoline intermediate;
s2, preparing naphazoline: adding 15.71kg of ethylenediamine and 3.37kg of solvent A into a reaction kettle, stirring at the rotating speed of 500r/min for 35min, adding 11.22kg of naphazoline intermediate at the temperature of 35 ℃, heating to 90 ℃, and continuously reacting for 1.5h at the same stirring speed to obtain 12.49kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 3;
s3, preparing a naphazoline hydrochloride crude product: adding 16.24kg of concentrated hydrochloric acid with the mass fraction of 37% into 12.49kg of naphazoline obtained in the step S2, reacting for 1.5h, and concentrating under reduced pressure at 35 ℃ and 0.075Mpa to obtain 14.57kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.57kg of a naphazoline hydrochloride crude product in 36.43kg of a solvent B, adding 2.19kg of coconut shell activated carbon, heating to 55 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 3 ℃, separating out crystals, filtering, washing and drying to obtain 14.29kg of naphazoline hydrochloride;
wherein, the solvent B is prepared by mixing water, acetone and ethanol according to the mass ratio of 2.
Example 4
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 7.5kg of methanol, 10kg of 1-naphthylacetonitrile and 2.7kg of methyl tert-butyl ether into a reaction kettle, fully stirring at the rotating speed of 750r/min for 22min, introducing 3.5kg of hydrogen chloride gas at the temperature of 38 ℃, reacting for 70min, cooling to 1.5 ℃, crystallizing, filtering and drying to obtain 11.56kg of naphazoline intermediate;
s2, preparing naphazoline: adding 17.34kg of ethylenediamine and 3.47kg of solvent A into a reaction kettle, stirring at the rotation speed of 550r/min for 33min, adding 11.56kg of naphazoline intermediate at the temperature of 38 ℃, heating to 95 ℃, and continuously reacting at the same stirring speed for 1.2h to obtain 12.55kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 7;
s3, preparing a naphazoline hydrochloride crude product: adding 17.57kg of concentrated hydrochloric acid with the mass fraction of 37.5% into 12.55kg of naphazoline obtained in the step S2, reacting for 1.8h, and concentrating under reduced pressure at the temperature of 38 ℃ and the pressure of 0.078Mpa to obtain 14.66kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.66kg of a naphazoline hydrochloride crude product in 41.05kg of a solvent B, adding 2.64kg of coconut shell activated carbon, heating to 58 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 4 ℃, separating out crystals, filtering, washing and drying to obtain 14.24kg of naphazoline hydrochloride;
wherein, the solvent B is prepared by mixing water, acetone and ethanol according to the mass ratio of 2.
Example 5
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 8kg of methanol, 10kg of 1-naphthylacetonitrile and 3kg of methyl tert-butyl ether into a reaction kettle, fully stirring at the rotating speed of 800r/min for 20min, introducing 4kg of hydrogen chloride gas at the temperature of 40 ℃, reacting for 60min, cooling to 2 ℃, crystallizing, filtering and drying to obtain 11.78kg of naphazoline intermediate;
s2, preparing naphazoline: adding 18.84kg of ethylenediamine and 3.53kg of solvent A into a reaction kettle, stirring at the rotating speed of 600r/min for 30min, adding 11.78kg of naphazoline intermediate at the temperature of 40 ℃, heating to 100 ℃, and continuously reacting at the same stirring speed for 1h to obtain 12.60kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 4;
s3, preparing a naphazoline hydrochloride crude product: adding 18.9kg of concentrated hydrochloric acid with the mass fraction of 38% into 12.60kg of naphazoline obtained in the step S2, reacting for 2 hours, and concentrating under reduced pressure at 40 ℃ and 0.08Mpa to obtain 14.72kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.72kg of a naphazoline hydrochloride crude product in 44.16kg of a solvent B, adding 2.94kg of coconut shell activated carbon, heating to 60 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 5 ℃, separating out crystals, filtering, washing and drying to obtain 14.22kgkg of naphazoline hydrochloride;
wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
In order to verify the yield and purity of naphazoline hydrochloride obtained by the synthesis and purification process of naphazoline hydrochloride provided by the application, the applicant sets comparative examples 1-6, wherein:
comparative example 1
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.32kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.38kg of ethylenediamine and 3.1kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.32kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting at the same stirring speed for 2h to obtain 11.93kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 2;
s3, preparing a naphazoline hydrochloride crude product: adding 13.34kg of concentrated hydrochloric acid with the mass fraction of 36% into 12.13kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 12.57kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 12.57kg of a naphazoline hydrochloride crude product in 25.14kg of a solvent B, adding 1.3kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain 11.95kg naphazoline hydrochloride
Wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
Comparative example 2
A process for synthesizing and refining naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.53kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.60kg of ethylenediamine and 3.15kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.53kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting at the same stirring speed for 2h to obtain 11.86kg of naphazoline;
wherein, the solvent A is methanol;
s3, preparing a naphazoline hydrochloride crude product: adding 13.05kg of concentrated hydrochloric acid with the mass fraction of 36% into 11.86kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 13.56kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 13.56kg of a naphazoline hydrochloride crude product in 27.12kg of a solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain naphazoline hydrochloride 12.75kg
Wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
Comparative example 3
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.51kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.63kg of ethylenediamine and 3.15kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.51kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting for 2h at the same stirring speed to obtain 11.93kg of naphazoline;
wherein the solvent A is N, N-dimethylformamide;
s3, preparing a naphazoline hydrochloride crude product: adding 13.12kg of concentrated hydrochloric acid with the mass fraction of 36% into 11.93kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 13.77kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 13.77kg of naphazoline hydrochloride crude product in 27.54kg of solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain naphazoline hydrochloride 12.96kg
Wherein the solvent B is prepared by mixing water, acetone and ethanol according to a mass ratio of 1.
Comparative example 4
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.50kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.62kg of ethylenediamine and 3.17kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.50kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting for 2h at the same stirring speed to obtain 12.04kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 2;
s3, preparing a naphazoline hydrochloride crude product: adding 13.24kg of concentrated hydrochloric acid with the mass fraction of 36% into 12.04kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 14.06kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.06kg of a naphazoline hydrochloride crude product in 28.12kg of a solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain 13.76kg naphazoline hydrochloride
Wherein the solvent B is prepared by mixing acetone and ethanol according to the mass ratio of 1.
Comparative example 5
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.55kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.64kg of ethylenediamine and 3.14kg of solvent A into a reaction kettle, stirring at the rotating speed of 400r/min for 40min, adding 10.55kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting for 2h at the same stirring speed to obtain 12.06kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 2;
s3, preparing a naphazoline hydrochloride crude product: adding 13.3kg of concentrated hydrochloric acid with the mass fraction of 36% into 12.06kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 14.09kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 14.09kg of a naphazoline hydrochloride crude product in 28.18 kg of a solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1 deg.C, precipitating crystal, filtering, washing, and drying to obtain naphazoline hydrochloride 13.55kg
Wherein the solvent B is prepared by mixing water and acetone according to a mass ratio of 1.
Comparative example 6
A synthetic refining process of naphazoline hydrochloride comprises the following steps:
s1, preparing a naphazoline intermediate: adding 6kg of methanol and 10kg of 1-naphthylacetonitrile into a reaction kettle, fully stirring at the rotating speed of 600r/min for 30min, introducing 1kg of hydrogen chloride gas at the temperature of 30 ℃, reacting for 90min, cooling to 0 ℃, crystallizing, filtering and drying to obtain 10.52kg of a naphazoline intermediate;
s2, preparing naphazoline: adding 12.63kg of ethylenediamine and 3.18kg of solvent A into a reaction kettle, stirring at the rotation speed of 400r/min for 40min, adding 10.52kg of naphazoline intermediate at the temperature of 30 ℃, heating to 80 ℃, and continuously reacting for 2h at the same stirring speed to obtain 12.01kg of naphazoline;
wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide with the mass ratio of 2;
s3, preparing a naphazoline hydrochloride crude product: adding 13.3kg of concentrated hydrochloric acid with the mass fraction of 36% into 12.01kg of naphazoline obtained in the step S2, reacting for 1h, and concentrating under reduced pressure at the temperature of 30 ℃ and the pressure of 0.07Mpa to obtain 13.95kg of crude naphazoline hydrochloride;
s4, refining naphazoline hydrochloride: dissolving 13.95kg of a naphazoline hydrochloride crude product in 27.9kg of a solvent B, adding 1.4kg of coconut shell activated carbon, heating to 50 ℃, filtering while hot, and collecting filtrate; and cooling the filtrate to 1 ℃, separating out crystals, filtering, washing and drying to obtain 13.43kg of naphazoline hydrochloride.
Wherein the solvent B is prepared by mixing water and ethanol according to a mass ratio of 1.
The yields and purities of naphazoline hydrochloride prepared in examples 1-5 and comparative examples 1-6 of the present application were respectively determined, and the following result parameters were obtained, and are shown in table 1.
Calculating the yield according to the formula of yield = [ (actual naphazoline hydrochloride mass)/(theoretical naphazoline hydrochloride mass) ] × 100%; the purity of naphazoline hydrochloride was determined by HPLC.
Table 1:
as can be seen from the data shown in table 1 above: examples 1-5 of the present application were compared with comparative examples 1-6,
the yield and the purity of the naphazoline hydrochloride prepared in the embodiments 1-5 are obviously improved, the quality is more excellent, and the naphazoline hydrochloride has a wider application prospect.
From example 1 and comparative example 1, it can be seen that: compared with the method that methyl tert-butyl ether is not added in the step S1 of the comparative example 1, the method that methyl tert-butyl ether is added in the step S1 of the example 1 has the advantages that the yield and the purity of the naphazoline hydrochloride prepared in the example 1 are obviously superior to those of the comparative example 1, and the methyl tert-butyl ether can effectively reduce the occurrence of side reactions and improve the yield of a naphazoline intermediate.
From example 1 and comparative examples 2 and 3, it can be seen that: the solvent A in the example 1 is prepared by compounding methanol and N, N-dimethylformamide according to a certain proportion, and compared with the solvent A in the comparative example 2 which only uses methanol or the solvent A in the comparative example 3 which only uses N, N-dimethylformamide, the yield and the purity of the naphazoline hydrochloride prepared in the example 1 are higher than those of the comparative examples 2 and 3, which shows that the solvent A can play an important role in improving the product purity and the yield.
From example 1 and comparative examples 4 to 6, it can be seen that: the solvent B in example 1 is obtained by mixing water, acetone and ethanol at a mass ratio of 1.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A synthetic refining process of naphazoline hydrochloride is characterized by comprising the following steps:
s1, preparing a naphazoline intermediate: adding methanol, 1-naphthylacetonitrile and methyl tert-butyl ether into a reaction kettle, fully stirring, introducing hydrogen chloride gas at a certain temperature, cooling, crystallizing, filtering and drying to obtain a naphazoline intermediate;
s2, preparing naphazoline: adding ethylenediamine and a solvent A into a reaction kettle, fully stirring, adding a naphazoline intermediate at a certain temperature, and heating for reaction for a period of time to obtain naphazoline;
s3, preparing a naphazoline hydrochloride crude product: adding concentrated hydrochloric acid into the naphazoline obtained in the step S2, decompressing and concentrating, and filtering to obtain a naphazoline hydrochloride crude product;
s4, refining naphazoline hydrochloride: dissolving the crude naphazoline hydrochloride in a solvent B, heating, filtering while hot, and collecting filtrate; then cooling and crystallizing the filtrate, filtering and washing to obtain naphazoline hydrochloride;
the solvent A is methanol and/or N, N-dimethylformamide; the solvent B is prepared by mixing water, acetone and ethanol according to the mass ratio of (1-2) to (4-6) to (80-90).
2. The process for synthesizing and refining naphazoline hydrochloride according to claim 1, wherein the mass ratio of methanol to 1-naphthylacetonitrile to methyl tert-butyl ether to hydrogen chloride in the step S1 is (6-8) to 10 (2-3) to (1-4).
3. The process for synthesizing and refining naphazoline hydrochloride according to claim 2, wherein the step S1 comprises the following specific operations:
adding methanol, 1-naphthylacetonitrile and methyl tert-butyl ether into a reaction kettle, fully stirring at the rotation speed of 600-800r/min for 20-30min, introducing hydrogen chloride gas at the temperature of 30-40 ℃, reacting for 60-90min, cooling to 0-2 ℃, crystallizing, filtering, and drying to obtain a naphazoline intermediate.
4. The process for synthesizing and refining naphazoline hydrochloride according to claim 1, wherein the mass ratio of the solvent A to the ethylenediamine to the naphazoline intermediate in the step S2 is 3 (12-16) to 10.
5. The process for synthesizing and refining naphazoline hydrochloride according to claim 1, wherein the solvent A is prepared by compounding methanol and N, N-dimethylformamide in a mass ratio of (2-4): 1.
6. The process for synthesizing and refining naphazoline hydrochloride according to claim 5, wherein the step S2 comprises the following specific operations:
adding ethylenediamine and a solvent A into a reaction kettle, stirring at a rotating speed of 400-600r/min for 30-40min, adding a naphazoline intermediate at a temperature of 30-40 ℃, heating to 80-100 ℃, and continuously reacting at the same stirring speed for 1-2h to obtain naphazoline.
7. The process for synthesizing and refining naphazoline hydrochloride according to claim 1, wherein the mass ratio of the naphazoline to the concentrated hydrochloric acid in the step S3 is 1 (1.1-1.5).
8. The process for synthesizing and refining naphazoline hydrochloride according to claim 7, wherein the step S3 comprises the following specific operations:
and (3) adding concentrated hydrochloric acid with the mass fraction of 36-38% into the naphazoline obtained in the step (S2), reacting for 1-2h, and concentrating under reduced pressure at the temperature of 30-40 ℃ and the pressure of 0.07-0.08Mpa to obtain a crude naphazoline hydrochloride product.
9. The process for synthesizing and refining naphazoline hydrochloride according to claim 1, wherein coconut shell activated carbon is added in the step S4, and the mass of the coconut shell activated carbon is 0.1-0.2 times of that of a crude naphazoline hydrochloride product.
10. The process for synthesizing and refining naphazoline hydrochloride according to claim 9, wherein the step S4 comprises the following specific operations:
dissolving the naphazoline hydrochloride crude product in a solvent B, adding coconut shell activated carbon, heating to 50-60 ℃, filtering while hot, and collecting filtrate; cooling the filtrate to 1-5 ℃, separating out crystals, filtering, washing and drying to obtain the naphazoline hydrochloride.
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