CN113912545A - Method for synthesizing and refining inorganic acid salt of naphazoline - Google Patents
Method for synthesizing and refining inorganic acid salt of naphazoline Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 238000007670 refining Methods 0.000 title claims abstract description 31
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- -1 inorganic acid salt Chemical class 0.000 title claims abstract description 10
- 229960005016 naphazoline Drugs 0.000 title claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 16
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 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 12
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 5
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 claims description 33
- 229960004186 naphazoline nitrate Drugs 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 238000006482 condensation reaction Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ZGMKMNLVGRQPMO-UHFFFAOYSA-N 2-naphthalen-1-yl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC2=CC=CC=C12 ZGMKMNLVGRQPMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000007039 two-step reaction Methods 0.000 abstract 1
- ZAHXYMFVNNUHCP-UHFFFAOYSA-N Naphazoline nitrate Chemical compound O[N+]([O-])=O.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 ZAHXYMFVNNUHCP-UHFFFAOYSA-N 0.000 description 22
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 21
- 239000007787 solid Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- PRPINYUDVPFIRX-UHFFFAOYSA-N 1-naphthaleneacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=CC2=C1 PRPINYUDVPFIRX-UHFFFAOYSA-N 0.000 description 3
- 239000005971 1-naphthylacetic acid Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 206010039083 rhinitis Diseases 0.000 description 3
- 208000027744 congestion Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- SYJXFKPQNSDJLI-HKEUSBCWSA-N neamine Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](N)C[C@@H]1N SYJXFKPQNSDJLI-HKEUSBCWSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 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
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing and refining a naphazoline inorganic acid salt, belonging to the field of medicine synthesis. The method takes 1-naphthylacetonitrile and ethylenediamine as raw materials, and carries out two-step reactions of catalytic condensation and salification with inorganic acid to obtain a crude product of the naphazoline inorganic acid salt, and finally, the crude product of the naphazoline inorganic acid salt is refined by processes of recrystallization, activated carbon decoloration and the like, and the purity of the refined pure product reaches up to 99.5 percent, so that the preparation method is simple in process, convenient to operate and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a method for synthesizing and refining inorganic acid salt of naphazoline.
Background
Naphazoline nitrate, chemical name 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole nitrate, molecular formula C14H15N3O3Molecular weight 273.29, and its preparation name is neomycin amine or neomycin A. The product can be used as sympathomimetic medicine, and is mainly used for treating common cold, rhinitis, nasal congestion, etc. It can be used alone or in combination with azithromycin to prolong the local retention time of the medicine. Naphazoline hydrochloride, chemical name is 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazoleHydrochloride of the formula C14H14N2 .HCl with molecular weight of 246.74, and its aqueous solution preparation is named as nasal drop. The product, as an adrenomimetic drug, can directly act on alpha adrenoceptor to contract blood vessels, so as to relieve symptoms such as congestion caused by allergy and corresponding inflammation, and is mainly used for treating mucosal congestion and swelling caused by acute or chronic rhinitis and nasosinusitis clinically. It can be used alone or combined with diphenhydramine hydrochloride, levofloxacin, etc. as compound preparation. Therefore, the application of the medicine is wide.
The existing synthetic method of naphazoline nitrate is mainly obtained by taking 1-naphthylacetic acid as a raw material and performing high-temperature condensation reaction with ethylenediamine, and the synthetic route is as follows:
the synthetic method of naphazoline hydrochloride is mainly obtained by taking 1-naphthylacetic acid as a raw material and carrying out high-temperature condensation reaction with ethylenediamine, and the synthetic route is as follows:
in the synthetic route, 1-naphthylacetic acid and ethylenediamine are subjected to condensation reaction under the reflux condition of 130 ℃, then the product free alkali is collected through reduced pressure distillation, salified with nitric acid or reacted with hydrogen chloride gas introduced into an ethanol/acetone system to obtain a naphazoline nitrate crude product or a naphazoline hydrochloride crude product, and finally the finished naphazoline nitrate or naphazoline hydrochloride product is obtained through refining. However, the process often results in incomplete condensation to form a large amount of impurities, and the raw material medicaments meeting pharmacopeia standards can be obtained only by continuous crystallization; meanwhile, the reduced pressure distillation temperature is more than 200 ℃, so that the product is easily deepened and even carbonized, and the requirements on distillation equipment are extremely high. The molar yield in the whole process is 30-35%, so that the production cost is greatly increased.
Disclosure of Invention
The invention provides a method for synthesizing and refining naphazoline nitrate aiming at the problems.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing and refining inorganic acid salt of naphazoline is characterized in that: 1-naphthylacetonitrile and ethylenediamine are used as raw materials, and are subjected to condensation reaction under the action of a catalyst A to obtain a crude product of naphthyloxazoline free alkali, the crude product is obtained by directly carrying out salifying reaction with inorganic acid without purification treatment, and then the crude product is refined and decolored to obtain a finished product of naphthyloxazoline inorganic acid salt; wherein, the catalyst A is one or more mixed catalysts of thioglycollic acid, 3-mercaptopropionic acid, thioacetamide and thiopropionamide.
The synthetic route is as follows:
as a preferable aspect of the present invention, the inorganic acid is nitric acid or hydrochloric acid; further preferred is concentrated nitric acid or concentrated hydrochloric acid.
As a preferable mode of the present invention, the condensation reaction temperature is 25 to 100 ℃; preferably, the method comprises the following steps: the condensation reaction temperature is 40-80 ℃.
As a preference of the present invention, the condensation reaction time is from 2 to 8 hours.
Preferably, the molar ratio of the ethylenediamine to the 1-naphthylacetonitrile in the condensation reaction is 1.1-2.5: 1, more preferably 1.2 to 1.8: 1.
As a preferable selection of the invention, the solvent for nitrate-forming reaction is methanol, ethanol, isopropanol, ethyl acetate and acetone.
As a preference according to the invention, the nitrate-forming reaction temperature is from 0 to 25 ℃ and preferably from 5 to 15 ℃.
As a preferred choice of the invention, the refining method selects one or more of methanol, ethanol, acetone and water to be mixed with solvent for recrystallization.
Has the advantages that:
for the synthesis and refining of the naphazoline nitrate, the method has the advantages of mild reaction conditions, simple operation process, convenient post-treatment, simple refining method, high product yield, purity of over 99.5 percent after refining, simple operation, low cost and easy industrial production.
For the synthesis and refining of naphazoline hydrochloride, the method has the advantages of mild reaction conditions, simple operation process, no need of high-temperature reduced pressure distillation, no need of introducing hydrogen chloride gas for post-treatment, simple refining method, high product yield, high purity of over 99.5 percent after refining, and high product molar yield of over 70 percent. Is an effective method with simple operation, low cost and easy industrialized production.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.
Example 1
Synthesis of naphazoline nitrate
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding a catalyst 3-mercaptopropionic acid (6.6g), then heating to 40 ℃, dropwise adding ethylenediamine (144g, 2.4mol, 1.2eq), dropwise adding for 1h, keeping the temperature for reaction for 8h after the dropwise adding is finished, and monitoring by TLC that the raw material disappears (V)PE/EA=5:1), stopping the reaction, cooling to room temperature, separating out a large amount of solids, adding 95% ethanol (900mL), stirring to dissolve the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction liquid to 5-10 ℃, dropwise adding 65% concentrated nitric acid, adjusting the pH to 2.5 until a large amount of light yellow solids are separated out, and filtering to obtain 427g of a naphazoline nitrate crude product, wherein the yield is 78.2% and the HPLC purity is 96.3%.
Refining of naphazoline nitrate
427g of the crude naphazoline nitrate product is added into 850mL of 90% ethanol, the mixture is heated and completely dissolved, then medical grade active carbon (8.5g) is added, reflux decolorization is carried out for 30min at 75-80 ℃, the mixture is filtered, cooled to 0-5 ℃, filtered and dried in vacuum for 8h at 50 ℃, and 350g of white powdery solid naphazoline nitrate refined product is obtained, wherein the yield is 91%. Measurement of m.p: 167.5-170 ℃ and the purity is 99.6%.
Example 2
Synthesis of naphazoline nitrate
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding catalysts of 3-mercaptopropionic acid (3.3g) and thiopropionamide (3.3g), then dropwise adding ethylenediamine (144g, 2.4mol, 1.2eq) when the temperature is raised to 80 ℃, dropwise adding for 1h, after the dropwise adding is finished, carrying out heat preservation reaction for 3h, and monitoring the disappearance of raw materials by TLC (V)PE/EA=5:1), stopping the reaction, cooling to room temperature, separating out a large amount of solids, adding 95% ethanol (850mL), stirring to dissolve the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction liquid to 5-10 ℃, dropwise adding 65% concentrated nitric acid, adjusting the pH to 2-3 until a large amount of light yellow solids are separated out, and filtering to obtain 514g of crude naphazoline nitrate, wherein the yield is 94.1% and the HPLC purity is 96.9%.
Refining of naphazoline nitrate
Adding 514g of the crude naphazoline nitrate into 1050mL of 80% ethanol, heating to completely dissolve, adding medical-grade activated carbon (10.2g), carrying out reflux decoloration at 75-80 ℃ for 30min, filtering, cooling to 0-5 ℃, filtering, and carrying out vacuum drying at 50 ℃ for 8h to obtain 422.8g of a white powdery solid naphazoline nitrate refined product, wherein the yield is 89%. Measurement of m.p: 167.6-168.5 ℃ and the purity is 99.7%.
Example 3
Synthesis of naphazoline nitrate
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding a catalyst of thiopropionamide (7.6g), then heating to 60 ℃, dropwise adding ethylenediamine (216g, 3.6mol, 1.8eq), dropwise adding for 1h, keeping the temperature for 4h after the dropwise adding is finished, and monitoring the disappearance of raw materials by TLC (V is monitored)PE/EA=5:1), stopping the reaction, cooling to room temperature, separating out a large amount of solids, then adding acetone (500mL), stirring to dissolve the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction liquid to 10-15 ℃, then dropwise adding 65% concentrated nitric acid, adjusting the pH to 2-3 until a large amount of light yellow solids are separated out, and filtering to obtain 496g of crude naphazoline nitrate, wherein the yield is 90.7%, and the HPLC purity is 96.5%.
Refining of naphazoline nitrate
Adding 496g of crude naphazoline nitrate into 7600mL of acetone, heating to dissolve completely, adding pharmaceutical grade active carbon (9.9g), refluxing and decoloring at 55-60 ℃ for 30min, filtering, cooling to 0-5 ℃, filtering, and vacuum drying at 50 ℃ for 8h to obtain 381g of white powdery solid naphazoline nitrate refined product with the yield of 85%. Measurement of m.p: 167.4-168.5 ℃ and the purity is 99.6%.
Example 4
Synthesis of naphazoline hydrochloride
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding a catalyst 3-mercaptopropionic acid (6.6g), then heating to 40 ℃, dropwise adding ethylenediamine (144g, 2.4mol, 1.2eq), dropwise adding for 1h, keeping the temperature for reaction for 8h after the dropwise adding is finished, and monitoring by TLC that the raw material disappears (V)PE/EA=5:1) stopping the reaction, cooling to room temperature, precipitating a large amount of solid, adding 95% ethanol (700mL), stirring to dissolve the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction solution to 5-10 ℃, then dropwise adding 37% concentrated hydrochloric acid, adjusting the pH value to 2-3 until a large amount of light yellow solid is precipitated, and filtering to obtain 385g of crude naphazoline hydrochloride product, wherein the yield is 78.1% and the HPLC purity is 95.8%.
Refining of naphazoline hydrochloride
Adding 385g of crude naphazoline hydrochloride product into 800mL of 90% ethanol, heating to completely dissolve, adding pharmaceutical grade activated carbon (7.7g), refluxing and decoloring at 75-80 ℃ for 30min, filtering, cooling to 0-5 ℃, filtering, and vacuum drying at 50 ℃ for 8h to obtain 350g of white powdery solid naphazoline hydrochloride refined product with the yield of 91%. Measurement of m.p: 255-259 ℃ and the purity is 99.6%.
Example 5
Synthesis of naphazoline hydrochloride
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding catalysts of 3-mercaptopropionic acid (3.3g) and thiopropionamide (3.3g), then dropwise adding ethylenediamine (144g, 2.4mol, 1.2eq) when the temperature is raised to 80 ℃, dropwise adding for 1h, after the dropwise adding is finished, carrying out heat preservation reaction for 3h, and monitoring the disappearance of raw materials by TLC (V)PE/EA=5:1) stopping the reaction, cooling to roomAnd (3) separating out a large amount of solid at a high temperature, adding 95% ethanol (850mL), stirring to dissolve the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction liquid to 5-10 ℃, then dropwise adding 37% concentrated hydrochloric acid, adjusting the pH value to 2-3 until a large amount of light yellow solid is separated out, and filtering to obtain 475g of the crude naphazoline hydrochloride product, wherein the yield is 95.9% and the HPLC purity is 96.7%.
Refining of naphazoline hydrochloride
Adding 475g of the crude naphazoline hydrochloride product into 900mL of 80% ethanol, heating to completely dissolve, adding pharmaceutical grade activated carbon (9.5g), carrying out reflux decolorization at 80-82 ℃ for 30min, filtering, cooling to 0-5 ℃, filtering, and carrying out vacuum drying at 50 ℃ for 10h to obtain 422.8g of a white powdery solid naphazoline hydrochloride refined product, wherein the yield is 89%. Measurement of m.p: 256-258 ℃ and the purity is 99.7 percent.
Example 6
Synthesis of naphazoline hydrochloride
Weighing 1-naphthylacetonitrile (334g, 2.0mol, 1.0eq) and adding into a 1L four-neck flask, then adding a catalyst of thiopropionamide (7.6g), then heating to 60 ℃, dropwise adding ethylenediamine (216g, 3.6mol, 1.8eq), dropwise adding for 1h, keeping the temperature for 4h after the dropwise adding is finished, and monitoring the disappearance of raw materials by TLC (V is monitored)PE/EA=5:1) stopping the reaction, cooling to room temperature, precipitating a large amount of solid, adding acetone (600mL), stirring to dissolve crude 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole, cooling the reaction solution to 10-15 ℃, dropwise adding 37% concentrated hydrochloric acid, adjusting the pH value to 2-3 until a large amount of light yellow solid is precipitated, and filtering to obtain 448g of crude naphazoline hydrochloride, wherein the yield is 90.8% and the HPLC purity is 96.3%.
Refining of naphazoline hydrochloride
Adding 448g of the crude naphazoline hydrochloride product into 600mL of acetone, heating to completely dissolve the crude naphazoline hydrochloride product, then adding medical-grade activated carbon (8.8g), decoloring for 30min at 55 ℃, filtering, cooling to 0-5 ℃, filtering, and vacuum-drying for 6h at 50 ℃ to obtain 381g of white powdery solid naphazoline hydrochloride refined product with the yield of 85%. Measurement of m.p: 256-259 ℃ and the purity is 99.6%.
Claims (10)
1. A method for synthesizing and refining inorganic acid salt of naphazoline is characterized in that: 1-naphthylacetonitrile and ethylenediamine are used as raw materials, and are subjected to condensation reaction under the action of a catalyst A to obtain a crude product of naphthyloxazoline free alkali, the crude product is obtained by directly carrying out salifying reaction with inorganic acid without purification treatment, and then the crude product is refined and decolored to obtain a finished product of naphthyloxazoline inorganic acid salt; wherein, the catalyst A is one or more mixed catalysts of thioglycollic acid, 3-mercaptopropionic acid, thioacetamide and thiopropionamide.
2. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the inorganic acid is nitric acid or hydrochloric acid; further preferred is concentrated nitric acid or concentrated hydrochloric acid.
3. The method for synthesizing and refining naphazoline nitrate according to claim 2, wherein the method comprises the following steps: the condensation reaction temperature is 25-100 deg.C, preferably 40-80 deg.C.
4. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the condensation reaction time is 2-8h, preferably 4-8 h.
5. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the molar ratio of the ethylenediamine to the 1-naphthylacetonitrile in the condensation reaction is (1.1-2.5): 1.
6. the method for synthesizing and refining naphazoline nitrate according to claim 5, wherein the method comprises the following steps: the molar ratio of the ethylenediamine to the 1-naphthylacetonitrile in the condensation reaction is (1.2-1.8): 1.
7. the method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the salt-forming solvent is methanol, ethanol, isopropanol, ethyl acetate and acetone.
8. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the temperature of the salt-forming reaction is 0 to 25 ℃ and preferably 5 to 15 ℃.
9. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the refining method comprises recrystallizing one or more of methanol, ethanol, isopropanol, acetone, and water with mixed solvent.
10. The method for synthesizing and refining naphazoline nitrate according to claim 1, wherein the method comprises the following steps: the decolorization is realized by adding pharmaceutical grade active carbon, wherein the mass ratio of the crude naphazoline inorganic salt product to the pharmaceutical grade active carbon is 45-55: 1.
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