CN113912545B - Method for synthesizing and refining naphazoline inorganic acid salt - Google Patents
Method for synthesizing and refining naphazoline inorganic acid salt Download PDFInfo
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- CNIIGCLFLJGOGP-UHFFFAOYSA-N SJ000285664 Natural products C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000007670 refining Methods 0.000 title claims abstract description 29
- 229960005016 naphazoline Drugs 0.000 title claims abstract description 25
- -1 naphazoline inorganic acid salt Chemical class 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 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
- 239000012043 crude product Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 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 11
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 claims description 7
- 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
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007039 two-step reaction Methods 0.000 abstract 1
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 40
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 19
- 229960004186 naphazoline nitrate Drugs 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 7
- 230000008034 disappearance Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
- SYJXFKPQNSDJLI-HKEUSBCWSA-N neamine Chemical group 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 4
- 239000005971 1-naphthylacetic acid Substances 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 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
- 238000004519 manufacturing process Methods 0.000 description 3
- 206010039083 rhinitis Diseases 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
- 230000001154 acute effect Effects 0.000 description 2
- 208000027744 congestion Diseases 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 239000000126 substance Substances 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
- IIDAJRNSZSFFCB-UHFFFAOYSA-N 4-amino-5-methoxy-2-methylbenzenesulfonamide Chemical compound COC1=CC(S(N)(=O)=O)=C(C)C=C1N IIDAJRNSZSFFCB-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
- ZAHXYMFVNNUHCP-UHFFFAOYSA-N Naphazoline nitrate Chemical group O[N+]([O-])=O.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 ZAHXYMFVNNUHCP-UHFFFAOYSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 239000000150 Sympathomimetic Substances 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 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
- 238000001035 drying Methods 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
- 239000000203 mixture Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000002904 solvent Substances 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
- 238000001308 synthesis method Methods 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing and refining naphazoline inorganic acid salt, belonging to the field of drug synthesis. The method takes 1-naphthalene acetonitrile and ethylenediamine as raw materials, carries out two-step reaction of salifying with inorganic acid to obtain crude naphazoline inorganic acid salt, and finally refines the crude naphazoline inorganic acid salt through processes such as recrystallization, active carbon decoloration and the like to obtain pure naphazoline inorganic acid salt, wherein the purity of the refined pure naphazoline inorganic acid salt is up to 99.5 percent, and the method is a preparation method which has simple process, convenient operation and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and relates to a method for synthesizing and refining naphazoline inorganic acid salt.
Background
Naphazoline nitrate, the chemical name is 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole nitrate, the molecular formula is C 14H15N3O3, the molecular weight is 273.29, and the preparation name is neomycin A or neomycin A. The product is used as a sympathomimetic medicine, and is mainly used for treating common cold, rhinitis, nasal congestion and the like clinically. It can be used alone or in combination with azithromycin to prolong the local residence time of the drug. Naphazoline hydrochloride, the chemical name is 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole hydrochloride, the molecular formula is C 14H14N2 . HCl, the molecular weight is 246.74, and the aqueous solution preparation is also called "Bijing". The product can be used as adrenomimetic drug to directly act on alpha adrenoceptor to shrink blood vessel, thereby relieving congestion and other symptoms caused by allergy and corresponding inflammation, and is clinically used for treating acute or acute and chronic rhinitis and mucous membrane congestion and swelling caused by sinusitis. It can be used alone or in combination with diphenhydramine hydrochloride, levofloxacin, etc. Therefore, the application in the medical field is relatively wide.
The existing method for synthesizing naphazoline nitrate is mainly obtained by carrying out high-temperature condensation reaction on 1-naphthylacetic acid serving as a raw material and ethylenediamine, and the synthetic route is as follows:
The synthesis method of naphazoline hydrochloride mainly comprises the steps of carrying out high-temperature condensation reaction on 1-naphthylacetic acid serving as a raw material and ethylenediamine, wherein the synthesis route is as follows:
In the synthetic route, firstly, 1-naphthalene acetic acid and ethylenediamine are subjected to condensation reaction under the reflux condition of 130 ℃, then the product is distilled under reduced pressure to collect free alkali, then the free alkali is salified with nitric acid or hydrogen chloride gas is introduced into an ethanol/acetone system to react to obtain crude naphazoline nitrate or crude naphazoline hydrochloride, and finally, the crude naphazoline nitrate or the finished naphazoline hydrochloride are obtained through refining. However, the process often leads to incomplete condensation to form a large amount of impurities, and the crude drug meeting pharmacopoeia standards can be achieved through continuous crystallization; meanwhile, the reduced pressure distillation temperature is above 200 ℃, the color of the product is extremely easy to deepen and even carbonize, and the requirements on distillation equipment are extremely high. The molar yield of 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, which aims at the problems.
The aim of the invention can be achieved by the following technical scheme:
A method for synthesizing and refining naphazoline inorganic acid salt is characterized in that: taking 1-naphthylacetonitrile and ethylenediamine as raw materials, carrying out condensation reaction under the action of a catalyst A to obtain crude naphazoline free alkali, directly carrying out salification reaction with inorganic acid without purification treatment to obtain crude naphazoline inorganic acid salt, and then refining and decoloring to obtain finished naphazoline inorganic acid salt; wherein the catalyst A is one or a mixture of more of thioglycollic acid, 3-mercaptopropionic acid, thioacetamide and thiopropionamide.
The synthetic route is as follows:
preferably, the inorganic acid is nitric acid or hydrochloric acid; concentrated nitric acid or concentrated hydrochloric acid is further preferred.
As a preferred aspect of the present invention, the condensation reaction temperature is 25 to 100 ℃; as preferable: the condensation reaction temperature is 40-80 ℃.
As a preferred aspect of the present invention, the condensation reaction time is 2 to 8 hours.
As a preferable mode of the invention, the molar ratio of the ethylenediamine to the 1-naphthylacetonitrile in the condensation reaction is 1.1-2.5:1, more preferably 1.2-1.8:1.
As one preferable mode of the invention, the nitrate forming reaction is carried out by selecting methanol, ethanol, isopropanol, ethyl acetate and acetone as solvents.
As a preferred aspect of the present invention, the nitrate forming reaction temperature is from 0 to 25℃and preferably from 5 to 15 ℃.
As one preferable mode of the invention, the refining method selects one or more mixed solvents of methanol, ethanol, acetone and water for recrystallization.
The beneficial effects are that:
The method has the advantages of mild reaction conditions, simple operation process, convenient post treatment, simple refining method, high product yield, purity of more than 99.5 percent after refining, and is an effective method with simple operation, low cost and easy industrialized production.
The method has the advantages of mild reaction conditions, simple operation process, no need of high-temperature reduced pressure distillation, no need of hydrogen chloride gas introduction, convenient post treatment, simple refining method, high product yield, purity of more than 99.5 percent after refining and molar yield of more than 70 percent. Is an effective method which has simple operation, low cost and easy industrialized production.
Detailed Description
The present invention will be further described with reference to examples, but the scope of the present invention is not limited thereto.
Example 1
Synthesis of naphazoline nitrate
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, 3-mercaptopropionic acid (6.6 g) as a catalyst is added, ethylenediamine (144 g,2.4mol,1.2 eq) is added dropwise at the temperature of 40 ℃ and 1H, the reaction is kept for 8H after dripping, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the reaction is cooled to room temperature, a large amount of solids are separated out, 95% ethanol (900 mL) is added, the crude 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 5-10 ℃, 65% concentrated nitric acid is added dropwise, the pH=2.5 is regulated until a large amount of light yellow solid is separated out, and the crude product 427g of naphazoline nitrate is obtained after filtering, the yield is 78.2%, and the HPLC purity is 96.3%.
Naphazoline nitrate refining
427G of naphazoline nitrate crude product is added with 850mL of 90% ethanol, heated and completely dissolved, then medical grade active carbon (8.5 g) is added, reflux decoloration is carried out for 30min at 75-80 ℃, filtration is carried out, cooling is carried out to 0-5 ℃, filtration is carried out, vacuum drying is carried out for 8h at 50 ℃, thus obtaining 350g of white powdery solid naphazoline nitrate refined product, and the yield is 91%. Measurement of m.p: 167.5-170 ℃ and the purity is 99.6 percent.
Example 2
Synthesis of naphazoline nitrate
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, 3.3g of catalyst 3-mercaptopropionic acid and thiopropionamide (3.3 g) are then added, ethylenediamine (144 g,2.4mol,1.2 eq) is then added dropwise at the temperature of 80 ℃ for 1H, after the dropwise addition, the reaction is kept for 3H after the dropwise addition, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the reaction is cooled to room temperature, a large amount of solids are separated out, then 95% ethanol (850 mL) is added, the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 5-10 ℃, 65% concentrated nitric acid is then added dropwise, the pH=2-3 is regulated until a large amount of light yellow solid is separated out, and the crude product of naphazoline nitrate 514g is obtained, the yield is 94.1%, and the HPLC purity is 96.9%.
Naphazoline nitrate refining
Adding 1050mL of 80% ethanol into 514g of naphazoline nitrate crude product, heating to dissolve completely, then adding medical grade active carbon (10.2 g), refluxing and decoloring for 30min at 75-80 ℃, filtering, cooling to 0-5 ℃, filtering, and vacuum drying for 8h at 50 ℃ to obtain white powdery solid naphazoline nitrate refined product 422.8g, wherein the yield is 89%. Measurement of m.p: 167.6-168.5 ℃ and the purity is 99.7 percent.
Example 3
Synthesis of naphazoline nitrate
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, then a catalyst thiopropionamide (7.6 g) is added, then ethylenediamine (216 g,3.6mol,1.8 eq) is added dropwise at the temperature of 60 ℃ and 1H is added dropwise, the reaction is kept for 4H after the dripping, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the reaction is cooled to the room temperature, a large amount of solids are separated out, then acetone (500 mL) is added, the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 10-15 ℃, then 65% concentrated nitric acid is added dropwise, the pH=2-3 is regulated until a large amount of light yellow solid is separated out, 496g of a crude product of naphthylazoline nitrate is obtained after filtration, the yield is 90.7%, and the HPLC purity is 96.5%.
Naphazoline nitrate refining
496G of naphazoline nitrate crude product is added with 7600mL of acetone, heated and completely dissolved, then medical grade active carbon (9.9 g) is added, reflux decoloration is carried out for 30min at 55-60 ℃, filtration is carried out, cooling is carried out to 0-5 ℃, filtration is carried out, vacuum drying is carried out for 8h at 50 ℃, thus obtaining white powdery solid naphazoline nitrate refined product 381g, and the yield is 85%. Measurement of m.p: 167.4-168.5 ℃ and the purity is 99.6 percent.
Example 4
Synthesis of naphazoline hydrochloride
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, 3-mercaptopropionic acid (6.6 g) as a catalyst is added, ethylenediamine (144 g,2.4mol,1.2 eq) is added dropwise at the temperature of 40 ℃ and is added dropwise for 1H, the reaction is kept for 8H after dripping, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the reaction is cooled to room temperature, a large amount of solids are separated out, 95% ethanol (700 mL) is added, the crude 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 5-10 ℃, 37% concentrated hydrochloric acid is added dropwise, the pH=2-3 is regulated until a large amount of light yellow solid is separated out, and then the crude product 385g of naphazoline hydrochloride is obtained after filtration, the yield is 78.1%, and the HPLC purity is 95.8%.
Naphazoline hydrochloride refining
385G of naphazoline hydrochloride crude product is added with 800mL of 90% ethanol, heated and completely dissolved, then medical grade active carbon (7.7 g) is added, reflux decoloration is carried out for 30min at 75-80 ℃, filtration is carried out, cooling is carried out to 0-5 ℃, filtration is carried out, vacuum drying is carried out for 8h at 50 ℃, thus obtaining 350g of white powdery solid naphazoline hydrochloride refined product, and the yield is 91%. Measurement of m.p: 255-259 ℃ and 99.6% purity.
Example 5
Synthesis of naphazoline hydrochloride
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, 3.3g of catalyst 3-mercaptopropionic acid and thiopropionamide (3.3 g) are then added, ethylenediamine (144 g,2.4mol,1.2 eq) is then added dropwise at the temperature of 80 ℃ for 1H, after the dripping, the reaction is kept for 3H, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the cooling is carried out to room temperature, a large amount of solids are separated out, then 95% ethanol (850 mL) is added, the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 5-10 ℃, then 37% concentrated hydrochloric acid is added dropwise, the pH=2-3 is regulated until a large amount of light yellow solid is separated out, and the crude product naphazoline hydrochloride is obtained, the yield is 95.475%, and the HPLC purity is 96.7%.
Naphazoline hydrochloride refining
475G of naphazoline hydrochloride crude product is added with 900mL of 80% ethanol, heated and completely dissolved, then medical grade active carbon (9.5 g) is added, reflux decoloration is carried out for 30min at 80-82 ℃, filtration is carried out, cooling is carried out to 0-5 ℃, filtration is carried out, vacuum drying is carried out for 10h at 50 ℃, thus obtaining white powdery solid naphazoline hydrochloride refined product 422.8g, and the yield is 89%. Measurement of m.p: 256-258 ℃ and the purity is 99.7 percent.
Example 6
Synthesis of naphazoline hydrochloride
1-Naphthylacetonitrile (334 g,2.0mol,1.0 eq) is weighed and added into a four-necked flask with 1L, then a catalyst thiopropionamide (7.6 g) is added, then ethylenediamine (216 g,3.6mol,1.8 eq) is added dropwise at the temperature of 60 ℃ and 1H is added dropwise, the reaction is kept for 4H after the dripping, TLC monitors the disappearance of raw materials (V PE/EA＝ 5:1), the reaction is stopped, the reaction is cooled to room temperature, a large amount of solids are separated out, then acetone (600 mL) is added, the crude product 4, 5-dihydro-2- (1-naphthylmethyl) -1H-imidazole is stirred and dissolved, the reaction solution is cooled to 10-15 ℃, then 37% concentrated hydrochloric acid is added dropwise, the pH=2-3 is regulated until a large amount of light yellow solid is separated out, and the crude product 448g of naphazoline hydrochloride is obtained after filtration, the yield is 90.8%, and the HPLC purity is 96.3%.
Naphazoline hydrochloride refining
Adding 600mL of acetone into 448g of naphazoline hydrochloride crude product, heating to dissolve completely, adding medical grade active carbon (8.8 g), decoloring for 30min at 55 ℃, filtering, cooling to 0-5 ℃, filtering, and drying at 50 ℃ in vacuum for 6h to obtain 381g of white powdery solid naphazoline hydrochloride refined product, wherein the yield is 85%. Measurement of m.p: 256-259 deg.c and purity 99.6%.
Claims (9)
1. A method for synthesizing and refining naphazoline inorganic acid salt is characterized in that: taking 1-naphthylacetonitrile and ethylenediamine as raw materials, carrying out condensation reaction under the action of a catalyst A to obtain crude naphazoline free alkali, directly carrying out salification reaction with inorganic acid without purification treatment to obtain crude naphazoline inorganic acid salt, and then refining and decoloring to obtain finished naphazoline inorganic acid salt; wherein the catalyst A is selected from thiopropionamide or a mixed catalyst of thiopropionamide and 3-mercaptopropionic acid; the temperature of the condensation reaction is 60-80 ℃, and the time of the condensation reaction is 4-8 h.
2. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the inorganic acid is concentrated nitric acid or concentrated hydrochloric acid.
3. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the mol ratio of the ethylenediamine to the 1-naphthylacetonitrile in the condensation reaction is (1.1-2.5): 1.
4. The method for synthesizing and purifying naphazoline inorganic acid salt according to claim 3, wherein: the mol ratio of ethylenediamine to 1-naphthylacetonitrile in the condensation reaction is (1.2-1.8): 1.
5. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the salifying reaction solvent is methanol, ethanol, isopropanol, ethyl acetate or acetone.
6. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the temperature of the salification reaction is 0-25 ℃.
7. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the temperature of the salification reaction is 5-15 ℃.
8. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the refining method comprises recrystallizing with one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone and water.
9. The method for synthesizing and refining naphazoline inorganic acid salt according to claim 1, wherein: the decoloring is carried out by adding medical grade active carbon, and the mass ratio of naphazoline inorganic salt crude product to medical grade active carbon is 45-55:1.
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| Thioacetamide catalysed transformation of nitriles to 2-substituted imidazolines;P. Dash 等;《JOURNAL OF CHEMICAL RESEARCH》;第490-491页 * |
| 朱洪法 等.《催化剂手册》.金盾出版社,2008,(第1版),第268页. * |
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