CN113912545B - Method for synthesizing and refining naphazoline inorganic acid salt - Google Patents

Method for synthesizing and refining naphazoline inorganic acid salt Download PDF

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CN113912545B
CN113912545B CN202010663047.1A CN202010663047A CN113912545B CN 113912545 B CN113912545 B CN 113912545B CN 202010663047 A CN202010663047 A CN 202010663047A CN 113912545 B CN113912545 B CN 113912545B
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naphazoline
inorganic acid
acid salt
refining
synthesizing
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CN113912545A (en
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殷茂华
路一飞
李光文
李剑平
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Yumen Qianhua Pharmaceutical Co ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04Heterocyclic 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
    • C07D233/06Heterocyclic 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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

Method for synthesizing and refining naphazoline inorganic acid salt
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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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041261A (en) * 2019-05-24 2019-07-23 广东先强药业有限公司 A kind of preparation method of naphcon

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041261A (en) * 2019-05-24 2019-07-23 广东先强药业有限公司 A kind of preparation method of naphcon

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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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