CN113912545A - Method for synthesizing and refining inorganic acid salt of naphazoline - Google Patents

Method for synthesizing and refining inorganic acid salt of naphazoline Download PDF

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CN113912545A
CN113912545A CN202010663047.1A CN202010663047A CN113912545A CN 113912545 A CN113912545 A CN 113912545A CN 202010663047 A CN202010663047 A CN 202010663047A CN 113912545 A CN113912545 A CN 113912545A
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naphazoline
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CN113912545B (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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Changzhou Tianhua 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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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

Method for synthesizing and refining inorganic acid salt of naphazoline
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:
Figure BDA0002579319870000011
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:
Figure BDA0002579319870000012
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:
Figure BDA0002579319870000021
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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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 (1)

* Cited by examiner, † Cited by third party
Title
P. DASH 等: "Thioacetamide catalysed transformation of nitriles to 2-substituted imidazolines", 《JOURNAL OF CHEMICAL RESEARCH》, vol. 1, pages 490 - 491 *

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