CN115677654A - Preparation method of articaine hydrochloride - Google Patents
Preparation method of articaine hydrochloride Download PDFInfo
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- CN115677654A CN115677654A CN202211653317.6A CN202211653317A CN115677654A CN 115677654 A CN115677654 A CN 115677654A CN 202211653317 A CN202211653317 A CN 202211653317A CN 115677654 A CN115677654 A CN 115677654A
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Abstract
The invention relates to the technical field of articaine hydrochloride, and discloses a preparation method of articaine hydrochloride, which comprises the following steps: adding 20-715 g of I, 5.28-190 g of potassium carbonate and 1.27-45 g of potassium iodide into 80-700 g of methyl isobutyl ketone, stirring, dropwise adding 12.56-436 g of n-propylamine at room temperature, keeping the temperature of 80-90 ℃ for reaction for 26 hours after dropwise adding is finished, cooling to room temperature after reaction is finished, washing twice with 80-2860 g of purified water respectively, separating liquid, carrying out pressure concentration on organic phase, adding 100-3575 ml of acetone into residue, cooling to room temperature, adjusting the pH to 2-3 with concentrated hydrochloric acid, cooling to 0-5 ℃ for crystallization for 2 hours, carrying out suction filtration, washing a filter cake once with 10-350 ml of acetone, and drying under reduced pressure at 80 ℃ for 10 hours to obtain 20-700 g of II; the preparation method of the articaine hydrochloride has the advantages of simple and convenient technological operation, high crude product yield and refining yield, high purity of the obtained product up to over 99.9 percent, capability of recycling the methyl isobutyl ketone, less waste liquid amount, reduction of environmental protection pressure and convenience for large-scale production of the product.
Description
Technical Field
The invention relates to the technical field of articaine hydrochloride, in particular to a preparation method of articaine hydrochloride.
Background
Articaine hydrochloride, chemical name: 4-methyl-3- [ [ 1-oxo-2- (propylamino) propyl ] amino ] -2-thiophenecarboxylic acid methyl ester hydrochloride, articaine hydrochloride is a local anaesthetic for oral use, particularly suitable for surgical procedures involving osteotomy and mucotomy. The compound articaine hydrochloride injection is the only oral special local anesthetic supplied in the domestic market at present. The articaine and lidocaine belong to amide local injection anesthetic. Compared with other local anesthetics, the articaine hydrochloride has the main advantages of quick anesthesia effect taking time, strong tissue infiltration, no need of blocking anesthesia, high anesthesia efficiency, wide safety range, proper anesthesia duration, lower allergy incidence rate, less influence on the cardiovascular system and low toxic and side effects.
Currently, the preparation of articaine hydrochloride mainly comprises the following two methods:
chemical impurities of Chinese medicaments, namely DMSO (dimethylsulfoxide) is used as a reaction solvent in a ratio of 14: 109 to 111, the I reacts with n-propylamine, and hydrochloric acid is added to form salt and crystallize to generate II.
(2) In RU 2184730, DMF is used as reaction solvent, I reacts with n-propylamine, hydrochloric acid is added to form salt, and crystallization is carried out to obtain II.
The above application has the following disadvantages:
route (1): DMSO is used as a solvent, water is required to be added for dilution during aftertreatment, and then an organic solvent is used for extracting a product, so that the generated waste liquid is large in amount, and DMSO is easy to crystallize in winter, so that the environmental protection pressure is large, the productivity is influenced, and a compound II obtained by using DMSO as a solvent is poor in purity, and a qualified product can be obtained by refining twice.
Route (2): DMF is used as a reaction solvent, water is required to be added for dilution during post-treatment, then the product is extracted by an organic solvent, the amount of generated waste liquid is large, DMF is a polar solvent, ester bonds are easy to hydrolyze, byproducts are more, the purity of the obtained compound II is poor, and the qualified product can be obtained only by two times of refining.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a preparation method of articaine hydrochloride, which has the advantages of reducing environmental protection pressure and being suitable for industrial production, and a large number of experimental researches find that methyl isobutyl ketone is used as a reaction solvent, potassium carbonate is used as an acid-binding agent, and potassium iodide is used as a catalyst, so that the obtained product has the advantages of high yield, high purity, small by-product and the like, and the problems that DMSO is used as a solvent, water is required to be added for dilution during post-treatment, and then an organic solvent is used for extracting the product are solved, so that the amount of generated waste liquid is large, and DMSO is easy to crystallize in winter, so that the environmental protection pressure is large, the yield is also influenced, and a compound II obtained by using DMSO as a solvent has poor purity, and a qualified product can be obtained only by refining twice; DMF is used as a reaction solvent, water is required to be added for dilution during post-treatment, then an organic solvent is used for extracting the product, the generated waste liquid is large in amount, DMF is a polar solvent, ester bonds are easy to hydrolyze, a large number of byproducts are generated, the purity of an obtained compound II is poor, and a qualified product can be obtained only by twice refining.
(II) technical scheme
In order to realize the purposes of reducing the environmental protection pressure and being suitable for industrial production, a large number of experimental researches find that the product obtained by using methyl isobutyl ketone as a reaction solvent, potassium carbonate as an acid-binding agent and potassium iodide as a catalyst has high yield, high purity and small by-product, the invention provides the following technical scheme: a preparation method of articaine hydrochloride comprises the following steps:
s1, preparation of crude articaine hydrochloride
Adding 20-715 g of I, 5.28-190 g of potassium carbonate and 1.27-45 g of potassium iodide into 80-700 g of methyl isobutyl ketone, stirring, dropwise adding 12.56-436 g of n-propylamine at room temperature, keeping the temperature of 80-90 ℃ for reaction for 26 hours after dropwise adding, cooling to room temperature after reaction, washing twice with 80-2860 g of purified water respectively, separating liquid, carrying out pressure concentration on organic phase, adding 100-3575 ml of acetone into residue, cooling to room temperature, adjusting the pH to 2-3 with concentrated hydrochloric acid, cooling to 0-5 ℃ for crystallization for 2 hours, carrying out suction filtration, washing a filter cake once with 10-350 ml of acetone, drying at 80 ℃ for 10 hours under reduced pressure to obtain 20-700 g of II, and conversion: 79.2 to 81.6 percent;
s2, preparation of articaine hydrochloride
Adding 20-700 g of II into 30-1050 g of methanol, heating to dissolve, adding activated carbon to decolor for 0.5h, filtering, adding 120-4500 g of ethyl acetate, cooling to 0-5 ℃ to crystallize, filtering, and drying under reduced pressure at 80 ℃ for 10 h to obtain 18-620 g of white solid, wherein the yield is 87.9-90.0%, and the purity is 99.90-99.95%.
Preferably, in the step S1, the material i, potassium carbonate and potassium iodide react with n-propylamine in methyl isobutyl ketone, after the reaction is finished, purified water is added to wash, the organic phase is concentrated, acetone is added, concentrated hydrochloric acid is added dropwise to form salt and crystallize, and the product is filtered, washed, dried and refined by isopropanol to obtain the compound ii.
Preferably, in the step S1, the reaction temperature is 80-90 ℃; the reaction time is 26-30 h.
Preferably, in the step S1, the mass volume ratio of the I to the acetone is 1g; salification pH = 1-2;
preferably, in step S1, the crystallization solvent is methanol and ethyl acetate.
Preferably, in step S1, the mass ratio of the crude articaine hydrochloride to methanol and ethyl acetate is 1.5.
Preferably, in the step S1, the reduced pressure drying temperature is: 80 to 90 ℃.
Preferably, in the step S1, i is an articaine hydrochloride intermediate in a state of a pale yellow solid, and ii is a crude articaine hydrochloride in a state of an off-white solid.
(III) advantageous effects
Compared with the prior art, the invention provides a preparation method of articaine hydrochloride, which has the following beneficial effects:
1. the preparation method of the articaine hydrochloride has the advantages of simple and convenient process operation, high crude product yield and refining yield, high purity of the obtained product up to more than 99.9 percent, capability of recycling the methyl isobutyl ketone, less waste liquid amount, reduction of environmental protection pressure and convenience for large-scale production of the product.
2. According to the preparation method of the articaine hydrochloride, a reaction solvent which is immiscible with water and has small reaction byproducts is selected, so that the environmental protection pressure is reduced, and the preparation method can be suitable for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first embodiment is as follows:
a preparation method of articaine hydrochloride comprises the following steps:
s1, preparation of crude articaine hydrochloride
Adding 20g of I, 5.28g of potassium carbonate and 1.27g of potassium iodide into 80g of methyl isobutyl ketone, stirring, dropwise adding 12.56g of n-propylamine at room temperature, keeping the temperature at 80 ℃ after the dropwise addition is finished, reacting for 26 hours, cooling to room temperature after the reaction is finished, respectively washing with 80g of purified water twice, separating liquid, concentrating the organic phase under reduced pressure, and adding 100ml of acetone into the residue. Cooling to room temperature, adjusting pH to 2 with concentrated hydrochloric acid, cooling to 5 deg.C, and crystallizing for 2 hr. Suction filtration, filter cake washed once with 10ml acetone, 80 ℃ decompression dried for 10 hours, II 20g, conversion: 81.6 percent.
Feeding the material I, potassium carbonate and potassium iodide to react with n-propylamine in methyl isobutyl ketone, after the reaction is finished, adding purified water to wash, concentrating an organic phase, adding acetone, dropwise adding concentrated hydrochloric acid to form salt and crystallize, filtering, washing, drying, and refining by using isopropanol to obtain the material II.
The crystallization solvent is methanol and ethyl acetate.
The mass ratio of the crude articaine hydrochloride to the methanol and the ethyl acetate is (1.5).
The I is an articaine hydrochloride intermediate in a light yellow solid state, the II is an articaine hydrochloride crude product in a white-like solid state.
S2, preparation of articaine hydrochloride
Adding 20g of II into 30g of methanol, heating to dissolve, adding activated carbon for decoloring for 0.5h, filtering, adding 120g of ethyl acetate, cooling to 5 ℃ for crystallization, performing suction filtration, and drying under reduced pressure at 80 ℃ for 10 h to obtain 18g of white solid, wherein the yield is 90.0% and the purity is 99.90%.
Example two:
s1, preparation of crude articaine hydrochloride
715g of I, 190g of potassium carbonate and 45g of potassium iodide are added into 80g of methyl isobutyl ketone, stirring is carried out, 436g of n-propylamine is dropwise added at room temperature, after the dropwise addition is finished, the reaction is carried out at 90 ℃ for 26 hours, after the reaction is finished, the temperature is reduced to the room temperature, 2860g of purified water is respectively used for washing twice, liquid separation is carried out, the organic phase is subjected to pressure reduction and concentration, and 3575ml of acetone is added into the residue. Cooling to room temperature, adjusting pH to 3 with concentrated hydrochloric acid, cooling to 5 deg.C, and crystallizing for 2 hr. Suction filtration, the filter cake washed once with 350ml acetone, dried under reduced pressure at 80 ℃ for 10 hours to give II 700g, conversion: 79.9 percent.
Feeding the material I, potassium carbonate and potassium iodide to react with n-propylamine in methyl isobutyl ketone, after the reaction is finished, adding purified water to wash, concentrating an organic phase, adding acetone, dropwise adding concentrated hydrochloric acid to form salt and crystallize, filtering, washing, drying, and refining by using isopropanol to obtain the material II.
The crystallization solvent is methanol and ethyl acetate.
The mass ratio of the crude articaine hydrochloride to the methanol and the ethyl acetate is 1.5.
The I is an articaine hydrochloride intermediate, the state is a light yellow solid, the II is an articaine hydrochloride crude product, and the state is a white-like solid.
S2, preparation of articaine hydrochloride
Adding 700g of II into 1050g of methanol, heating to dissolve and clear, adding activated carbon to decolor for 0.5h, filtering, adding 4500g of ethyl acetate, cooling to 5 ℃ to crystallize, filtering, and drying under reduced pressure at 80 ℃ for 10 h to obtain 620g of white solid, wherein the yield is 88.6%, and the purity is 99.93%.
Example three:
s1, preparation of crude articaine hydrochloride
Adding 175kg of I, 46kg of potassium carbonate and 26kg of potassium iodide into 700kg of methyl isobutyl ketone, stirring, dropwise adding 107kg of n-propylamine at room temperature, keeping the temperature at 90 ℃ for reaction for 26 hours after dropwise adding, cooling to room temperature after the reaction is finished, respectively washing with 700kg of purified water twice, separating liquid, carrying out organic phase decompression concentration, and adding 690kg of acetone into the residue. Cooling to room temperature, adjusting pH to 3 with concentrated hydrochloric acid, cooling to 5 deg.C, and crystallizing for 2 hr. Suction filtration, washing the filter cake with 70kg acetone once, drying under reduced pressure at 80 ℃ for 20 hours to obtain II 170kg, conversion: 79.2 percent.
Feeding the material I, potassium carbonate and potassium iodide to react with n-propylamine in methyl isobutyl ketone, after the reaction is finished, adding purified water to wash, concentrating an organic phase, adding acetone, dropwise adding concentrated hydrochloric acid to form salt, crystallizing, filtering, washing, drying, and refining by using isopropanol to obtain the material II.
The crystallization solvent is methanol and ethyl acetate.
The mass ratio of the crude articaine hydrochloride to the methanol and the ethyl acetate is (1.5).
The I is an articaine hydrochloride intermediate, the state is a light yellow solid, the II is an articaine hydrochloride crude product, and the state is a white-like solid.
S2, preparation of articaine hydrochloride
Adding 165kg of II into 248kg of methanol, heating to dissolve, adding activated carbon to decolor for 0.5h, filtering, adding 4990kg of ethyl acetate, cooling to 5 ℃ to crystallize, performing suction filtration, and drying under reduced pressure at 80 ℃ for 10 h to obtain 145kg of white solid, wherein the yield is 87.9%, and the purity is 99.95%.
The preparation method of the articaine hydrochloride has the advantages that the process operation is simple and convenient, the crude product yield and the refined yield are high, the purity of the obtained product reaches more than 99.9 percent, the methyl isobutyl ketone can be recycled, the amount of the generated waste liquid is small, the environmental protection pressure is reduced, and the large-scale production of the product is facilitated; a reaction solvent which is immiscible with water and has small reaction byproducts is selected, so that the environmental protection pressure is reduced, and the method is suitable for industrial production.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A preparation method of articaine hydrochloride is characterized by comprising the following steps:
s1, preparation of crude articaine hydrochloride
Adding 20-715 g of I, 5.28-190 g of potassium carbonate and 1.27-45 g of potassium iodide into 80-700 g of methyl isobutyl ketone, stirring, dropwise adding 12.56-436 g of n-propylamine at room temperature, keeping the temperature of 80-90 ℃ for reaction for 26 hours after dropwise adding is finished, cooling to room temperature after reaction is finished, washing twice with 80-2860 g of purified water respectively, separating liquid, carrying out pressure concentration on organic phase, adding 100-3575 ml of acetone into residue, cooling to room temperature, adjusting the pH to 2-3 with concentrated hydrochloric acid, cooling to 0-5 ℃ for crystallization for 2 hours, carrying out suction filtration, washing a filter cake once with 10-350 ml of acetone, drying under reduced pressure at 80 ℃ for 10 hours to obtain 20-700 g of II, and obtaining the conversion rate: 79.2 to 81.6 percent of the crude product, wherein the input I is an articaine hydrochloride intermediate in a light yellow solid state, the obtained II is an articaine hydrochloride crude product in a white-like solid state;
s2, preparation of articaine hydrochloride
Adding 20-700 g of II into 30-1050 g of methanol, heating to dissolve, adding activated carbon to decolor for 0.5h, filtering, adding 120-4500 g of ethyl acetate, cooling to 0-5 ℃ to crystallize, filtering, and drying under reduced pressure at 80 ℃ for 10 h to obtain 18-620 g of white solid, wherein the yield is 87.9-90.0%, and the purity is 99.90-99.95%.
2. The preparation method of articaine hydrochloride according to claim 1, wherein in step S1, the raw materials i, potassium carbonate, potassium iodide are reacted with n-propylamine in methyl isobutyl ketone, after the reaction, purified water is added for washing, the organic phase is concentrated, acetone is added, concentrated hydrochloric acid is added dropwise for salt crystallization, and the product is filtered, washed, dried and refined by isopropanol to obtain ii.
3. The preparation method of articaine hydrochloride according to claim 1, wherein in step S1, the reaction temperature is 80-90 ℃; the reaction time is 26-30 h.
4. The preparation method of articaine hydrochloride according to claim 1, wherein in step S1, the mass-to-volume ratio of i to acetone is 1g; salification pH = 1-2.
5. The preparation method of articaine hydrochloride according to claim 1, wherein in the step S1, the crystallization solvents are methanol and ethyl acetate.
6. The preparation method of articaine hydrochloride according to claim 1, wherein in step S1, the mass ratio of the crude articaine hydrochloride to the methanol and the ethyl acetate is 1.5.
7. The method for preparing articaine hydrochloride according to claim 1, wherein in step S1, the reduced-pressure drying temperature is all: 80-90 ℃.
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| CN202211653317.6A CN115677654B (en) | 2022-12-22 | 2022-12-22 | Preparation method of atecan hydrochloride |
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| CN202211653317.6A CN115677654B (en) | 2022-12-22 | 2022-12-22 | Preparation method of atecan hydrochloride |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2184730C1 (en) * | 2001-05-16 | 2002-07-10 | Государственный научный центр Российской Федерации "НИОПИК" | Method of synthesis of 4-methyl-3-[2-(n-propyl- -amino)propionylamino]thiophene-2-carboxylic acid methyl ester hydrochloride |
| CN102060840A (en) * | 2010-12-31 | 2011-05-18 | 蚌埠丰原医药科技发展有限公司 | Preparation method of articaine hydrochloride |
| CN102321067A (en) * | 2011-07-28 | 2012-01-18 | 蚌埠丰原涂山制药有限公司 | Preparation method of articaine hydrochloride |
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- 2022-12-22 CN CN202211653317.6A patent/CN115677654B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2184730C1 (en) * | 2001-05-16 | 2002-07-10 | Государственный научный центр Российской Федерации "НИОПИК" | Method of synthesis of 4-methyl-3-[2-(n-propyl- -amino)propionylamino]thiophene-2-carboxylic acid methyl ester hydrochloride |
| CN102060840A (en) * | 2010-12-31 | 2011-05-18 | 蚌埠丰原医药科技发展有限公司 | Preparation method of articaine hydrochloride |
| CN102321067A (en) * | 2011-07-28 | 2012-01-18 | 蚌埠丰原涂山制药有限公司 | Preparation method of articaine hydrochloride |
Non-Patent Citations (3)
| Title |
|---|
| SOWELL, J. WALTER等: "Synthesis of alkylaminoalkylamides of substituted 2-aminopyrroles as potential local anesthetic and antiarrhythmic agents. I: α-amines" * |
| WANG, L. D.;等: "Synthesis and vasodepressor screen of a series of 2-(2-alkylaminoalkylamido)-3-carbamyl-4-methyl-5-benzylpyrroles" * |
| 段亚波等: "盐酸阿替卡因的简便合成方法" * |
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