CN115806543A

CN115806543A - Articaine hydrochloride intermediate and preparation method and application thereof

Info

Publication number: CN115806543A
Application number: CN202310049970.XA
Authority: CN
Inventors: 卞德利; 刘志文
Original assignee: Jinan Xuanzheng Pharmaceutical Co ltd
Current assignee: Jinan Xuanzheng Pharmaceutical Co ltd
Priority date: 2023-02-01
Filing date: 2023-02-01
Publication date: 2023-03-17

Abstract

The invention provides an articaine hydrochloride intermediate, a preparation method and application thereof, relating to the technical field of biological medicine, wherein the preparation method of the articaine hydrochloride intermediate comprises the following steps: carrying out oximation reaction on 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene and hydroxylamine hydrochloride to obtain 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime; and secondly, carrying out aromatization reaction on the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime in the presence of an aromatization catalyst to obtain 3-amino-4-methyl-2-thiophene methyl formate or a derivative thereof. The preparation method of the application uses the aromatization catalyst capable of promoting the generation of carbon ions, accelerates the reaction process, reduces the generation of side reactions, further improves the reaction yield and the purity of reaction products, and provides quality guarantee for the subsequent preparation of the articaine hydrochloride.

Description

Articaine hydrochloride intermediate and preparation method and application thereof

Technical Field

The application relates to the technical field of biological medicines, in particular to an articaine hydrochloride intermediate and a preparation method and application thereof.

Background

The 3-amino-4-methyl-2-thiophenecarboxylate is a key intermediate for synthesizing the local anesthetic articaine hydrochloride, and the structural formula is as follows:

at present, there are two main ways for obtaining thiophene ring, one is to directly use thiophene to perform corresponding substitution reaction, and the other is to use corresponding raw materials to perform cyclization reaction, and then modify corresponding groups to obtain target products.

For substitution reaction, a cyano substitution method of thiophene ring is mentioned in the patent with publication number US3855243A, but because of the aromaticity of thiophene ring, substitution at 2-position and 5-position is dominant, so that the reaction process has difficulty in selectivity, resulting in low yield of final product.

In the prior patents and documents, the synthesis methods of thiophene rings in the cyclization reaction can be mainly classified into the following two types according to the raw materials:

route one: 2-methacrylonitrile and methyl thioglycolate are taken as main raw materials, and a target product is obtained through reactions such as cyano oxidation and the like after cyclization;

and a second route: methyl methacrylate and methyl thioglycolate are taken as main raw materials, and the target product is obtained after oximation, rearrangement and neutralization after cyclization.

Corresponding to the first route, the specific method described in the Journal of Chinese medicinal Chemistry, volume 14, phase 2, is to add methyl thioglycolate to sodium methoxide and methanol, drop-add 2-methacrylonitrile, then neutralize with hydrochloric acid, oxidize with hydrogen peroxide, and then rearrange with hydrochloric acid to obtain the target product. In addition, the method described in patent publication No. CN102321067a is to react starting materials of methyl thioglycolate and 2-methacrylonitrile in a mixed solution of sodium methoxide and methanol, after the reaction is finished, adjust pH to 7 with concentrated hydrochloric acid and add hydrogen peroxide dropwise, then add concentrated hydrochloric acid dropwise to the reaction system, and concentrate under reduced pressure to obtain the target product.

The hydrogen peroxide is used in the route, the hydrogen peroxide belongs to explosive chemicals, certain dangers exist in the storage and use processes, and meanwhile, the reaction yield of the route is low, and the yield in the literature is only 46.4%.

Corresponding to the second route, methyl methacrylate and methyl thioglycolate are firstly cyclized to obtain 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene, and the patent with the publication number of US4847386A and the synthesis Communications2002 Vol 132P 2565-2568 describe a method that 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene is dissolved in acetonitrile, hydroxylamine hydrochloride is added for oximation, products are separated out from diethyl ether, and the solid obtained by filtration is neutralized by ammonia water to obtain the target product. However, it is known that the operation of diethyl ether is difficult, and the yield described in the literature is only 64%, i.e., there is also a problem that the yield is low. Furthermore, the patent with publication number CN108299382A improves the above process, and the reaction yield reaches more than 90% by using a catalyst. However, there are two problems in this method, one is that the catalyst for the reaction is one or more of zinc chloride, ferric chloride, cobalt chloride, nickel chloride and cuprous chloride, and although the amount is 0.5-5% of the reaction substrate, the amount is enough to generate complex in the rearrangement stage, resulting in color of the target product; secondly, the HPLC purity of the target product obtained by the process is less than 99.0 percent. These two problems can affect the quality of the articaine hydrochloride in the subsequent production process of the articaine hydrochloride.

In view of the above, a method for synthesizing 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester with high yield and high purity is needed.

Disclosure of Invention

The invention aims to provide a preparation method of an articaine hydrochloride intermediate with high yield and high purity, and specifically comprises the steps of firstly carrying out oximation reaction on 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene and hydroxylamine hydrochloride to generate 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime under the action of a catalyst, and further carrying out aromatization reaction on the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester.

In one aspect, the application provides a preparation method of an articaine hydrochloride intermediate, comprising the following steps:

carrying out oximation reaction on 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene and hydroxylamine hydrochloride to obtain 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime;

secondly, carrying out aromatization reaction on the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime to obtain 3-amino-4-methyl-2-thiophene methyl formate or a derivative thereof; the aromatization reaction is carried out in the presence of an aromatization catalyst, wherein the aromatization catalyst is selected from one or more of an ion catalyst, an acid catalyst and a transition metal catalyst.

Preferably, the aromatization catalyst is an ionic catalyst and/or an acid catalyst.

The aromatization catalyst provided by the application can promote the generation of carbon ions, promote the reaction process and effectively avoid rearrangement side reactions.

Further, the ionic catalyst is iodine; the acid catalyst is concentrated sulfuric acid and/or acetic acid; the transition metal catalyst is a palladium compound.

Preferably, the ionic catalyst is elemental iodine; the acid catalyst is concentrated sulfuric acid and/or acetic anhydride; the transition metal catalyst is palladium acetate.

More preferably, the aromatization catalyst is selected from one or more of elemental iodine, concentrated sulfuric acid and acetic anhydride.

Preferably, the reaction temperature of the aromatization reaction is 20 ℃ to 132 ℃, and the reaction is 1 ℃ to 12 h.

When the aromatization catalyst is concentrated sulfuric acid, the mass ratio of the concentrated sulfuric acid to the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime is 200, 378, and the reaction conditions are 30-35 ℃ and 3-12 h is reacted.

In a preferred embodiment, 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime is dropwise added into an ethyl acetate solution containing concentrated sulfuric acid, the temperature is kept between 30 and 35 ℃, and the reaction is continued for 3 to 12 h after the dropwise addition is finished; after the reaction is finished, the temperature is reduced to 0-5 ℃,2 h is crystallized, filtered and dried, and the 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester inorganic acid salt is obtained.

When the aromatization catalyst is palladium acetate, the mass ratio of pivaloyl chloride, palladium acetate, potassium carbonate, tricyclohexylphosphine to 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophenone oxime is 13.945, 8.6, 18.9, the reaction conditions are 79-80 ℃, and the reflux reaction is 4-5 h.

Wherein, palladium acetate is used as a transition metal catalyst, pivaloyl chloride is used as an amino protecting group to participate in the intermediate state of the reaction, tricyclohexylphosphine is used as a ligand catalyst to participate in the reaction, and potassium carbonate belongs to an acid-base regulator.

In a preferred embodiment, pivaloyl chloride and potassium carbonate are added into an ethyl acetate solution containing 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime dropwise, the mixture is heated and stirred to 50-60 ℃, palladium acetate and tricyclohexylphosphine are added, the mixture is refluxed and reacted at 79-80 ℃ to obtain 4-5 h; and after the reaction is finished, cooling to room temperature, washing, drying and concentrating to obtain the 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester inorganic acid salt. After the reaction is finished, an alkali such as sodium carbonate, potassium carbonate or potassium hydroxide can be selected to neutralize the acidity of the reaction solution, so as to ensure the subsequent reaction.

When the aromatization catalyst is acetic anhydride, the mass ratio of the acetic anhydride, acetyl chloride, pyridine and 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime is 108.7-7.9, the reaction conditions are that the temperature is 130-132 ℃, and the reflux reaction is 1-10 h.

Wherein acetyl chloride is used as an amino protection reagent, and pyridine is used as a reaction acid-binding agent.

In a preferred embodiment, 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, acetic anhydride, acetyl chloride and pyridine are mixed and subjected to reflux reaction at 130-132 ℃ to obtain 1-10 h; after the reflux is finished, removing acetyl protecting groups by using hydrochloric acid, distilling the solvent after the reaction is finished, and purifying to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester acetate.

When the aromatization catalyst is elemental iodine and concentrated sulfuric acid, the mass ratio of the elemental iodine to the concentrated sulfuric acid to the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime is 1.26 to 18.9, the solvent is toluene or ethylene glycol dimethyl ether, the reaction condition is 105-109 ℃, and the reflux reaction is 1-12 h; preferably, the temperature is 105 ℃, and the reaction is 12 h.

The concentrated sulfuric acid is used for promoting the molecular structure of the carbocation catalyst, and belongs to the same use purpose with elementary iodine, but the principle of generating the carbon ions by the catalysis of the elementary iodine is different from the principle of generating the carbon ions by the catalysis of acid.

In a preferred embodiment, elemental iodine and concentrated sulfuric acid are added into a toluene solution containing 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, the mixture is refluxed and reacted at 105 ℃ to obtain 12 h; after the reaction is finished, heating and concentrating to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester acetate.

In the above reaction, other substances except the aromatization catalyst, such as acyl chloride (acetyl chloride, pivaloyl chloride) are amino protecting groups, pyridine is an acid-binding agent in the amino protection process, and the catalyst is not a catalyst for catalyzing the carbon ion generation process, which is required by the core of the application, and is used for avoiding the nucleophilic reaction between the unprotected ammonium ion and the carbon ion in the reaction process.

Preferably, the aromatization reaction is carried out under acidic conditions selected from concentrated sulfuric acid and/or acetic acid.

Preferably, the aromatization reaction solvent is selected from the group consisting of toluene, ethyl acetate and/or ethylene glycol dimethyl ether.

Further, the oximation reaction is carried out under neutral or weakly alkaline conditions.

Further, the weakly alkaline condition is selected from one or more of sodium bicarbonate, sodium carbonate and sodium acetate.

Preferably, the weakly alkaline condition is sodium acetate and/or sodium bicarbonate, and the pH is 7-9.

Furthermore, the reaction temperature of the oximation reaction is 0-30 ℃, and the reaction time is 1-4 h.

Preferably, the oximation reaction solvent is a polar solvent, and the polar solvent is selected from one or more of acetonitrile, methanol and ethanol.

Further, the mass ratio of the 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene to the hydroxylamine hydrochloride in the oximation reaction is 1: (0.1-1).

Preferably, the mass ratio of the 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene to hydroxylamine hydrochloride is 1: (0.3-0.5); more preferably, the mass ratio of the 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene to hydroxylamine hydrochloride is 1.

Furthermore, the step one also comprises a step of extracting 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime after oximation reaction, and an extraction solvent is toluene and/or dichloromethane.

Further, the second step also comprises a step of neutralizing the aromatization reaction product under alkaline conditions.

Wherein the neutralization reaction converts the inorganic acid salt of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester or the carboxylic acid salt of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester in the aromatization reaction product into 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester.

Preferably, the alkaline condition is ammonia water, and the pH is 8.0-9.5.

More preferably, the molar ratio of the inorganic acid salt of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester to ammonia water is 1: (1.1-1.3).

On the other hand, the application also provides an articaine hydrochloride intermediate prepared by the method, wherein the articaine hydrochloride intermediate is 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester, and the HPLC purity of the 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester is more than 95% and can reach 99.1% at most.

In a preferred embodiment, the present application provides a method for preparing an articaine hydrochloride intermediate, comprising the steps of:

carrying out oximation reaction on 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene and hydroxylamine hydrochloride under the alkalescent condition, and carrying out reduced pressure concentration and extraction to obtain 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime;

secondly, carrying out aromatization reaction on the 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime under the catalysis of an aromatization catalyst to obtain 3-amino-4-methyl-2-thiophene methyl formate, or 3-amino-4-methyl-2-thiophene methyl formate inorganic acid salt or 3-amino-4-methyl-2-thiophene methyl formate carboxylate;

neutralizing the 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester inorganic acid salt under alkaline conditions to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester.

The aromatization catalyst is selected from one or more of elementary iodine, concentrated sulfuric acid and acetic anhydride.

As can be understood by those skilled in the art, the step three can be selected according to actual conditions to be carried out in a one-pot method with the step two.

The reaction equation of the present application is as follows:

wherein, the formula 1 is 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene, the formula 2 is 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, and the formula 3 is 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester. That is, in the present application, the compound of formula 1 is first oximated to obtain the compound of formula 2, and then the compound of formula 2 is rearranged to the compound of formula 3 in the presence of the aromatization catalyst, so that good yield is obtained, and the yield can reach 82.1% at most.

Taking the patent with publication number CN108299382a as an example, the reaction equation of the prior art is as follows:

in the prior art, the yield in the synthesis process from 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene to 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester in all the documents, specific experiments and production is low, and the highest conversion rate is not more than about 70%.

The reason why the yield is low is found in the present application is due to beckmann rearrangement, which is a side reaction during the reaction. The beckmann rearrangement product is shown as formula 4. The essential difference between beckmann rearrangement and aromatization is that aromatization produces the elimination of one molecule of water within the molecule.

(formula 4)

Specifically, the Semmler-Wolff aromatization reaction, the reaction mechanism in this application, is as follows:

the reaction mechanism of the Beckmann rearrangement reaction is as follows:

it can thus be seen that in the Semmler-Wolff aromatization reaction: the formation reaction of the target compound requires aromatization, specifically 1,3-elimination of hydroxyl group and alpha tertiary carbon ion in oxime. Under the action of an ionization catalyst, thiophene tertiary carbon is ionized to form a pi bond, oxime group nitrogen is ionized to form a ring structure, one molecule of water elimination occurs in a molecule, the pi bond is built at 4,5 of thiophene, imine double bonds are rearranged in the molecule, and the 2,3 pi bond is built. Wherein, the construction of 4,5 double bonds belongs to the E1 reaction process, and the ionization of tertiary carbon is the key of the process rate.

Whereas the Beckmann rearrangement reaction is the rearrangement of intramolecular atoms, the rearrangement of oximes (aldoximes or ketoximes) to amides under the catalysis of strong acids. The oxime hydroxy group gets a proton from the acid to form a leaving group and simultaneously forms an electron deficient nitrogen atom, which promotes the intramolecular 1,2-migration of a hydrocarbon group on the carbon atom adjacent to it. Deprotonation of oxygen, protonation of nitrogen and tautomerization produce the product, the amide.

From this, it is known that the construction of the double bond at 4,5 belongs to the E1 reaction process, and the rate of the process is critical for the ionization of tertiary carbon. The ionization of the tertiary carbon is accelerated, the 4-position tertiary carbon can be effectively prevented from moving to an oxime structure by 1,2-in the Beckmann rearrangement reaction process, namely, the six-membered ring of the rearrangement side reaction is prevented from being formed, and the reaction yield is further improved.

The invention has the following beneficial effects:

1. the application provides a preparation method of a novel articaine hydrochloride intermediate, which adopts a method of carrying out oximation reaction firstly, carrying out aromatization reaction after separating to obtain 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, and avoids the use of a metal ion catalyst and reduces the content of metal ions in a product by separating the processes of oximation reaction and aromatization reaction. Because the product contains sulfur element, a chelate with a darker color can be formed once the product is chelated with metal ions, and the metal ions in the chelate are difficult to separate from the product, the metal ions are finally brought into the articaine hydrochloride, so that the produced articaine hydrochloride contains heavy metal residues, and the appearance and residue items of the articaine hydrochloride do not meet the requirements of pharmacopeia. The method ensures that the target product has no darker color, and provides quality guarantee for the subsequent preparation of the articaine hydrochloride.

2. The application uses a specific catalyst capable of promoting the generation of carbon ions, accelerates the aromatization reaction process, reduces the generation of side reactions, and ensures that the HPLC purity of a target product is kept above 95 percent while improving the reaction yield.

3. The novel preparation method of the articaine hydrochloride intermediate avoids the use of dangerous materials such as hydrogen peroxide and the like, increases the safety of the process, and is green and environment-friendly in the whole process.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:

FIG. 1 is a hydrogen spectrum of methyl 3-amino-4-methyl-2-thiophenecarboxylate sulfate;

FIG. 2 is a hydrogen spectrum of methyl 3-amino-4-methyl-2-thiophenecarboxylate;

FIG. 3 is a putative diagram of the catalytic reaction mechanism of experiment 2.3.

Detailed Description

In order to more clearly explain the overall concept of the present application, the following detailed description is given by way of example in conjunction with the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present invention. It will be apparent, however, to one skilled in the art, that the present invention may be practiced without one or more of these specific details. In other instances, well-known features have not been described in order to avoid obscuring the invention.

The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.

In the following embodiments, reagents or instruments used are not indicated by manufacturers, and are all conventional products available by commercial purchase, unless otherwise specified.

Example 1 Synthesis of Thiophenemenoxime

The reaction mechanism of this example is as follows:

experiment 1.1

1. Adding 600 mL methanol into a flask, controlling the temperature of ice brine to be below 20 ℃, adding 105 g sodium acetate, and stirring until the sodium acetate is basically dissolved;

2. adding 89 g of hydroxylamine hydrochloride into the solution in batches, and stirring for more than 20 min to ensure that the hydroxylamine hydrochloride is dissolved;

3. dissolving 200 g of 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene in 200 mL methanol, dropwise adding the solution into the methanol solution of hydroxylamine hydrochloride at the temperature of below 20 ℃, and stirring to react 1 h after the dropwise adding is finished;

4. after the reaction is finished, concentrating methanol, dissolving the reaction product 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime with 600 mL toluene, washing once with 300 mL10% sodium carbonate aqueous solution, and washing once with 300 mL tap water;

5. the toluene solution is added with 100 g anhydrous sodium sulfate, dried for 30 min, filtered to remove the sodium sulfate, and then concentrated to dryness under vacuum at the temperature of below 50 ℃ to obtain 191.4 g product with the yield of 87%.

Experiment 1.2

1. Adding 600 mL methanol into a flask, controlling the temperature of ice salt water to be below 20 ℃, adding 139.8g (1.3 equivalent weight) of sodium bicarbonate, stirring for more than 15 min, and suspending the sodium bicarbonate in the methanol;

3. dissolving 200 g of 2-methoxycarbonyl-4-methyl-3-oxo-tetrahydrothiophene in 200 mL methanol, dropwise adding the solution into the methanol solution of hydroxylamine hydrochloride at the temperature of below 20 ℃, and stirring to react 1 h after the dropwise adding is finished;

5. the toluene solution was dried for 30 min with 100 g anhydrous sodium sulfate, filtered to remove sodium sulfate, and concentrated to dryness under vacuum at 50 ℃ to give 183.7g of product in 83.5% yield.

Experiment 1.3

1. Adding 600 mL methanol into a flask, controlling the temperature of ice brine to be below 20 ℃, adding 68 g sodium carbonate, and stirring until the sodium carbonate is basically dissolved;

5. adding 100 g anhydrous sodium sulfate into the toluene solution, drying for 30 min, filtering out the sodium sulfate, and concentrating under vacuum at a temperature below 50 ℃ to dryness to obtain a 167.2 g product with the yield of 76%.

And (4) conclusion: in this example, it was found that the alkalinity of sodium carbonate in the neutralization of hydroxylamine hydrochloride could cause some destruction of the ester of the thiophene active site, resulting in a decrease in yield, and therefore sodium carbonate was not suitable for use in the process.

Sodium acetate or sodium bicarbonate is preferred herein as a weakly basic reagent for the reaction of 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene with hydroxylamine hydrochloride.

Example 2 Synthesis of thiophene Ring

2-methoxycarbonyl-4-methyl-3-tetrahydrothiophenone oxime was prepared according to the preferred protocol in example 1 and the experiment of this example was continued.

Experiment 2.1

The reaction mechanism of experiment 2.1 is as follows:

1. 100 mL acetic anhydride, 18.9 g (0.1 Mol) 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, 7.85 g (0.1 Mol) acetyl chloride, 7.9 g pyridine are added into a 250 mL flask, and heated to reflux at the temperature of 130-132 ℃ to react for 6 h;

2. after the TLC technology monitoring reaction is finished, distilling out the solvent;

3. continuously adding 100 mL ethanol and 50 mL32% concentrated hydrochloric acid, and refluxing 4 h until the reaction is finished;

4. distilling the solvent, adding 50 mL ethanol with water, adding 50 mL ethanol, performing hot melting, freezing and crystallizing to obtain hydrochloride of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester;

5. filtering out refined hydrochloride of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester, dissolving with 76 g water, adjusting pH to 8-8.5 with 25% ammonia water (about 18 mL), adding 1.79 g activated carbon, stirring for 30 min at 60 ℃, filtering out activated carbon, freezing and crystallizing at-5-0 ℃ to obtain 12 h, filtering, and drying to obtain 12.32 g of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester, wherein the yield is 71.9%, and the purity is 99.1%.

Experiment 2.2

The reaction mechanism of experiment 2.2 is as follows:

1. adding 800 mL ethyl acetate into a flask, slowly adding 200 g concentrated sulfuric acid, and controlling the temperature of a stirring water bath to be 30-40 ℃;

2. taking 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime 378 g, adding 800 mL ethyl acetate for dissolving, then dropwise adding the solution into a solution formed by concentrated sulfuric acid and ethyl acetate, keeping the temperature at 30-35 ℃, and continuing to react for 8-10 h after dropwise adding is finished;

3. after the reaction is finished, cooling to 0-5 ℃, crystallizing 2 h, filtering and drying to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester sulfate with the weight of 414 g, wherein the hydrogen spectrum of the compound is shown in figure 1;

4. continuously dropwise adding 25% ammonia water into 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester sulfate, adjusting the pH to about 8.0-8.5 (the using amount of the ammonia water is about 200 g), concentrating the reaction solution to be dry in a water bath at 50 ℃ after the ammonia water is dropwise added, adding 1.2 g purified water, keeping the temperature at 25-30 ℃, stirring 2 h, then cooling to 0-5 ℃, centrifuging, and drying to obtain the target compound 250.6 g, wherein the yield is 73.2%, and the purity is 97.3%.

Experiment 2.3

The reaction mechanism of experiment 2.3 is as follows:

1. 100 mL of DME (ethylene glycol dimethyl ether), 18.9 g (0.1 Mol) 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, 1.26 g (0.05 Mol) elemental iodine and 9.8g concentrated sulfuric acid are added into a 250 mL flask, heated to reflux, the temperature is 105 ℃, and 12 h is reacted;

2. monitoring the complete disappearance of the raw materials by TLC technology, and cooling to below 30 ℃;

3. adding 100 mL water into the reaction flask, stirring, and carrying out quenching reaction by using a solution formed by dissolving 2 g sodium thiosulfate in 10 mL water (according to color indication, no yellowish turbid substances are separated out after the quenching is finished by dropwise adding sodium thiosulfate);

4. vacuum heating is started, the temperature is kept at 50 ℃ until glycol dimethyl ether is not distilled out any more, the temperature is reduced to 0-5 ℃, 12 h is stirred, 14.05 g of 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester is obtained, the yield is 82.1%, and the purity is 98.3%.

The specific reaction mechanism of experiment 2.3 is shown in fig. 3, and the hydrogen spectrum of the final product 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester is shown in fig. 2.

Experiment of the invention2.4

The reaction mechanism of experiment 2.4 is as follows:

1. adding 250 mL ethyl acetate, 18.9 g (0.1 Mol) 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophene ketoxime, 13.26 g (0.11 Mol) pivaloyl chloride and 8.3 g (0.06 Mol) potassium carbonate into a 500 mL flask, heating to 50-60 ℃, and stirring for 30 min;

2. continuously adding 0.945 g palladium acetate and 7.56 g triphenylphosphine (tricyclohexylphosphine), heating to reflux at 79-80 ℃ and about 4-5 h until the thin layer monitoring reaction is not performed any more;

3. cooling the solution to room temperature, filtering out inorganic salts and insoluble substances, washing with 100 mL water for three times, drying with anhydrous sodium sulfate, and concentrating;

4. dissolving the product with three times of methanol, adjusting pH to 2 by adding concentrated hydrochloric acid, and refluxing to 1 h;

5. after the solution is cooled to room temperature, the pH value is adjusted to 8-8.5 by using 25% ammonia water, 5% by weight of active carbon of a concentrated product is added, the mixture is stirred for 30 min at 60 ℃, finally the active carbon is filtered out, and the mixture is frozen at 0-5 ℃ for 12 h to obtain 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester 4.61 g, the yield is 26.9%, and the purity is 95.27%.

And (4) conclusion: in the crude product of the reaction of this example, a large amount of unreacted raw material was detected because of palladium acetate poisoning (chelation of sulfur and palladium) due to sulfur of the thiophene ring. It follows that the most classical aromatization process is not suitable for the preparation of the compounds of the present application.

The above description is only an example of the present application and is not intended to limit the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.

Claims

1. A preparation method of an articaine hydrochloride intermediate is characterized by comprising the following steps:

2. The method of claim 1, wherein the ionic catalyst is iodine; the acid catalyst is concentrated sulfuric acid and/or acetic acid; the transition metal catalyst is a palladium compound.

3. The method according to claim 1, wherein the oximation reaction is carried out under neutral or weakly alkaline conditions.

4. The preparation method according to claim 3, wherein the weakly alkaline conditions are selected from one or more of sodium bicarbonate, sodium carbonate and sodium acetate.

5. The method of claim 1, wherein the oximation reaction is carried out at a temperature of 0 ℃ to 30 ℃ for a time of 1 to 4 h.

6. The process according to claim 1, wherein the mass ratio of 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene to hydroxylamine hydrochloride in the oximation reaction is 1: (0.1-1).

7. The method according to claim 1, wherein the first step further comprises a step of extracting 2-methoxycarbonyl-4-methyl-3-tetrahydrothiophenone oxime after the oximation reaction, and the extraction solvent is toluene and/or dichloromethane.

8. The method of claim 1, wherein the second step further comprises a step of neutralizing the aromatization reaction product under alkaline conditions.

9. An articaine hydrochloride intermediate prepared according to any one of claims 1-8, wherein the articaine hydrochloride intermediate is methyl 3-amino-4-methyl-2-thiophenecarboxylate, and the HPLC purity of the methyl 3-amino-4-methyl-2-thiophenecarboxylate is greater than 95%.