阅读说明：本技术 一种阿司匹林与碱性氨基酸的络合物的制备方法 (Preparation method of complex of aspirin and basic amino acid ) 是由 韦亚锋 徐正秀 徐新 陈昀 王璐 吴成柱 于 2020-11-23 设计创作，主要内容包括：本发明公开了阿司匹林与碱性氨基酸的络合物的制备方法,所述方法包括以下步骤：阿司匹林与碱性氨基酸在相转移催化剂的作用下,在无水有机溶剂中反应生成络合物。本发明的方法得到的络合物纯度高,杂质含量低。(The invention discloses a preparation method of a complex of aspirin and basic amino acid, which comprises the following steps: aspirin and basic amino acid react in anhydrous organic solvent under the action of phase transfer catalyst to produce complex. The complex obtained by the method has high purity and low impurity content.)

1. A process for the preparation of a complex of aspirin and a basic amino acid, characterized in that it comprises the following steps: aspirin and basic amino acid react in anhydrous organic solvent under the action of phase transfer catalyst to produce complex.

2. The process according to claim 1, wherein the phase transfer catalyst is a quaternary ammonium salt based catalyst, preferably one or more of a mono-quaternary ammonium salt and a di-quaternary ammonium salt.

3. The process of claim 2, wherein the mono-quaternary ammonium salt is tetrabutylammonium iodide; and/or the biquaternary ammonium salt is Gemini biquaternary ammonium salt.

4. The method according to claim 1, wherein the anhydrous organic solvent is selected from one or more of alcohols, ketones and oxygen-containing heterocycles;

wherein, the alcohol is preferably one or more of methanol, ethanol and isopropanol,

and/or, the ketones are preferably acetone,

and/or, the oxygen-containing heterocycle is preferably tetrahydrofuran;

further preferably, the anhydrous organic solvent is methanol or ethanol.

5. The method according to claim 1, wherein the molar ratio of aspirin to basic amino acid is (1.0-1.2): 1.0, preferably 1.1: 1.0.

6. The method according to claim 1, wherein the amount of the phase transfer catalyst is 0.2 to 1.0%, preferably 0.5% of the total weight of the aspirin and the basic amino acid.

7. The method of claim 1, wherein the basic amino acid is selected from one or more of lysine, arginine, and histidine; preferably, the basic amino acid is D, L-lysine.

8. The process according to claim 1, wherein the reaction temperature is between 25 and 60 ℃, preferably 35 ± 5 ℃.

9. The process according to claim 1, wherein the reaction time is 18 to 24 hours, preferably 20 to 22 hours.

10. The method of claim 1, wherein the end point of the reaction is determined by detection of amino acid residues by the indetrione method.

Technical Field

The invention belongs to the technical field of organic synthesis of medicines, and particularly relates to a preparation method of a stable complex formed by salifying aspirin and alkaline amino acid.

Background

Aspirin (o-acetylsalicylic acid) is a drug with analgesic, antipyretic and antirheumatic effects. Aspirin, however, has low solubility in blood, limiting its adequate absorption and utilization in the human body. Therefore, it is necessary to find a substance having high solubility containing physiological activity of aspirin, and its salt just satisfies this need.

The preparation of aspirin salts can be carried out by reacting it with basic amino acids to form salts. Wherein the salification of aspirin and lysine is a classical preparation method. The drug formed by salifying aspirin and lysine is called aspirin-lysine on the market.

The synthesis process of lysine pilin on the market is described in documents of Chinese patents CN101248036B and CN1298314C and 'research on processes for realizing industrial production of lysine pilin' of Wangyu & Hanyu, and takes aspirin and aqueous solution of D, L-lysine as starting materials, and produces the lysine pilin by salting in the aqueous solution or aqueous solution of organic alcohol.

However, the aspirin-lysine raw material generated by the process generally contains high free salicylic acid impurities, and the content of the aspirin in 0 day is about 0.1-0.3%, because aspirin is easy to degrade in a system containing water to generate free salicylic acid. And aspirin lysine will also gradually degrade during storage to produce free salicylic acid. The effective period of the aspirin-lysine injection is generally two years, and the control limit of free salicylic acid of the quality standard of the shelf life is less than or equal to 0.8 percent, so that the problem that the number of the free salicylic acid impurities in the aspirin-lysine raw powder is not more than 0.8 percent in the storage period within two years when the initial value is 0.2 to 0.3 percent is solved, and the problem is troublesome for current aspirin-lysine injection manufacturers. For the above reasons, the lower the value of 0-day free salicylic acid in aspirin-lysine raw material, the more likely it is to ensure the quality of aspirin-lysine product for injection within the effective period.

Although the literature reports that glycine auxiliary materials added into aspirin lysine for injection have the effect of enhancing the stability of aspirin lysine and can inhibit the generation of free salicylic acid, the method is a modified prescription designed because the impurities of the free salicylic acid in the raw material of aspirin lysine cannot be effectively reduced, and the problem that the free salicylic acid in the raw powder of aspirin is higher is not fundamentally solved.

In conclusion, it is necessary to establish a salting process for aspirin-lysine that is effective in reducing free salicylic acid impurities.

Disclosure of Invention

In order to solve the technical problems, the invention provides a novel method for generating a complex by aspirin and basic amino acid, which uses aspirin and basic amino acid crystals as raw materials to directly generate salts of the complex in an anhydrous organic solvent in the presence of a phase transfer catalyst.

The technical scheme adopted by the invention for solving the technical problem comprises the following contents:

the invention provides a preparation method of a complex of aspirin and basic amino acid, which comprises the following steps: aspirin and basic amino acid react in anhydrous organic solvent under the action of phase transfer catalyst to produce complex.

It is necessary to add a phase transfer catalyst to the reaction system of the present invention. The reaction system is heterogeneous because aspirin is soluble in an organic solvent, and crystals obtained by the reaction of aspirin with a basic amino acid have low solubility in the organic solvent. To solve the problems of reaction rate and progress, it is necessary to add a phase transfer catalyst.

In some embodiments, the phase transfer catalyst is a quaternary ammonium salt based catalyst, preferably one or more of a mono-quaternary ammonium salt and a di-quaternary ammonium salt.

Preferably, the mono-quaternary ammonium salt may be tetrabutylammonium iodide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, benzyltriethylammonium chloride (TEBA). More preferably, the mono-quaternary ammonium salt is tetrabutylammonium iodide.

Preferably, the diquaternary ammonium salt is a Gemini diquaternary ammonium salt, preferably 2-butenylbis (dimethyl-n-hexadecane) ammonium bromide. The Gemini surfactant is also called Gemini surfactant or Gemini surfactant, and the molecular structure of the Gemini surfactant is characterized in that two single-chain ionic head groups are combined on a linking group to form a functional structure which is hydrophilic and oleophilic. The special structure enables the Gemini surfactant to have more excellent interface performance than the traditional surfactant.

Other alternative diquaternary surfactants include: n, N' -bis (ethyl dimethyl fatty acid) acetate, ammonium chloride, dimethyl N-dodecyl phthalic acid diethyl ester bisammonium bromide, etc.

The method is realized in an anhydrous organic solvent reaction system. Because aspirin cannot be degraded to free salicylic acid in anhydrous organic solvents, the low impurity content of the obtained complex salt is ensured.

In some embodiments, the anhydrous organic solvent is selected from one or more of alcohols, ketones, and oxygenated heterocycles. The alcohol is preferably one or more of methanol, ethanol and isopropanol, the ketone is preferably acetone, and the oxygen-containing heterocycle is preferably tetrahydrofuran; further preferably, the anhydrous organic solvent is methanol or ethanol.

In contrast to conventional processes, the reaction of the present invention requires the use of an excess of aspirin. The reason is that residual aspirin in the resulting complex salt can be removed by washing with an organic solvent, while its residue in the complex cannot be removed when the amount of basic amino acid and crystals is excessive.

In some embodiments, the molar ratio of aspirin to basic amino acid is (1.0-1.2): 1.0, preferably 1.1: 1.0.

In some embodiments, the phase transfer catalyst is used in an amount of 0.2 to 1.0%, preferably 0.5%, based on the total weight of aspirin and the basic amino acid.

In some embodiments, the basic amino acid is selected from one or more of lysine, arginine, and histidine; preferably, the basic amino acid is D, L-lysine.

In some embodiments, the reaction temperature is between 25 ℃ and 60 ℃, preferably 35 ± 5 ℃.

In some embodiments, the reaction time is 18 to 24 hours, preferably 20 to 22 hours.

In some embodiments, the reaction endpoint is determined by detection of amino acid residues by the indetrione method.

The invention has the beneficial effects that:

it has now surprisingly been found that salt formation of aspirin with a basic amino acid can be achieved in an anhydrous organic solvent system. Especially, aspirin and D, L-lysine are salified in an anhydrous system to form an aspirin-lysine complex, so that an unexpected effect is achieved, particularly, the obtained product is high in purity, and the content of free salicylic acid impurities is reduced. The method of the invention reduces the content of free salicylic acid impurities in the complex salt. Because the aspirin and the crystal of the basic amino acid are complexed into salt in an anhydrous system, the aspirin cannot be degraded into free salicylic acid in a reaction system, and the complex salt is ensured to contain less impurities.

The method has the advantages of high product yield and obvious cost reduction. Another unexpected effect of the present invention process for forming complex salts is a significant increase in product yield. Since the complex salt is easily soluble in water, the product may be reduced in yield in a reaction system containing water due to its greater solubility in a solvent. Taking aspirin and D, L-lysine to produce aspirin-lysine as an example, the yield of the aspirin-lysine aspirin-lysine ester in the traditional process is about 70-80%, while the yield in the invention can reach 90-95%, and the yield is improved by 15-20%, so that the.

Detailed Description

The following examples are provided to illustrate the present invention, but the present invention is not limited to the examples.

Example 1

This example provides a method for producing a complex by reacting aspirin with D, L-lysine, specifically:

180.2g (1.0mol) of aspirin, 1.6g of tetrabutylammonium iodide and 450.0g of absolute ethanol were added to a 1000ml reaction flask at room temperature, and stirred until completely dissolved. 146.2g (1.0mol) of D, L-lysine crystals were added thereto, and the reaction temperature was controlled at 35 ℃. The reaction system is in a heterogeneous turbid state, and the reaction is continued for 18 hours under heat preservation. A large amount of white crystals are separated out in the reaction system, and the reaction progress is monitored by the indetrione method until the reaction is finished. Cooling to 20-25 ℃, filtering to obtain white crystal of aspirin-lysine, and washing with absolute ethyl alcohol. Vacuum drying at 60 + -2 deg.C for 6 h. 294.0g (0.90mol) of aspirin lysine white crystal are obtained, and the yield is 90.0%.

The aspirin content of the Aspirin-lysine complex is 53.8 percent, and the free salicylic acid content of the Aspirin-lysine complex is 0.06 percent.

Example 2

This example provides a method for producing a complex by reacting aspirin with D, L-lysine, specifically:

198.2g (1.1mol) of aspirin, 1.7g of tetrabutylammonium iodide and 475.0g of absolute ethanol were added to a 1000ml reaction flask at room temperature, and stirred until completely dissolved. 146.2g (1.0mol) of D, L-lysine crystals were added thereto, and the reaction temperature was controlled at 35 ℃. The reaction system is in a heterogeneous turbid state, and the reaction is continued for 18 hours under heat preservation. A large amount of white crystals are separated out in the reaction system, and the reaction progress is monitored by the indetrione method until the reaction is finished. Cooling to 20-25 ℃, filtering to obtain white crystal of aspirin-lysine, and washing with absolute ethyl alcohol. Vacuum drying at 60 + -2 deg.C for 6 h. 316.8g (0.92mol) of aspirin lysine white crystal is obtained, and the yield is 92.0%.

The aspirin content of the aspirin complex is 55.1 percent, and the free salicylic acid content of the aspirin complex is 0.05 percent.

Example 3

This example provides a method for producing a complex by reacting aspirin with D, L-lysine, specifically:

198.2g (1.1mol) of aspirin, 1.7g of 2-butenylbis (dimethyl-n-hexadecane) ammonium bromide and 475.0g of absolute ethanol were added to a 1000ml reaction flask at room temperature, and stirred until completely dissolved. 146.2g (1.0mol) of D, L-lysine crystals were added thereto, and the reaction temperature was controlled at 35 ℃. The reaction system is in a heterogeneous turbid state, and the reaction is continued for 18 hours under heat preservation. A large amount of white crystals are separated out in the reaction system, and the reaction progress is monitored by the indetrione method until the reaction is finished. Cooling to 20-25 ℃, filtering to obtain white crystal of aspirin-lysine, and washing with absolute ethyl alcohol. Vacuum drying at 60 + -2 deg.C for 6 h. 327.2g (0.95mol) of aspirin lysine white crystals are obtained, and the yield is 95.0%.

The aspirin content of the aspirin complex is 55.5 percent, and the free salicylic acid content of the aspirin complex is 0.04 percent.

Example 4

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: tetrabutylammonium iodide was replaced with tetrabutylammonium bromide.

The aspirin content of the aspirin complex is 55.2 percent, and the free salicylic acid content of the aspirin complex is 0.06 percent.

Example 5

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: tetrabutylammonium iodide was replaced with benzyltriethylammonium chloride.

The aspirin content in the Aspirin-lysine complex is 54.8%, and the free salicylic acid content in the Aspirin-lysine complex is 0.05%.

Example 6

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: absolute ethanol was replaced with acetone.

The aspirin content of the Aspirin-lysine complex is 55.0 percent, and the free salicylic acid content of the Aspirin-lysine complex is 0.06 percent.

Example 7

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: anhydrous ethanol was replaced with tetrahydrofuran.

The aspirin content of the aspirin complex is 55.2 percent, and the free salicylic acid content of the aspirin complex is 0.05 percent.

Example 8

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: adjusting the mass ratio of aspirin to basic amino acid to be 1.2: 1.0.

the aspirin content in the Aspirin-lysine complex is 54.6%, and the free salicylic acid content in the Aspirin-lysine complex is 0.04%.

Example 9

This example provides a method for reacting aspirin with a basic amino acid to form a complex. Compared with the example 1, the material molar ratio and other process parameters are unchanged, and the differences are only that: d, L-lysine was replaced with arginine.

The aspirin content of the Aspirin-lysine complex is 50.6 percent, and the free salicylic acid content of the Aspirin-lysine complex is 0.07 percent.

Example 10

This example provides a method for the reaction of aspirin with D, L-lysine to form a complex. Compared with example 1, the difference is only that: the absolute ethanol was replaced with 95% aqueous ethanol.

The aspirin content in the Aspirin-lysine complex is 54.2%, and the free salicylic acid content in the Aspirin-lysine complex is 0.10%.

Comparative example 1

This comparative example is a conventional process for preparing aspirin-lysine.

180.2g (1.0mol) of aspirin and 360.0g of absolute ethanol were added to a 1000ml reaction flask at room temperature, and stirred until completely dissolved. Then 503.4g of aqueous solution of D, L-lysine with the concentration of 29.0 percent (containing 1.0mol of lysine) is dripped, the reaction temperature is controlled at 30 ℃, and the dripping is finished within 0.5 h. And continuing the reaction for 0.5h, reducing the temperature to 5-10 ℃ to obtain aspirin-lysine white crystals after a large amount of white crystals appear, and washing with absolute ethyl alcohol. Vacuum drying at 60 + -2 deg.C for 6 h. 262.8g (0.805mol) of aspirin lysine white crystal is obtained, and the yield is 80.5%.

The aspirin content of the Aspirin-lysine complex is 44.8 percent, and the free salicylic acid content of the Aspirin-lysine complex is 0.26 percent.

From the above results, it is understood that the process of the present invention does not require the use of an excess of aspirin, and that a lysine-aspirin complex is obtained in an anhydrous system. The product yield is high, the purity is high, the content of free salicylic acid impurities is very low and is below 0.10%, and compared with the prior art, the content of the free salicylic acid impurities is reduced by about 2.6-6.5 times. Therefore, the method improves the quality of aspirin-lysine, further reduces the irritation and sensitization of the medicine, greatly improves the safety of the medicine, and has very important significance for clinical medication.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications, such as reaction material mixture ratio, catalyst type, organic solvent type, reaction temperature, reaction time, etc., can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.