阅读说明：本技术 一种苯磺酸左旋氨氯地平环合杂质的合成方法 (Synthesis method of levamlodipine besylate cyclization impurity ) 是由 江鸿 于士兵 吕传涛 林红杰 高艺 于 2020-07-17 设计创作，主要内容包括：本发明提供一种苯磺酸左旋氨氯地平环合杂质的合成方法,属于有机化合物合成技术领域。所述合成方法包括：以(S)-(-)-3-乙基-5-甲基-2-(2-氨基乙氧甲基)-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸酯苯磺酸盐为原料,在酸性环境下,加压环合,经氢化还原即得AMLDEG-3。本发明提供的苯磺酸左旋氨氯地平环合杂质AMLDEG-3的合成方法具有原料来源丰富、反应简便高效、成本低等优点,从而有利于开展对苯磺酸左旋氨氯地平药物的质量研究,因此具有良好的实际应用之价值。(The invention provides a synthesis method of levamlodipine besylate cyclization impurities, belonging to the technical field of organic compound synthesis. The synthesis method comprises the following steps: taking (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate as a raw material, pressurizing and cyclizing under an acidic environment, and obtaining the AMLDEG-3 through hydrogenation reduction. The synthesis method of the levamlodipine besylate cyclization impurity AMLDEG-3 provided by the invention has the advantages of rich raw material sources, simple and efficient reaction, low cost and the like, thereby being beneficial to developing the quality research of levamlodipine besylate medicines and having good practical application value.)

1. A synthesis method of levamlodipine besylate cyclization impurities is characterized by comprising the following steps: taking (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate as a raw material, pressurizing and cyclizing under an acidic environment, and obtaining the AMLDEG-3 through hydrogenation reduction.

2. The synthesis method according to claim 1, wherein the reaction temperature is 110-140 ℃; the reaction pressure is 0.2-0.8 MPa.

3. The method of claim 1, wherein benzene sulfonic acid is added to provide an acidic environment during the reaction.

4. The synthesis method according to claim 1, wherein the benzenesulfonic acid is a solution of benzenesulfonic acid, and the solvent used in the solution is any one or more of tetrahydrofuran, toluene and xylene, preferably tetrahydrofuran.

5. The synthesis method according to claim 4, wherein the benzenesulfonic acid solution is a solution of benzenesulfonic acid in tetrahydrofuran at a concentration of 5-20% (w/v).

6. The synthesis process as claimed in claim 1, wherein the catalyst used in the reaction is Pd/C, Pd (OH)₂Any one of/C and Rainy Ni, preferably Pd/C.

7. The synthetic method of claim 1 further comprising a step of purifying the product.

8. The method of synthesis of claim 1, wherein the purification step comprises: filtering the product, concentrating, adding organic solvent for dissolving, adding water for washing, concentrating the organic phase to dryness, adding organic solvent again, heating for dissolving, cooling for crystallizing, filtering again and drying.

9. The method of synthesis according to claim 8, wherein the organic solvent is ethyl acetate; or the like, or, alternatively,

adding the organic solvent again, heating and dissolving, wherein the temperature is controlled to be 60-70 ℃; or the like, or, alternatively,

and in cooling crystallization, the temperature is controlled to be 10-20 ℃.

10. The application of the AMLDEG-3 prepared by the synthesis method in any one of claims 1 to 9 in the quality research of levamlodipine besylate drugs.

Technical Field

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of levamlodipine besylate cyclization impurities.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Levamlodipine besylate (CAS:103129-82-4) with the molecular formula: c₂₀H₂₅N₂O₅Cl·C₆H₆O₃S, the name of Chinese culture science is as follows: (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate benzenesulfonate. The structural formula is as follows:

compared with other similar products, the levamlodipine besylate has long antihypertensive effect time and slow and lasting antihypertensive effect, prevents rebound effect after drug withdrawal to a great extent, and avoids hypotension. The medicine can also effectively treat diseases such as angina pectoris, and the higher affinity of the medicine to blood vessels is helpful for prolonging the exercise time of patients with blood cardiomyopathy and the time from exercise to angina attack. At present, the levamlodipine besylate is widely used clinically, and a large number of clinical practices show that the levamlodipine besylate is a long-acting, safe and effective medicament and has better clinical treatment effect.

Document 1(Structure isolation of thermal degradation of amlodipine, Magn. Reson. chem.2007; 45: 688-:

the inventors found that although the literature reports the above three impurities, no synthetic method thereof is disclosed. However, when the quality of the raw material medicine is controlled, the content of impurities in the raw material medicine needs to be monitored by using an impurity reference substance so as to ensure that the prepared product meets the medicinal requirements, and then the prepared product can be used for preparing safe and effective medicinal preparations. Therefore, the rapid acquisition of the drug impurity reference substance has important significance for developing drug quality research.

Disclosure of Invention

Aiming at the problems in the prior art, the invention aims to provide the synthesis method of the levamlodipine besylate cyclization impurity AMLDEG-3, which has the advantages of rich raw material sources, simple, convenient and efficient reaction and low cost, thereby being beneficial to developing the quality research of levamlodipine besylate drugs and having good practical application value.

In order to achieve the technical purpose, the technical scheme provided by the invention is as follows:

in a first aspect of the present invention, there is provided a method for synthesizing levamlodipine besylate cyclization impurities, comprising: taking (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate as a raw material, pressurizing and cyclizing under an acidic environment, and obtaining the AMLDEG-3 through hydrogenation reduction. By adopting the synthesis method, the (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate is fully utilized as a raw material, and the reaction is simple, convenient and efficient.

In a second aspect of the invention, the application of the AMLDEG-3 in the quality research of levamlodipine besylate drugs is provided.

The beneficial technical effects of one or more technical schemes are as follows:

the technical scheme provides the synthesis method of the levamlodipine besylate cyclization impurity AMLDEG-3, which has the advantages of abundant raw material sources, simple, convenient and efficient reaction and low cost, and meanwhile, the product yield is high, the prepared product is easy to purify, the content of other impurities is extremely low, and the method is very favorable for applying the method to the medicine quality research of the levamlodipine besylate, so that the method has good practical application value.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings according to the provided drawings without creative efforts.

FIG. 1 is a MS spectrum of the amlodipine besylate cyclization impurity AMLDEG-3 prepared in example 1 of the present invention.

FIG. 2 shows the synthesis of the impurity AMLDEG-3 in the amlodipine besylate prepared in example 1 of the present invention¹H NMR spectrum.

FIG. 3 shows the synthesis of the impurity AMLDEG-3 of Levamlodipine besylate cyclization prepared in example 1 of the present invention¹³C NMR spectrum.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

As described above, although the literature reports three impurities generated during the synthesis of levamlodipine besylate, the synthesis method thereof is not disclosed. However, when the quality of the raw material medicine is controlled, the content of impurities in the raw material medicine needs to be monitored by using an impurity reference substance so as to ensure that the prepared product meets the medicinal requirements, and then the prepared product can be used for preparing safe and effective medicinal preparations. Therefore, the rapid acquisition of the drug impurity reference substance has important significance for developing drug quality research.

In view of the above, in one embodiment of the present invention, there is provided a method for synthesizing levamlodipine besylate cyclization impurity AMLDEG-3, the method comprising: taking (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate as a raw material, pressurizing and cyclizing under an acidic environment, and obtaining the AMLDEG-3 through hydrogenation reduction. By adopting the synthesis method, the (S) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate is fully utilized as a raw material, and meanwhile, the reaction is simple, convenient and efficient, and the cost is low.

In another embodiment of the invention, the reaction temperature is 110-140 ℃; the reaction pressure is 0.2-0.8 MPa. By controlling the reaction temperature and the reaction pressure, the reaction rate can be improved, and the reaction time can be shortened, and experiments prove that the reaction time is controlled to be limited to 4 hours by optimizing various reaction parameters and conditions.

In yet another embodiment of the present invention, benzene sulfonic acid is added to the reaction to provide an acidic environment.

In another embodiment of the present invention, the benzenesulfonic acid is a solution of benzenesulfonic acid, and the solvent used in the solution is any one or more of tetrahydrofuran, toluene and xylene, preferably tetrahydrofuran; therefore, the benzenesulfonic acid solution is a tetrahydrofuran solution of benzenesulfonic acid, and the concentration is 5-20% (w/v), such as 5%, 10%, 15% or 20%.

In yet another embodiment of the present invention, the catalyst used in the reaction is Pd/C, Pd (OH)₂Any one of/C and Rainy Ni, preferably Pd/C.

Specifically, the synthetic route is as follows:

in yet another embodiment of the present invention, the synthesis method further comprises a purification step of the product.

In yet another embodiment of the present invention, the purification step comprises: filtering the product, concentrating, adding organic solvent for dissolving, adding water for washing, concentrating the organic phase to dryness, adding organic solvent again, heating for dissolving, cooling for crystallizing, filtering again and drying.

In another embodiment of the present invention, the organic solvent is preferably ethyl acetate.

In another embodiment of the present invention, the organic solvent is added again to raise the temperature for dissolution, wherein the temperature is controlled to be 60-70 ℃.

In another embodiment of the present invention, the temperature is controlled to be 10-20 ℃ during the cooling crystallization.

In another embodiment of the invention, the application of the amleg-3 in the quality research of levamlodipine besylate drugs is provided.

The present invention will be further described with reference to the following examples. The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Based on the embodiments of the present invention, those skilled in the art can change the present invention without creating any inventive changes.