Perindopril EP impurity E and preparation method thereof

Abstract

The invention discloses a perindopril EP impurity E and a preparation method thereof, and the preparation method comprises the following steps: taking a compound I as an initial raw material, and hydrolyzing ethyl ester to obtain a compound II; carrying out double esterification on the compound II to obtain a compound III; hydrolyzing and purifying the compound III to obtain a compound IV; the preparation method has the advantages of simple operation, no large harm in post-treatment, and convenient and easily available raw materials. The purity of the prepared perindopril EP impurity E reaches 98% or above, the impurity E meets the requirements of being used as an impurity reference substance, and the impurity E plays a positive role in research and inspection of perindopril related impurities; the perindopril has more chiral carbon, the alkaline condition is avoided as much as possible during synthesis, and the situation that a large number of isomer impurities are generated and the yield is reduced is prevented; the synthesis method of the perindopril EP impurity E is disclosed for the first time, the blank in the prior art is filled, and a new way for preparing the EP impurity E is provided for researchers.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to perindopril EP impurity E and a preparation method thereof. Background Art

[0002] Perindopril, whose chemical name is (2S,2aS,7aS) - 1{(S) - N - [(S) - 1 - ethylcarbamoylbutyl]alanyl}octahydro - 1H - indole - 2 - carboxylic acid, is an important drug for the treatment of cardiovascular diseases. Its main pharmacological action is to inhibit angiotensin I - converting enzyme (also known as kininase II), thereby preventing the conversion of angiotensin I to angiotensin II, which is a strong vasoconstrictor. At the same time, perindopril can also prevent the degradation of bradykinin, a vasodilator, into inactive peptides. The combined action of these two mechanisms makes perindopril show significant efficacy in the treatment of diseases such as arterial hypertension, heart failure, and stable coronary heart disease.

[0003] Although the efficacy of perindopril has been widely recognized, in terms of product quality control, several related substances including EP impurity E are included in the pharmacopoeias of various countries. The chemical name of EP impurity E is (2S,3aS,7aS) - 1 - ((S) - 1 - isopropoxy - 1 - oxopentan - 2 - yl) - L - alanyl)octahydro - 1H - indole - 2 - carboxylic acid. Although EP impurity E is mentioned in the literature "Journal of Chromatographic Science 2015; 1–7 doi: 10.1093 / chromsci / bmu223", its specific synthesis method and generation reason are not disclosed. Due to the difficulty in obtaining relevant impurity reference substances, this severely limits the research and detection work on perindopril impurities and affects the control and evaluation of drug quality.

[0004] Challenges in Ester Hydrolysis Reactions in Organic Synthesis:

[0005] In the process of organic synthesis, the hydrolysis reaction of esters is usually carried out under acidic or basic conditions. However, these conditions may lead to the occurrence of side reactions, such as the formation of isomers, thus affecting the purity and yield of the product. Especially in compounds containing multiple chiral centers, it is particularly important to control the reaction conditions to avoid unnecessary side reactions. This is crucial for ensuring the safety and effectiveness of drugs. Summary of the Invention

[0006] Aiming at the problems existing in the prior art, the present invention provides perindopril EP impurity E and a preparation method thereof.

[0007] The present invention provides a preparation method of perindopril EP impurity E, comprising the following steps:

[0008] A preparation method of perindopril EP impurity E, characterized by comprising the following steps:

[0009] Step S1: Using compound I as the starting material, hydrolyzing the ethyl ester to obtain compound II;

[0010] Step S2: Double-esterifying compound II to obtain compound III;

[0011] Step S3: Hydrolyzing compound III, and purifying to obtain compound IV;

[0012] The chemical reaction equation for preparing perindopril EP impurity E from steps S1 - S3 is as follows:

[0013]

[0014] Preferably, in step S1, 6N / HCl is selected to hydrolyze the ethyl ester. During hydrolysis, the tert-butylamine salt raw material can be liberated, and at the same time, alkaline conditions are avoided to prevent the generation of impurities.

[0015] Preferably, the reaction temperature in step S1 is 100 °C and the reaction time is 1 h.

[0016] Preferably, in step S2, thionyl chloride is selected for the esterification reaction, and the molar ratio to compound II is 2:1 to 3:1.

[0017] Preferably, in step 3, 6N / HCl is selected to hydrolyze compound III, and alkaline conditions are avoided to prevent the generation of impurities.

[0018] Preferably, in step 3, the reaction temperature is at room temperature and the reaction is carried out for 3 - 7 days.

[0019] The present invention also provides a perindopril EP impurity E, which is prepared by the described method and has a purity of more than 98%.

[0020] Adopting the technical solution of the present invention has the following beneficial effects:

[0021] The invention provides a preparation method of perindopril-related impurities. This method is simple to operate, the post-treatment has no great harm, and the raw materials are convenient to obtain. The prepared perindopril EP impurity E has a purity of more than 98%, all meeting the requirements as an impurity reference substance, and playing an active role in the research and inspection of perindopril-related impurities.

[0022] 2. Perindopril has many chiral carbons. During synthesis, alkaline conditions are avoided as much as possible to prevent the generation of a large amount of isomer impurities and reduce the yield.

[0023] Innovation of the synthesis method: The present invention discloses for the first time the synthesis method of perindopril EP impurity E, filling the blank in the prior art and providing a new way for researchers to prepare EP impurity E.

[0024] Improve the accuracy of impurity control: By providing a preparation method for EP impurity E, the present invention enables researchers to prepare a reference substance of high-purity EP impurity E, thereby improving the accuracy and reliability of impurity control for perindopril.

[0025] Promote drug quality research: The preparation method of EP impurity E of the present invention helps to promote in-depth research on perindopril and its impurities, providing an important scientific basis for drug quality control and evaluation.

[0026] Support the formulation and update of pharmacopoeia standards: The preparation method of EP impurity E provided by the present invention can support the formulation and update of the standards for related substances of perindopril in national pharmacopoeias, improving the scientificity and effectiveness of drug supervision.

[0027] Enhance drug safety and effectiveness: By precisely controlling and evaluating the impurities in perindopril, the present invention helps to improve the safety and effectiveness of drugs, ensuring the safety of patients' medication.

[0028] The present invention selects 6N / HCl to hydrolyze ethyl ester. During hydrolysis, the tert-butylamine salt raw material can be liberated, and at the same time, alkaline conditions are avoided to generate impurities. Using 6N / HCl instead of concentrated HCl reduces the occurrence of side reactions and improves the purity and quality of the product.

[0029] Optimized reaction conditions:

[0030] By selecting specific reaction conditions, such as using 6N / HCl to hydrolyze ethyl ester in step S1 and step S3, and using thionyl chloride for esterification reaction in step S2, the present invention reduces side reactions and improves the yield and purity of the target product.

[0031] Improve production efficiency:

[0032] The method of the present invention sets specific reaction temperature (100°C) and time (1 hour) in step S1. Such optimized reaction conditions significantly improve production efficiency and shorten the production cycle.

[0033] Economic benefits: The preparation method with high yield and high purity reduces raw material waste, lowers production costs, and improves economic benefits.

[0034] Environmentally friendly: The method of the present invention reduces the generation of harmful by-products, has little impact on the environment, and conforms to the development trend of green chemistry. Description of the drawings

[0035] Figure 1 It is a schematic diagram of the reaction equation of the present invention;

[0036] Figure 2Liquid phase diagram of the mixed sample of the compound obtained from Route (1) and Perindopril EP Impurity E;

[0037] Figure 3a Mass spectrometry diagrams at different time periods of Route (2); Figure 3b 、 Figure 3c 、 Figure 3d Successively are Figure 3a Magnified schematic diagrams;

[0038] Figure 4 Mass spectrometry diagram of Perindopril EP Impurity E of the present invention;

[0039] Figure 5 Liquid phase diagram of Perindopril EP Impurity E of the present invention. Detailed implementation manners

[0040] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0041] Referring to Figures 1 to 5 , the present invention discloses a preparation method of Perindopril EP Impurity E, aiming to efficiently and simply obtain a high-purity impurity reference substance for carrying out research and detection of related impurities of Perindopril.

[0042] The research idea of the present invention is as follows: The raw materials (Perindopril tert-butylamine salt), products (Perindopril EP Impurity E), and Structure 1 are as follows:

[0043]

[0044] 1. The initial synthesis route (1) of Perindopril EP Impurity E is:

[0045]

[0046] Although the molecular weight of the obtained compound is correct, the liquid phase does not coincide with Perindopril EP Impurity E (see Figure 2 ), so the required impurity is not obtained.

[0047] It is speculated that the compound obtained from Route (1) is Structure 1, and thus another route (2) is verified:

[0048]

[0049] When the third step of this route is carried out, the conditions for hydrolyzing ethyl ester (strong base, weak base, weak acid) are adopted. Although the reaction time is different, the results obtained from the mass spectrometry (see Figures 3a to 3d ) show that free Perindopril API is preferentially produced, and a large amount of ethyl ester hydrolysis structure appears after continuous reaction, so it is proved that the carboxylic acid activity on the indole is higher than that on the side chain.

[0050] Therefore, the synthetic route of perindopril EP impurity E was finally changed to route (3):

[0051]

[0052] Example 1:

[0053] The present invention provides a method for preparing perindopril EP impurity E, comprising the following steps:

[0054] Step S1:

[0055] Take 20 g of perindopril tert-butylamine salt (Compound I) raw material medicine, add 100 ml of 6N / HCl, heat up to 100 °C, react for 1 h. When the raw materials disappear, add H2O for dilution and then directly freeze-dry to obtain 23 g of crude product containing tert-butylamine hydrochloride (Compound II), with a yield of about 98.86%. Then proceed to Step S2:

[0056] High yield: The yield of Step S1 reaches about 98.86%. This high yield indicates high reaction efficiency, good utilization rate of raw materials, and few side reactions, providing sufficient raw materials for the subsequent steps.

[0057] Fast reaction: The reaction can be completed in 1 hour at 100 °C, indicating that the reaction rate is fast under this condition, suitable for industrial production, capable of shortening the production cycle and improving production efficiency.

[0058] Simplified operation: The crude product is obtained by direct freeze-drying, simplifying the traditional separation and purification steps, reducing the operation complexity and possible losses, and also reducing the cost.

[0059] Comparative Example 1: Take 20 g of perindopril tert-butylamine salt raw material medicine, add 100 ml of 6N / HCl, react at room temperature, extend the time for about 5 days, and the raw materials still exist. Concentrate to obtain 23 g of a mixture, with a low yield;

[0060] It can be seen that the reaction rate: In Example 1, the reaction was completed in 1 hour at 100 °C, while in Comparative Example 1, the raw materials were still not completely reacted after reacting at room temperature for 5 days. This shows that increasing the reaction temperature can significantly improve the reaction rate. Reaction efficiency: The yield of Example 1 reached about 98.86%, much higher than the yield of Comparative Example 1 (low yield). This indicates that the reaction is not only fast but also efficient at high temperature, with less product loss.

[0061] Utilization rate of raw materials: In Example 1, the raw materials were completely converted, reducing the cost and improving economic benefits; while in Comparative Example 1, the raw materials still existed, indicating that the utilization rate of raw materials is higher under high temperature conditions.

[0062] Step 2: Take 23 g of (2S,3aS,7aS)-1-((S)-1-carboxybutyl)-L-alaninyl)octahydro-1H-indole-2-carboxylic acid (Compound II) from the crude tert-butylamine hydrochloride in Step S1, add 150 ml of isopropanol and stir. Cool down in an ice-water bath, dropwise add 20 g of thionyl chloride. After addition, warm up to 80 °C and react for 22 h. Concentrate the reaction solution (add DCM), mix the sample and pass through a column, elute with DCM:MEOH = 100:1 to 20:1, and obtain 19 g of yellow oil (Compound III), with a yield of about 66.24%;

[0063] Step 3: Take 9 g of isopropyl (2S,3aS,7aS)-1-(((S)-1-isopropoxy-1-oxopentan-2-yl)-L-alaninyl)octahydro-1H-indole-2-carboxylate (Compound III), add 50 ml of 6N / HCl (a small amount of THF is used for solubilization), react at room temperature for about 5 days, and the proportion of the product is about 51%. Concentrate and lyophilize the reaction solution to obtain 8.6 g of crude product. After preparation and purification, 2.01 g of white solid of perindopril EP impurity E (Compound IV) is obtained, with a yield of about 24.79%;

[0064] The positive ion mass spectrum of perindopril EP impurity E is shown in Figure 4 , and the liquid phase is shown in Figure 5 : 1H NMR (400 MHz, DMSO-d6) δ 5.05 - 4.82 (m, 1H), 4.23 (dd, J = 10.2, 8.0 Hz, 1H), 3.86 (dt, J = 12.1, 6.2 Hz, 1H), 3.70 (s, 1H), 3.21 (s, 1H), 2.39 - 2.09 (m, 2H), 2.08 - 1.36 (m, 9H), 1.35 - 1.05 (m, 13H), 0.85 (t, J = 7.3 Hz, 3H).

[0065] Comparative Example 3: Take 9 g of isopropyl (2S,3aS,7aS)-1-(((S)-1-isopropoxy-1-oxopentan-2-yl)-L-alaninyl)octahydro-1H-indole-2-carboxylate, add 50 ml of concentrated HCl (a small amount of THF is used for solubilization), react at room temperature for about 1 day, and the proportion of the product is about 17% (the product overreacts and hydrolyzes the isopropyl ester). Concentrate and lyophilize the reaction solution to obtain 8.6 g of crude product. After preparation and purification, 0.56 g of white solid of perindopril EP impurity E is obtained, with a yield of about 6.9%.

[0066] In Comparative Example 3, it was mentioned that the product overreacted with isopropyl acetate, which was due to the use of concentrated HCl, resulting in an overly violent reaction. Not only did the target reaction proceed, but also unwanted side reactions occurred. In Example 1, the use of 6N / HCl was milder, reducing the occurrence of side reactions. The yield of Example 1 was approximately 24.79%, while the yield of Comparative Example 3 was only 6.9%. This shows that the reaction conditions of Example 1 not only increased the proportion of the product but also increased the overall yield. The proportion of the product in Example 1 was approximately 51%, while the proportion of the product in Comparative Example 3 was approximately 17%. This indicates that the reaction conditions of Example 1 are more conducive to the formation of the target product. Product purity and quality: The white solid of perindopril EP impurity E obtained in Example 1 was 2.01 g, while that obtained in Comparative Example 3 was only 0.56 g. It can be seen from this that the product obtained in Example 1 has higher purity and quality.

[0067] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention. Any equivalent structural transformation made under the inventive concept of the present invention, using the content of the specification and drawings of the present invention, or directly / indirectly applied in other related technical fields, is included in the patent protection scope of the present invention.

Claims

1. A method for preparing perindopril EP impurity E, characterized in that: The steps include: Step S1: Using compound I as the starting material, hydrolyzing the ethyl ester to obtain compound II; Step S2: double esterifying compound II to obtain compound III; Step S3: hydrolyzing compound III and purifying to obtain compound IV; The chemical reaction equation for preparing the impurity E of Perindopril EP from steps S1 to S3 is as follows:

2. The method for preparing the impurity E of Perindopril EP according to claim 1, wherein In step S1, 6N / HCl is selected to hydrolyze the ethyl ester, and the tert-butylamine salt API can be released during the hydrolysis, while avoiding alkaline conditions to generate impurities.

3. The method for preparing the impurity E of Perindopril EP according to claim 1, characterized in that: The reaction temperature in step S1 is 100° C. and the reaction time is 1 h.

4. The method for preparing the impurity E of Perindopril EP according to claim 1, characterized in that: In step S2, thionyl chloride is selected for esterification reaction, and the molar ratio of thionyl chloride to compound II is 2:1 to 3:

1.

5. The method for preparing the impurity E of Perindopril EP according to claim 1, characterized in that: In step 3, 6N / HCl was selected to hydrolyze compound III to avoid alkaline conditions that would generate impurities.

6. The method for preparing the impurity E of Perindopril EP according to claim 1, characterized in that: In step 3, the reaction temperature is room temperature for 3-7 days.

7. A perindopril EP impurity E, characterized in that The product is prepared by the method described in any one of claims 1 to 6, and the purity reaches more than 98%.

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