A method for purifying a sacubitril sodium intermediate

Abstract

The application provides a refining method of a sacubitril valsartan sodium intermediate, and relates to the field of drug intermediate synthesis. The sacubitril valsartan sodium intermediate compound is (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The application also relates to a control method of specific impurities in the refining process of the compound, which comprises the following steps: mixing the sacubitril valsartan sodium intermediate crude product with ethyl acetate or isopropyl acetate, then heating to a reflux state, keeping the reflux state for 1-2 hours, and then performing slow cooling, pressure filtration, vacuum drying and other process procedures to obtain the sacubitril valsartan sodium intermediate (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The sacubitril valsartan sodium intermediate obtained by the refining method has high purity, no solvent residue, mild reaction conditions and is easy to be industrialized.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical intermediate synthesis, and relates to a refining method of a sacubitril valsartan sodium intermediate, in particular to a refining method of (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride. BACKGROUND

[0002] Sacubitril valsartan sodium is a small molecule drug developed by Novartis, which is a brain natriuretic peptide (NEP) inhibitor. The mechanism of action is to block the RAAS angiotensin II receptor and inhibit NEP, dilate blood vessels, prevent and reverse cardiovascular remodeling and sodium excretion.

[0003] The sacubitril valsartan sodium intermediate (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride is a very key intermediate for synthesizing sacubitril valsartan sodium, and the chemical structure is as follows:

[0004]

[0005] In addition to being a key intermediate for synthesizing sacubitril valsartan sodium, (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride is widely used in many fields. In the textile industry, a certain concentration of (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride is usually prepared as an active substance to prepare an antibacterial agent. After the textile fabric such as cloth and cotton is treated by immersion and dyeing, the growth of bacteria can be effectively inhibited, and the antibacterial property is durable, and good antibacterial effect can still be obtained after multiple washing [1] . In the aquaculture industry, (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride can reduce ammonia and phosphate in the water environment, inhibit the growth of algae, and balance the ecological system of the marine aquaculture environment. Disinfecting the surface of tableware with (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride for 5-10 min can kill 99.9% of Escherichia coli [2] , meeting the requirements of the national relevant health standards. At present, (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride and polyaminopropyl biguanide salt are mainly used as active ingredients in contact lens care solutions on the market. In addition, (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride can also be used for disinfection of surgical gowns and disinfection of part of medical devices.

[0006] At present, in the preparation method of the intermediate compound (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methyl valerate hydrochloride of sacubitril valsartan sodium, mixed solvents are mostly used for purification, which has problems such as multiple types of solvents, high toxicity of solvents, complex operation process, low yield, low purity, difficult recovery of solvents, high environmental pressure and the like. WO2008 / 083967 discloses a preparation method of sacubitril valsartan sodium, however, due to the excessive addition of thionyl chloride in the synthesis route, a large amount of acidic substances exist in the prepared intermediate ((2R, 4S)-4-amino-5-diphenyl-4-yl-2-methyl valerate hydrochloride), which leads to low purity of the intermediate.

[0007] Therefore, whether market demand or technical requirements indicate that it is necessary to further study the synthesis of the intermediate (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methyl valerate hydrochloride of sacubitril valsartan sodium, and the refining method and impurity control of the intermediate are the research hotspots.

[0008] [1] V. B. Subramanian, N. K. Katari, V. Ponnam, et al. Stability-indicating reversed-phase-HPLC method development and validation for sacubitril / valsartan complex in the presence of impurities and degradation products: Robustness by quality-by-design approach, Biomed [J]. Chromatogr. 36(1) (2022) e5240.

[0009] [2] Y. Zhang, Y. Wu, Preparation of sacubitril valsartan sodium salt [J]. Peop. Rep. China. 2021, p. 14 pp. SUMMARY

[0010] Based on the problems and deficiencies in the prior art, the present application aims to provide a refining method of the intermediate of sacubitril valsartan sodium and control of specific impurities, so as to obtain the intermediate of sacubitril valsartan sodium with high purity and low content of specific impurities.

[0011] The technical scheme of the present application is as follows:

[0012] In one aspect, the present application provides a method for purifying a sacubitril valsartan sodium intermediate, comprising the following steps:

[0013] (1) Weigh the sacubitril valsartan sodium intermediate and dissolve it in an organic solvent by heating;

[0014] (2) Cool, filter and separate, vacuum dry the filter cake, and obtain the purified sacubitril valsartan sodium intermediate.

[0015] The sacubitril valsartan sodium intermediate is (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methyl pentanoic acid ethyl ester hydrochloride, and its compound structure is as follows:

[0016]

[0017] Specifically, the organic solvent in the step (1) and step (3) comprises one or more of n-heptane, ethyl acetate, isopropyl acetate, ethanol, methyl acetate or isopropyl alcohol.

[0018] Further specifically, the organic solvent in the step (1) and step (3) comprises one or more of ethyl acetate, isopropyl acetate or methyl acetate.

[0019] Preferably, the organic solvent in the step (1) and step (3) is ethyl acetate.

[0020] Specifically, the volume of the organic solvent in the step (1) is 3-12 times the mass of the sacubitril valsartan sodium intermediate.

[0021] Further specifically, the volume of the organic solvent in the step (1) is 5-10 times the mass of the sacubitril valsartan sodium intermediate.

[0022] Specifically, the heating in the step (1) is heating to a reflux state, and the reflux temperature is selected from 75-88℃.

[0023] Preferably, the reflux temperature is 75-78℃.

[0024] Specifically, the cooling step in the step (2) is first naturally cooled to 0-25℃, then stirred for 1-2 hours, then cooled to 0-5℃, and then stirred for 1-2 hours.

[0025] Specifically, the vacuum drying temperature in the step (2) is 40-60℃.

[0026] Preferably, the vacuum drying temperature in the step (2) is 50-55℃.

[0027] Specifically, the above-mentioned purification method is applied in the fields of food, agriculture, textile industry, medical treatment, pharmaceutical and / or chemical industry.

[0028] In another aspect, the present application provides a method for controlling a specific by-product impurity in a sacubitril / valsartan sodium intermediate, the specific by-product impurity having a structural formula as shown below:

[0029]

[0030] In yet another aspect, the present application provides a method for HPLC detection of a sacubitril / valsartan sodium intermediate.

[0031] Specifically, the HPLC parameters are as follows:

[0032] Chromatograph: Agilent liquid chromatograph 1260;

[0033] Chromatographic column: 3 C18, 100 mm x 4.6 mm;

[0034] Mobile phase A: 0.1% phosphoric acid aqueous solution;

[0035] Mobile phase B: acetonitrile;

[0036] Gradient:

[0037]

[0038] Column flow rate: 1.0 mL / min, column temperature: 30°C;

[0039] Wavelength: UV 254 nm, injection volume: 10 μL;

[0040] The peak time of the sacubitril / valsartan sodium intermediate is 8.3 minutes.

[0041] The present application has the following beneficial effects:

[0042] (1) The method for refining the sacubitril / valsartan sodium intermediate compound according to the present application has the advantages of fewer types of solvents, easy operation, high purity and yield of the sacubitril / valsartan sodium intermediate.

[0043] (2) The method for controlling the specific degradation impurity according to the present application has the advantages of low content of the specific degradation impurity in the obtained product, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 Figure 1 is an HPLC chart of a sacubitril / valsartan sodium intermediate sample before process optimization.

[0045] Figure 2 Figure 2 is an HPLC chart of a sacubitril / valsartan sodium intermediate sample after process optimization in Example 3. DETAILED DESCRIPTION

[0046] The present application will be described in conjunction with specific examples, the following examples are not used to limit the present application, but only for the description of the present application, so that the technical solutions of the present application are easier to understand. The experimental methods described in the following examples, such as no special instructions, are all conventional methods; the reagents and materials, such as no special instructions can be obtained from commercial channels.

[0047] Example 1 Purification method of sacubitril valsartan sodium intermediate

[0048] 10g of sacubitril valsartan sodium intermediate was dissolved in 50mL of ethyl acetate, heated to 75-78℃ reflux, and stirred for 1 hour, cooled to 20-25℃, stirred for 1-2h, and then cooled to 0-5℃, stirred for 1-2h, filtered, and the filter cake was washed with ethyl acetate, and dried at 50-55℃ under vacuum to obtain 9.5g of sacubitril valsartan sodium intermediate, with a yield of 95% and a purity of 99.95%.

[0049] Example 2 Purification method of sacubitril valsartan sodium intermediate

[0050] 10g of sacubitril valsartan sodium intermediate was dissolved in 50mL of ethyl acetate, heated to 75-78℃ reflux, and stirred for 1 hour, cooled to 20-25℃, stirred for 1-2h, and then cooled to 0-5℃, stirred for 1-2h, filtered, and the filter cake was washed with ethyl acetate, and dried at 50-55℃ under vacuum to obtain 9.5g of sacubitril valsartan sodium intermediate, with a yield of 95% and a purity of 99.95%.

[0051] Example 3 Purification method of sacubitril valsartan sodium intermediate

[0052] 10g of sacubitril valsartan sodium intermediate was dissolved in 50mL of ethyl acetate, heated to 75-78℃ reflux, and stirred for 1 hour, cooled to 20-25℃, stirred for 1-2h, and then cooled to 0-5℃, stirred for 1-2h, filtered, and the filter cake was washed with ethyl acetate, and dried at 50-55℃ under vacuum to obtain 9.5g of sacubitril valsartan sodium intermediate, with a yield of 95% and a purity of 99.95%.

[0053] Comparative Example 1 Purification method of sacubitril valsartan sodium intermediate

[0054] 10g of sacubitril valsartan sodium intermediate was dissolved in 50mL of ethyl acetate, heated to 75-78℃ reflux, and stirred for 1 hour, cooled to 20-25℃, stirred for 1-2h, and then cooled to 0-5℃, stirred for 1-2h, filtered, and the filter cake was washed with ethyl acetate, and dried at 50-55℃ under vacuum to obtain 9.5g of sacubitril valsartan sodium intermediate, with a yield of 95% and a purity of 99.95%.

[0055] Refinement process of sacubitril valsartan sodium intermediate

[0056] The 5 g of sacubitril valsartan sodium intermediate was dissolved in 25 mL of isopropyl acetate, heated to 65-70 °C and refluxed, and stirred for 1 hour. The temperature was lowered to 20-25 °C and stirred for 1-2 hours. The temperature was further lowered to 0-5 °C and stirred for 1-2 hours. Filtration was performed, the filter cake was washed with ethyl acetate, and vacuum drying was performed at 50-55 °C to obtain 3.9 g of sacubitril valsartan sodium intermediate, with a yield of 78% and a purity of 99.34%.

[0057] Refinement process of sacubitril valsartan sodium intermediate

[0058] The 5 g of sacubitril valsartan sodium intermediate was dissolved in 25 mL of isopropyl acetate, heated to 65-70 °C and refluxed, and stirred for 1 hour. The temperature was lowered to 20-25 °C and stirred for 1-2 hours. The temperature was further lowered to 0-5 °C and stirred for 1-2 hours. Filtration was performed, the filter cake was washed with ethyl acetate, and vacuum drying was performed at 50-55 °C to obtain 3.9 g of sacubitril valsartan sodium intermediate, with a yield of 78% and a purity of 99.34%.

[0059] Refinement process of sacubitril valsartan sodium intermediate

[0060] The 5 g of sacubitril valsartan sodium intermediate was dissolved in 25 mL of isopropyl acetate, heated to 65-70 °C and refluxed, and stirred for 1 hour. The temperature was lowered to 20-25 °C and stirred for 1-2 hours. The temperature was further lowered to 0-5 °C and stirred for 1-2 hours. Filtration was performed, the filter cake was washed with ethyl acetate, and vacuum drying was performed at 50-55 °C to obtain 3.9 g of sacubitril valsartan sodium intermediate, with a yield of 78% and a purity of 99.34%.

[0061] Refinement process of sacubitril valsartan sodium intermediate

[0062] The 5 g of sacubitril valsartan sodium intermediate was dissolved in 25 mL of isopropyl acetate, heated to 65-70 °C and refluxed, and stirred for 1 hour. The temperature was lowered to 20-25 °C and stirred for 1-2 hours. The temperature was further lowered to 0-5 °C and stirred for 1-2 hours. Filtration was performed, the filter cake was washed with ethyl acetate, and vacuum drying was performed at 50-55 °C to obtain 3.9 g of sacubitril valsartan sodium intermediate, with a yield of 78% and a purity of 99.34%.

[0063] Experimental method 1: Determination of yield and purity

[0064] Experimental method: The sacubitril valsartan sodium intermediate obtained in Examples 1-3 and Comparative Examples 1-4 was determined by HPLC to determine the yield and purity of the sacubitril valsartan sodium intermediate. The results are shown in Table 1.

[0065] Table 1: Sacubitril valsartan sodium intermediate

[0066]

[0067]

[0068] The above data show that the yield of the sacubitril valsartan sodium intermediate prepared in Example 3 is as high as 98%, and the purity is 99.90%, which has the highest yield and purity compared with the sacubitril valsartan sodium intermediates prepared by other methods. And if any step in the preparation method is changed, the yield and purity of the prepared sacubitril valsartan sodium intermediate will be reduced to different degrees.

[0069] Experimental method 2: determination of specific degradation impurity content

[0070] Before process optimization, the preparation method of the sacubitril valsartan sodium intermediate was as follows: 10 g of raw material (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid was dissolved in 50 ml of anhydrous ethanol, and 4.7 g of thionyl chloride was added dropwise at room temperature. After the dropwise addition was completed, the temperature was increased to reflux and stirred for 1-2 h. After the temperature was increased, the reaction solution was concentrated under reduced pressure and evaporated to dryness. The reaction solution was evaporated with anhydrous ethanol for three times to obtain a sacubitril valsartan sodium intermediate sample.

[0071] The sacubitril valsartan sodium intermediate sample prepared before process optimization and the sacubitril valsartan sodium intermediate sample prepared in the example were detected according to the HPLC detection method described in experimental method 1. The HPLC chart of the sacubitril valsartan sodium intermediate sample prepared before process optimization is shown in Figure 1 The HPLC chart of the sacubitril valsartan sodium intermediate sample prepared in Example 3 is shown in Figure 2 .

[0072] The above data show that the chemical shift of the specific impurity is 12.646 min, and the peak area of the specific degradation impurity in the sacubitril valsartan sodium intermediate sample prepared after process optimization is small, indicating that the content of the specific degradation impurity in the sacubitril valsartan sodium intermediate prepared after process optimization is low.

[0073] The above detailed description is a specific description of one of the feasible embodiments of the present application, which is not used to limit the patent scope of the present application. It should be noted that any equivalent implementation or change made without departing from the present application should be included in the scope of the technical solutions of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A method for purifying a sacubitril / valsartan sodium intermediate, characterized in that, Includes the following steps: (1) Weigh the sacubitril-valsartan sodium intermediate and dissolve it in ethyl acetate by heating; (2) Cooling, filtering and separating, vacuum drying of the filter cake to obtain the refined sacubitril-valsartan sodium intermediate; The intermediate of sacubitril / valsartan sodium is (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylvalerate ethyl hydrochloride; The heating in step (1) is to heat to the reflux state, and the reflux temperature is 75-78℃; The cooling step in step (2) is to first cool naturally to 25°C, then stir for 1-2 hours, then cool to 0-5°C, and then stir for 1-2 hours. The vacuum drying temperature in step (2) is 50-55℃; The volume of ethyl acetate in step (1) is 3-12 times the mass of the sacubitril / valsartan sodium intermediate.

2. The refining method according to claim 1, characterized in that, The volume of ethyl acetate in step (1) is 5-10 times the mass of the sacubitril / valsartan sodium intermediate.

3. The refining method according to any one of claims 1-2, characterized in that, The refining method is used in the food, agriculture, textile, medical, pharmaceutical and / or chemical industries.

Images