Preparation method of sacubitril valsartan sodium

Abstract

The invention relates to a preparation method of sacubitril, which comprises the following steps: (1) reacting (S)-1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-ol with succinimide under the condition of triphenylphosphine and DEAD (Diethylaminoethyl Adenine) to obtain (R)-1-(1-([1, 1'-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone; (2) adding water and an alkaline reagent into the product in the step (1) to obtain (R)-4-(([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid; (3) carrying out oxidation and wittig reaction on the product obtained in the step (2) to prepare (4R)-5-[1, 1 '-biphenyl]-4-yl-4-[(3-carboxyl-1-oxopropyl) amino]-2-methyl-2-pentenoic acid-1-ethyl ester; (4) performing palladium-carbon catalytic reaction on the product obtained in the step (3) for alkali adjustment to prepare a sacubitril sodium salt aqueous solution; and (5) performing free extraction on the sacubitril sodium salt, concentrating, adding acetone and isopropanol to prepare a mixed solution, and reacting with valsartan and sodium hydroxide to prepare the sacubitril valsartan sodium. The method is simple and convenient to operate, can obtain the product with high purity and high yield, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing sacubitril / valsartan sodium. Background Technology

[0002] Sacubitril / valsartan sodium, as a novel anti-heart failure drug, offers a more effective treatment option for heart failure patients through its unique dual mechanism of action and synergistic effect, possessing significant clinical application value. Through the dual mechanism and synergistic effect of these two components, sacubitril / valsartan sodium can effectively treat chronic heart failure with reduced ejection fraction, and its efficacy and safety have been confirmed by large clinical studies such as PARADIGM-HF. Sacubitril / valsartan sodium is primarily used to treat adult patients with chronic heart failure with reduced ejection fraction (NYHA class II-IV, LVEF ≤ 40%), reducing the risk of cardiovascular death and hospitalization for heart failure. The structural formula of sacubitril / valsartan sodium is as follows:

[0003]

[0004] According to the synthetic route of sacubitril / valsartan sodium disclosed in patents WO2008031567A1 and CN105026361A, (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol is used as the raw material. The process involves photoelectrophoresis, acidic hydrolysis of the amide, Boc protection, oxidation, Wittig reaction, alkaline hydrolysis, hydrogenation, deprotection under thionyl chloride conditions, and esterification to obtain (2R,4S)-5-([1,1-biphenyl]-4-yl)-4-amino-2-methylvaleric acid ethyl ester hydrochloride. This is then reacted with succinic anhydride to obtain sacubitril, followed by the addition of sodium hydroxide and calcium chloride to form the calcium salt. Next, acid hydrolysis and extraction concentration are required to obtain free sacubitril acid. Finally, it reacts with valsartan and sodium hydroxide to obtain sacubitril / valsartan sodium. The total number of steps is eleven. The original synthetic route is as follows:

[0005]

[0006] The main problems with the original research route in large-scale production are as follows: 1. After hydrolyzing (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-diketoic acid, the exposed amino group requires a Boc protection step to prevent side reactions. In subsequent steps, thionyl chloride is used to remove the protecting group, and the large amount of acidic gas generated by thionyl chloride can easily corrode the production equipment. 2. After acid hydrolysis of the amide in the photoelectrodeization reaction, the amide is regenerated by reacting (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylvalerate ethyl hydrochloride with succinic anhydride in subsequent steps. Other process impurities are easily generated during the reaction. 3. The process of preparing sacubitril into calcium salt increases the number of steps and introduces calcium ions, which also poses a challenge to the quality control of the active pharmaceutical ingredient. 4. The entire production process is relatively long, with a total of eleven reaction steps and complicated synthesis and post-processing operations. Summary of the Invention

[0007] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a simple, convenient method for the industrial production of sacubitril / valsartan sodium with high purity and high yield.

[0008] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0009] A method for preparing sacubitril / valsartan sodium includes the following steps:

[0010] (1) Under an inert atmosphere, (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-ol was dissolved in an organic solvent. After cooling to -10 to 5°C, triphenylphosphine, succinimide, and diethyl azodicarbonate were added sequentially, and the reaction was carried out at the same temperature. After the reaction was completed, the solvent was removed by concentration, and the resulting solid was purified by adding solvent to the solid and slurrying. After cooling to crystallize, the solid was filtered, washed, and dried to obtain (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione.

[0011] Its structural formula is

[0012] (2) The (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione obtained in step (1) was mixed with water and an alkaline reagent, and the mixture was kept at 60-85°C until the raw material was completely converted. After the reaction was completed, the reaction solution was extracted with an organic solvent. The separated organic layer was washed with water and concentrated. The crude product was then pulped with an alkane solvent, filtered, and dried to obtain (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid.

[0013] Its structural formula is

[0014] (3) The (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid obtained in step (2), halide salt, base, and organic solvent-water mixed solvent are mixed, and sodium hypochlorite solution is added dropwise at low temperature to carry out the oxidation reaction; after the reaction is completed, the reaction is quenched, the aqueous phase is separated, and Wittig reagent is added to the obtained organic phase to carry out the reaction; after the reaction is completed, the organic phase is separated and concentrated, and the crude product is dissolved in alcohol-water mixed solvent by heating, acidified to precipitate crystals, filtered and dried to obtain the (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid ethyl ester.

[0015] Its structural formula is

[0016] (4) The (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester obtained in step (3) is subjected to catalytic hydrogenation. After the reaction is completed, the organic solvent is removed by concentration to obtain crude sacubitril free acid. The crude sacubitril free acid reacts with the base in the aqueous phase to form an aqueous solution of sacubitril sodium salt. Then, it is extracted with an organic extractant to separate the organic phase and obtain a purified sacubitril sodium aqueous solution.

[0017] (5) Sacubitril sodium salt aqueous solution was freed to obtain sacubitril free acid, and acetone and isopropanol were added to prepare a mixed solution. Then valsartan and sodium hydroxide were added to react and high-purity sacubitril valsartan sodium was prepared.

[0018] Furthermore, the organic solvent mentioned in step (1) is tetrahydrofuran, and its amount is 8 to 12 times the weight of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol.

[0019] Furthermore, the purification solvent mentioned in step (1) is selected from isopropanol, methanol, and ethanol, with ethanol being preferred;

[0020] Furthermore, in step (1), the molar ratio of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol, triphenylphosphine, succinimide and diethyl azodicarbonate is 1:(1.5-2.0):(1.5-2.0):(1.5-2.0).

[0021] In step (1), the weight ratio of solid to solvent is 1:4 to 8, preferably 1:6, the stirring time is 0.5 to 2 hours, the crystallization temperature is -5 to 5°C, and the rinsing solvent is cold ethanol at 0 to 5°C.

[0022] The (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione obtained in step (1) was added to water and an alkaline reagent, heated to 65-85℃, and kept at the temperature until the reaction was completed. After purification and crystallization, (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid was obtained.

[0023] Furthermore, step (2) also includes a purification step, specifically: after the reaction is completed, dichloromethane is added directly to the reaction solution, and after stirring and extraction, water is added to wash the organic layer. The obtained organic layer is concentrated, and the crude product is stirred, cooled and crystallized with n-heptane, and then filtered.

[0024] The obtained (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid was mixed with a halide salt, a base, and an organic solvent-water mixture. Sodium hypochlorite solution was added dropwise at a low temperature of -10 to 5°C to carry out the oxidation reaction. After the reaction was completed, the mixture was quenched, the aqueous phase was separated, and Wittig reagent was added to the resulting organic phase for further reaction. After the reaction was completed, the organic phase was separated and concentrated. The crude product was dissolved in an alcohol-water mixture by heating, acidified to crystallize, filtered, dried, and then spun dry to prepare (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester.

[0025] Furthermore, the halide salt mentioned in step (3) is potassium bromide or sodium bromide, and its molar ratio with (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is (1.5~2.0):1;

[0026] Furthermore, the alkali mentioned in step (3) is sodium bicarbonate or sodium carbonate, preferably sodium bicarbonate, and the molar ratio of sodium bicarbonate to (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is (1.5~2.0):1;

[0027] Furthermore, in step (3), the molar ratio of available chlorine in sodium hypochlorite to (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is (1.0~1.5):1;

[0028] Furthermore, in step (3), the Wittig reagent is ethoxyformylethylene triphenylphosphine, and the molar ratio of its reactant to (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is (1.0-1.3):1; the Wittig reaction is carried out at 15-30°C.

[0029] Furthermore, the alcohol-water mixed solvent used for crystallization in step (3) is methanol-water or ethanol-water, wherein the mass ratio of alcohol to water is (2:1 to 3:1); the acidification is the addition of acetic acid or hydrochloric acid until the pH is 3 to 6.

[0030] Furthermore, the crystallization process described in step (3) is as follows: the crude product is dissolved in an alcohol-water mixed solvent at 60-70°C, acid is added dropwise, and the mixture is kept at 55-65°C for 2-4 hours to crystallize, and then the temperature is lowered to 10-20°C to grow crystals.

[0031] The (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester obtained in step (3) is added to a reactor. The weight ratio of (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester, anhydrous ethanol, and 10% palladium on carbon is 1:3:0.015. After hydrogenation catalysis, the mixture is concentrated to obtain crude sacubitril free acid. Water and alkaline reagents are added to prepare an aqueous solution of sacubitril sodium salt. The alkaline reagent is one of sodium carbonate, sodium bicarbonate, potassium carbonate, and sodium hydroxide, with sodium carbonate being preferred.

[0032] Furthermore, the prepared sacubitril sodium salt aqueous solution was added to ethyl acetate, stirred and extracted, the phases were separated, the aqueous phase was retained, ethyl acetate was added again, and the mixture was stirred and extracted a second time, the phases were separated, and the purified sacubitril sodium salt aqueous solution was retained.

[0033] The purified sacubitril sodium salt aqueous solution was added to ethyl acetate, hydrochloric acid was added dropwise and stirred to release the free acid, and the organic layer was concentrated after extraction to obtain sacubitril free acid. Acetone and isopropanol were added to the free acid to prepare a mixed solution, and then valsartan and sodium hydroxide were added to react to prepare high-purity sacubitril valsartan sodium.

[0034] Furthermore, the sacubitril free acid mixed solution described in step (5) is obtained by dissolving sacubitril free acid in isopropanol and acetone;

[0035] Furthermore, in the sacubitril free acid mixed solution described in step (5), the mass ratio of sacubitril free acid:isopropanol:acetone is 1:1.5-2.5:8-10;

[0036] Furthermore, in step (5), the molar ratio of sacubitril free acid to valsartan is 1:1, and the sodium hydroxide is added dropwise in the form of an aqueous solution with a concentration of 40-50%. The dropwise addition method involves heating to 50-60°C and controlling the dropwise addition time to 2-5 hours.

[0037] Furthermore, the crystallization method described in step (5) involves adding sodium hydroxide aqueous solution and then keeping it at 50-60°C for 4 hours, cooling it down to 40-45°C and keeping it at that temperature for ≥1 hour, cooling it down to 35-40°C and keeping it at that temperature for ≥4 hours, continuing to cool it down to 10-20°C and keeping it at that temperature for ≥1 hour, then cooling it down to 0-5°C, filtering it, rinsing it with acetone below 0°C and drying it to obtain sacubitril / valsartan sodium.

[0038] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0039] The beneficial effects of this invention are as follows:

[0040] This invention avoids the synthetic and post-processing steps of amino protection, deprotection, esterification, hydrolysis, introduction of succinic anhydride to form amides, and sacubitril to form calcium salts, thereby further improving the yield. At the same time, the sacubitril free acid is adjusted by sodium salt to avoid the introduction of calcium ions, simplifying the steps. Finally, isopropanol and acetone are added to the system to add the sacubitril free acid to the reaction in solution form, prolonging the dropping time of sodium hydroxide aqueous solution, avoiding the risk of excessively high local concentration of sodium hydroxide aqueous solution and producing hydrolysis impurities. By optimizing the crystallization steps of sacubitril / valsartan sodium, the preparation method of sacubitril / valsartan sodium has high purity, reduces synthetic steps and increases yield, and is safe, environmentally friendly, and cost-effective, making it suitable for industrial production. Attached Figure Description

[0041] Figure 1 The HPLC chromatogram of sacubitril / valsartan sodium is shown in Embodiment 1 of the present invention. Detailed Implementation

[0042] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0043] This invention utilizes (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol and succinimide in a photoelectrophoretic reaction under triphenylphosphine and DEAD conditions. After the reaction is complete, purification yields an intermediate (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione with a purity greater than 99%. Water and alkaline reagents are then added, and the mixture is heated until the reaction is complete. After purification and crystallization, the intermediate (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid is obtained. The solid (R)-4-(([1,1'-biphenyl]-4- (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester was prepared by oxidation of 3-hydroxypropyl-2-yl)amino-4-oxobutyric acid. The obtained intermediate was subjected to palladium-carbon catalytic reaction to obtain crude sacubitril. Sacubitril sodium salt aqueous solution was prepared by adjusting the alkali. Sacubitril sodium salt was extracted and concentrated. A mixed solution was prepared by adding acetone and isopropanol. The solution was reacted with added valsartan and sodium hydroxide. Sacubitril-valsartan sodium with a single impurity of less than 0.10% and a purity of greater than 99.9% was prepared by the given crystallization scheme.

[0044] The synthetic route of sacubitril / valsartan sodium in this invention is as follows:

[0045]

[0046] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The embodiments employ...

[0047] The implementation conditions can be further adjusted according to different requirements of specific applications. Implementation conditions not specified are standard conditions in this industry. The technical features involved in the various embodiments of this invention can be combined with each other as long as they do not conflict with each other.

[0048] Example 1

[0049] (1) Preparation of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione

[0050] Add 50.0 g of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol to the reaction flask, add 500 ml of tetrahydrofuran, stir until completely dissolved, and cool to -5 to 0 °C under nitrogen protection. Then add 89.17 g of triphenylphosphine and 33.69 g of succinimide. After stirring the mixture, a 40g tetrahydrofuran solution containing 59.21g of diethyl azodicarbonate (DEAD) was added at approximately -5 to 0°C. The temperature was raised to 15–20°C, and the reaction was controlled until complete. The mixture was concentrated under reduced pressure in a 50°C water bath. Approximately 120g of the solid was added to 720g of ethanol, and the mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0°C, filtered, and the filter cake was washed with 0°C ethanol. The mixture was then dried in a 50°C forced-air oven to obtain 60.5g of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione intermediate, with a purity of 99.1% and a yield of 91%.

[0051] 1 H-NMR (400MHz, CDCl3) δ2.55-2.66 (m, 4H, CH2), 3.17-3.30 (m, 2H, CH2), 3.76 (dd, J=11.2, 4.8Hz, 1H, CH2), 4.23 (d, J=10.8Hz, 1H, CH2), 4.67-4.4 4 (m, 1H, CH), 7.26 (d, J=8.4Hz, 2H, Ar-H), 7.34-7.38 (m, 1H, Ar-H), 7.43-7.47 (m, 2H, Ar-H), 7.54 (d, J=8.4Hz, 2H, Ar-H), 7.58-7.60 (m, 2H, Ar-H);

[0052] (2) Preparation of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid

[0053] Add 60g of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione to a reaction flask, along with 360.0g of water and 60.0g of sodium carbonate. Heat to 70-80℃, maintain the temperature and stir for 10 hours, and take samples for monitoring. After the reactants have reacted completely, add 300g of dichloromethane to the reaction solution and stir to extract for 30 minutes. After separation, wash the dichloromethane layer with 50g of water and separate the organic layer. Concentrate the organic layer under reduced pressure in a water bath at 40℃ to dryness. Add 200g of n-heptane to the crude product and stir for 2 hours. After cooling to 0℃, filter and dry at 50℃ to obtain 51.2g of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid with a purity of 99.2% and a yield of 85.5%.

[0054] (3) Preparation of (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester

[0055] Add 50.0 g of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid, 36.3 g of potassium bromide, 26.1 g of sodium bicarbonate, 625 g of ethyl acetate, and 325 g of water to a reaction flask and stir until homogeneous. Cool to -5°C and add 115 g of sodium hypochlorite solution containing 11% available chlorine dropwise. After the addition is complete, maintain the reaction temperature for 1 hour, add 10 g of sodium thiosulfate to quench the reaction, allow to stand and separate the aqueous phase. Add 55.50 g of ethoxyformyl ethylidene triphenylphosphine to the organic phase and stir to react at room temperature for 3 hours. Take a sample for control. After the raw materials have reacted completely, the aqueous layer is separated by allowing the mixture to stand. The organic phase is concentrated to dryness under reduced pressure at 40–50 °C, yielding approximately 60.0 g of solid. This solid is added to a solution prepared with 643 g of methanol and 258 g of water. The mixture is stirred and heated to 60–70 °C, and stirred until dissolved. 5 g of acetic acid is added dropwise, followed by stirring to induce crystallization for 2–3 hours. The solution is then cooled to 10–20 °C, filtered, and dried to obtain 52 g of (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester, with a purity of 99.3% and a yield of 83.2%.

[0056] 1 H-NMR (400MHz, DMSO-d6) δ1.15 (t, J=7.1Hz, 3H, OCH2CH3), 1.98 (s, 3H, C=CCH3), 2.38 (t, J=7.2Hz, 2H, COCH2CH2 CO2H), 2.58 (t, J=7.2Hz, 2H, COCH2CH2CO2H), 3.30-3.45 (m, 2H, NHCH2CH), 4.05 (q, J=7.1Hz, 2H, OCH2CH3), 4.55 -4.65 (m, 1H, NHCH2CH), 6.75 (s, 1H, C=CH), 7.33 (d, J=8.3Hz, 2H, Ar-H), 7.45 (t, J=7.4Hz, 1H, Ar-H), 7.56 (t, J= 7.4Hz, 2H, Ar-H), 7.65 (d, J=8.3Hz, 2H, Ar-H), 7.70 (d, J=7.2Hz, 2H, Ar-H), 8.20 (t, J=5.8Hz, 1H, NH), 12.10 (br s, 1H, CO2H);

[0057] (4) Preparation of sacubitril sodium salt

[0058] Add 20g of (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester, 60.0g of anhydrous ethanol, and 0.3g of 10% palladium on carbon to a hydrogenation reactor. After sealing the reactor, purge with nitrogen three times and with hydrogen four times. Heat to 50-60℃, maintain pressure at 2.0MPa, and keep the reaction at this temperature for 10 hours. After the raw materials have reacted completely, concentrate the reaction solution to dryness to obtain crude sacubitril free acid. Add 50g of water and 25g of sodium carbonate and stir to dissolve, thus obtaining a sacubitril sodium salt aqueous solution. Add 50g of ethyl acetate and stir to extract. Separate the organic layer and retain the aqueous phase to obtain a purified sacubitril sodium salt aqueous solution, which can be directly used in the next step.

[0059] (5) Preparation of sacubitril / valsartan sodium

[0060] Add 100g of ethyl acetate to the above-mentioned sacubitril sodium salt aqueous solution, cool to below 10℃, add 6g of 10% hydrochloric acid dropwise and stir for 1 hour. Separate the liquid and retain the organic layer. Concentrate under reduced pressure at 50℃ to dryness to obtain 18.2g of sacubitril free acid. Add 145.6g of acetone and 36.4g of isopropanol to the free acid and stir until homogeneous to obtain a mixed solution. Then add 19.2g of valsartan and stir to dissolve. Prepare 10.6g of 50% sodium hydroxide aqueous solution. Heat the reaction system to 50-60℃ and slowly add the prepared sodium hydroxide solution dropwise. A sodium hydroxide aqueous solution was prepared, and the dropwise addition was controlled for 2–5 hours. After the addition was completed, the solution was kept at a constant temperature and stirred for 4 hours. The temperature was then lowered to 40–45°C and held for ≥1 hour. The temperature was then lowered to 35–40°C and held for ≥4 hours. The temperature was then further lowered to 10–20°C and held for ≥1 hour. Finally, the temperature was lowered to 0–5°C, filtered, washed with 5g of acetone below 0°C, and dried to obtain 38.8g of sacubitril / valsartan sodium with a purity of 99.94%. The two-step yield was 83%, and all single impurities were less than 0.1%. The purity is shown in the attached figure. Figure 1 (XST: valsartan sodium; SKBQ: sacubitril).

[0061] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing sacubitril / valsartan sodium, characterized in that, Includes the following steps: (1) Under an inert atmosphere, (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-ol was dissolved in an organic solvent. After cooling to -10 to 5°C, triphenylphosphine, succinimide, and diethyl azodicarbonate were added sequentially, and the reaction was carried out at the same temperature. After the reaction was completed, the solvent was removed by concentration, and the resulting solid was purified by adding solvent to the solid and slurrying. After cooling to crystallize, the solid was filtered, washed, and dried to obtain (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione. Its structural formula is (2) The (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione obtained in step (1) was mixed with water and an alkaline reagent, and the mixture was kept at 60-85°C until the raw material was completely converted. After the reaction was completed, the reaction solution was extracted with an organic solvent. The separated organic layer was washed with water and concentrated. The crude product was then pulped with an alkane solvent, filtered, and dried to obtain (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid. Its structural formula is (3) The (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid obtained in step (2), halide salt, base, and organic solvent-water mixed solvent are mixed, and sodium hypochlorite solution is added dropwise at low temperature to carry out the oxidation reaction; after the reaction is completed, the reaction is quenched, the aqueous phase is separated, and Wittig reagent is added to the obtained organic phase to carry out the reaction; after the reaction is completed, the organic phase is separated and concentrated, and the crude product is dissolved in alcohol-water mixed solvent by heating, acidified to precipitate crystals, filtered and dried to obtain the (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid ethyl ester. The structural formula is (4) The (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester obtained in step (3) is subjected to catalytic hydrogenation. After the reaction is completed, the organic solvent is removed by concentration to obtain crude sacubitril free acid. The crude sacubitril free acid reacts with the base in the aqueous phase to form an aqueous solution of sacubitril sodium salt. Then, it is extracted with an organic extractant to separate the organic phase and obtain a purified sacubitril sodium aqueous solution. (5) Sacubitril sodium salt aqueous solution was freed to obtain sacubitril free acid, and acetone and isopropanol were added to prepare a mixed solution. Then valsartan and sodium hydroxide were added to react and high-purity sacubitril valsartan sodium was prepared.

2. The preparation method according to claim 1, characterized in that, The organic solvent in step (1) is tetrahydrofuran, and its amount is 8 to 12 times the weight of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol; the molar ratio of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-ol, triphenylphosphine, succinimide and diethyl azodicarbonate in step (1) is 1:1.5 to 2.0:1.5 to 2.0:1.5 to 2.0; the purification solvent in step (1) is selected from one or more of isopropanol, methanol and ethanol.

3. The preparation method according to claim 1, characterized in that, In step (1), after the reaction is complete, the solid to solvent weight ratio is 1:4 to 8, the stirring time is 0.5 to 2 hours, the crystallization temperature is -5 to 5℃, and the rinsing solvent is cold ethanol at 0 to 5℃.

4. The preparation method according to claim 1, characterized in that, The alkaline reagent mentioned in step (2) is any one or a mixture of several of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide; the mass ratio of the alkaline reagent mentioned in step (2) to (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione is 0.8 to 1.5:1; the amount of water used in step (2) is 5 to 8 times the weight of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione).

5. The preparation method according to claim 1, characterized in that, The reaction described in step (2) further includes the following post-processing steps: S1: After the reaction is complete, add dichloromethane, stir and extract, then add water to wash the organic layer. S2: Concentrate the organic layer obtained in step S1, and then use n-heptane to stir, cool, crystallize, and filter.

6. The preparation method according to claim 1, characterized in that, The halide salt mentioned in step (3) is potassium bromide or sodium bromide, and its molar ratio with (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is 1.5 to 2.0:1; the base mentioned in step (3) is sodium bicarbonate or sodium carbonate, and its molar ratio with (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid is 1.5 to 2.0:1; the oxidation reaction mentioned in step (3) is carried out at -10 to 5°C. The reaction is carried out at 15–30 °C, with the effective chlorine of sodium hypochlorite and the molar ratio of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid being 1.0–1.5:1; the Wittig reagent in step (3) is ethoxyformylethylene triphenylphosphine, with the molar ratio of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid being 1.0–1.3:1; the Wittig reaction is carried out at 15–30 °C.

7. The preparation method according to claim 1, characterized in that, In step (3), the organic solvent in the organic solvent-water mixture is ethyl acetate or dichloromethane, and the weight ratio of (R)-4-(([1,1'-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)amino-4-oxobutyric acid to the organic solvent and water is 1:10.0~13.0:6.0~8.

0.

8. The preparation method according to claim 1, characterized in that, The alcohol-water mixed solvent used for crystallization in step (3) is methanol-water or ethanol-water, wherein the mass ratio of alcohol to water is 2:1 to 3:1; the acidification is the addition of acetic acid or hydrochloric acid until the pH is 3 to 6; the crystallization process in step (3) is as follows: the crude product is dissolved in an alcohol-water mixed solvent at 60 to 70°C, acid is added dropwise, and the mixture is kept at 55 to 65°C for 2 to 4 hours to crystallize, and then the temperature is lowered to 10 to 20°C to grow crystals.

9. The preparation method according to claim 1, characterized in that, Step (4) specifically involves adding (4R)-5-[1,1'-biphenyl]-4-yl-4-[(3-carboxy-1-oxopropyl)amino]-2-methyl-2-pentenoic acid-1-ethyl ester, anhydrous ethanol, and 10% palladium on carbon obtained in step (3) to a reactor in a weight ratio of 1:3:0.

015. The hydrogenation catalytic reaction temperature is 50-60℃, and the pressure is 1.5-2.0 MPa. The alkali is one of sodium carbonate, sodium bicarbonate, potassium carbonate, and sodium hydroxide. In step (4), the organic extractant is used for extraction, and the organic phase is separated to obtain a purified sacubitril sodium aqueous solution. S1: Add ethyl acetate to the prepared sacubitril sodium salt aqueous solution, stir and extract, separate the phases, retain the aqueous phase, add ethyl acetate again, stir and extract a second time, separate the phases, and retain the purified sacubitril sodium salt aqueous solution.

10. The preparation method according to claim 1, characterized in that, Step (5) of freeing sacubitril sodium salt aqueous solution specifically involves adding ethyl acetate to the sacubitril sodium salt aqueous solution, adding hydrochloric acid dropwise, stirring to free it, extracting and concentrating the organic layer to obtain sacubitril free acid, and adding acetone and isopropanol to the free acid to prepare a mixed solution; the mass ratio of sacubitril free acid:isopropanol:acetone in the sacubitril free acid mixed solution is 1:1.5~2.5:8~10; the molar ratio of sacubitril free acid to valsartan is 1:1; the sodium hydroxide used is added dropwise in the form of an aqueous solution; the sodium hydroxide aqueous solution... The concentration is 40-50%. The addition method involves heating to 50-60℃ and controlling the addition time to 2-5 hours. After the sodium hydroxide aqueous solution is added, a crystallization step is also included. The crystallization method is as follows: after the sodium hydroxide aqueous solution is added, the temperature is maintained at 50-60℃ for 4 hours, then cooled to 40-45℃ and maintained for ≥1 hour, then cooled to 35-40℃ and maintained for ≥4 hours, then cooled to 10-20℃ and maintained for ≥1 hour, then cooled to 0-5℃, filtered, washed with acetone below 0℃ and dried to obtain sacubitril / valsartan sodium.

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