A process for the preparation of sacubitril valsartan sodium

Abstract

The present application relates to a kind of preparation methods of sacubitril valsartan sodium, comprising: (1) the toluene suspension of (2R, 4S) 5- ([1, 1 '-biphenyl] 4-yl) 4-amino-2-methyl pentanoic acid ethyl ester hydrochloride is reacted with succinic anhydride to obtain sacubitril crude product, then acid-base is adjusted to obtain sacubitril free acid, and form sacubitril free acid acetone solution;(2) the sacubitril free acid obtained in (1) is reacted with valsartan, sodium hydroxide in the mixed solution of acetone and isopropyl alcohol, to obtain sacubitril valsartan sodium;Wherein, the acid-base adjustment in step (1) includes sequentially using citric acid aqueous solution to adjust acid, using sodium hydroxide aqueous solution to adjust alkali, using hydrochloric acid to adjust acid;The sodium hydroxide in step (2) is added in the form of sodium hydroxide aqueous solution, and the sodium hydroxide in the sodium hydroxide aqueous solution is 0.05-0.2 mol / mL in molar concentration, can obtain product with high purity and high yield, suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of sacubitril valsartan sodium. BACKGROUND

[0002] Sacubitril valsartan sodium is an anti-heart failure drug developed by Novartis, which is a compound combination of angiotensin II inhibitor valsartan and enkephalinase inhibitor sacubitril, and is mainly used for chronic heart failure (NYHA II-IV grade, LVEF≤40%) adult patients with reduced ejection fraction, and can reduce the risk of cardiovascular death and heart failure hospitalization. The structural formula of sacubitril valsartan sodium is as follows:

[0003]

[0004] WO2008031567 and WO20080839 disclose a synthesis route of sacubitril valsartan sodium, in which (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is used as a raw material, reacts with ethanol under the catalysis of thionyl chloride to obtain (2R,4S)-5-([1,1-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, then reacts with succinic anhydride to obtain sacubitril crude product, is purified by sodium hydroxide and calcium chloride, then is dissociated and extracted by dilute hydrochloric acid, and is concentrated to obtain a free acid, and finally reacts with valsartan and sodium hydroxide to obtain sacubitril valsartan sodium. The synthesis route is as follows:

[0005]

[0006] The main problems to be solved in the route applied to mass production are as follows: 1, (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride needs to be treated by centrifugation with n-heptane after preparation, and there are hidden dangers in safety and environmental protection, and the centrifugation with n-heptane only removes volatile substances, and does not improve the purity of the intermediate; 2, (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride reacts with succinic anhydride in isopropyl acetate to produce ester exchange reaction impurities; 3, since the purity of sacubitril free acid is relatively low, only about 95%, the prior art first prepares sacubitril calcium to improve the purity, and then prepares a free acid and salts with valsartan, which not only increases many processes, but also introduces calcium ions and chlorine ions, thereby unnecessarily challenging the quality of sacubitril valsartan sodium raw material medicine; 4, the free acid of sacubitril and valsartan are salted with sodium hydroxide aqueous solution in acetone, and the local concentration of sodium hydroxide is prone to be too high to produce hydrolysis impurities, thereby reducing the yield; 5, the API preparation process is relatively complicated, and repeated distillation is needed for isopropyl acetate, which is difficult to control. SUMMARY

[0007] The technical problem solved by the present application is to provide a preparation method of high-purity saku bivalirudin sodium suitable for industrial production.

[0008] To achieve the above-mentioned purposes, the technical scheme adopted by the present application is as follows:

[0009] The preparation method of saku bivalirudin sodium comprises the following steps:

[0010] (1) reacting the toluene suspension of (2R, 4S)-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methyl pentanoic acid ethyl ester hydrochloride with succinic anhydride to obtain saku bivalirudin crude product, then adjusting the saku bivalirudin crude product with acid and alkali to obtain saku bivalirudin free acid, and forming an acetone solution of saku bivalirudin free acid;

[0011] (2) reacting the saku bivalirudin free acid obtained in (1) with valsartan and sodium hydroxide in a mixed solution of acetone and isopropyl alcohol to obtain saku bivalirudin sodium;

[0012] In step (1), the adjustment with acid and alkali comprises sequentially adjusting with citric acid aqueous solution, adjusting with sodium hydroxide aqueous solution, and adjusting with hydrochloric acid.

[0013] In step (2), the sodium hydroxide is added in the form of sodium hydroxide aqueous solution, and the molar concentration of sodium hydroxide in the sodium hydroxide aqueous solution is 0.05-0.2 mol / mL.

[0014] In step (1),

[0015] Preferably, the toluene suspension of (2R, 4S)-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methyl pentanoic acid ethyl ester hydrochloride is obtained by dissolving (2R, 4S)-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methyl pentanoic acid ethyl ester hydrochloride in toluene.

[0016] Further, the mass ratio of toluene to (2R, 4S)-N-Boc-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methyl pentanoic acid in the toluene suspension of (2R, 4S)-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methyl pentanoic acid ethyl ester hydrochloride is (4-7): 1; preferably (4-6): 1.

[0017] Preferably, the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride in the toluene suspension is obtained by reacting (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid with anhydrous ethanol under the action of thionyl chloride, and then distilling toluene.

[0018] Further, the molar ratio of the thionyl chloride to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (1.0-2.0):1; preferably (1.2-1.7):1; further preferably (1.4-1.6):1.

[0019] Further, the mass ratio of the anhydrous ethanol to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (4.0-6.0):1; preferably (4.5-5.5):1.

[0020] According to a specific and preferred embodiment, after mixing (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid with anhydrous ethanol, the thionyl chloride is slowly added at a speed of 0.8-3 g / min under the condition of controlling the temperature at 0-10°C, and the reaction is carried out at a temperature of 65-80°C for 40-90 min, and sampling TLC is used for control until the spot of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride and other spots disappear, and then toluene is added for distillation, and (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride is obtained.

[0021] Further, after mixing (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid with anhydrous ethanol, the thionyl chloride is slowly added at a speed of 1-2.5 g / min under the condition of controlling the temperature at 0-5°C, and the reaction is carried out at a temperature of 70-75°C for 50-70 min, and sampling TLC is used for control until the spot of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride and other spots disappear, and then toluene is added for distillation, and (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride is obtained.

[0022] Further, the mass ratio of the toluene added in the continuous distillation in the preparation of the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (4.0-6.0):1; preferably (4.5-5.5):1.

[0023] Preferably, the toluene suspension of the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride is stirred with succinic anhydride at 0-10°C, then triethylamine is added at -5-5°C, and the reaction is carried out at 20-30°C for 0.5-2h to obtain the crude sacubitril.

[0024] Further, the molar ratio of the succinic anhydride, triethylamine and (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (1.0-1.4):(1.0-1.5):1.

[0025] Further, the molar ratio of the succinic anhydride, triethylamine and (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (1.0-1.2):(1.1-1.4):1.

[0026] Preferably, the molar concentration of the citric acid in the aqueous citric acid solution is 0.2-0.5M; preferably 0.3-0.4M; further preferably 0.3-0.35M.

[0027] Further, the molar ratio of the citric acid in the aqueous citric acid solution to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (0.3-0.8):1; preferably (0.4-0.6):1; further preferably (0.45-0.55):1.

[0028] Preferably, the molar concentration of the sodium hydroxide in the aqueous sodium hydroxide solution is 0.5-1.2M; preferably 0.6-1.0M; further preferably 0.7-0.9M.

[0029] Further, the molar ratio of the sodium hydroxide in the aqueous sodium hydroxide solution to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (0.4-0.7):1; preferably (0.5-0.6):1; further preferably (0.55-0.6):1.

[0030] Further, the pH of the system is adjusted to 9-11 by using the sodium hydroxide aqueous solution.

[0031] Preferably, the molar ratio of hydrogen chloride in the hydrochloric acid to (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (0.7-1.5):1; preferably (0.9-1.2):1.

[0032] According to a specific and preferred embodiment, the step of adjusting the acid-base is specifically:

[0033] S1. washing with an aqueous citric acid solution, separating the organic phase, washing the obtained organic phase with water, and separating the organic phase;

[0034] S2. adding water and sodium hydroxide aqueous solution to the organic phase obtained in S1 to adjust the pH of the system, stirring, separating the layers, adding toluene to the aqueous phase, stirring, standing, separating the layers, and retaining the aqueous phase;

[0035] S3. adding dichloromethane and hydrochloric acid to the aqueous phase obtained in S2 to react, washing the organic phase with water, retaining the organic phase, adding anhydrous sodium sulfate, stirring, filtering, washing the filter cake with dichloromethane, concentrating the filtrate under reduced pressure, and adding acetone to continue distillation.

[0036] Further, after washing with the aqueous citric acid solution in S1, the reaction system is clear.

[0037] Further, the stirring time after adding water and sodium hydroxide aqueous solution in S2 is controlled to be 15-30 min; preferably 15-25 min.

[0038] Further, the mass ratio of water in the water and sodium hydroxide aqueous solution added in S2 is (2.5-3.5):1; preferably (2.8-3.2):1.

[0039] Further, the stirring time after adding toluene in S2 is controlled to be 3-10 min, and the standing time is controlled to be 20-50 min; further preferably, the stirring time after adding toluene in S2 is controlled to be 4-7 min, and the standing time is controlled to be 25-40 min.

[0040] Further, the stirring time after adding dichloromethane and hydrochloric acid in S3 is controlled to be 30-90 min; preferably 50-70 min.

[0041] Further, the stirring time after adding anhydrous sodium sulfate in S3 is controlled to be 20-50 min; preferably 25-40 min.

[0042] When the acid-base is used for adjustment in the present application, the amount of acetone added during the continuous distillation can be adjusted according to the amount of reactants. Preferably, the amount of acetone added during the continuous distillation in S3 is equal to the amount of (2R, 4S)-N-Boc-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid.

[0043] Preferably, the acetone solution of sacubitril free acid is formed by dissolving sacubitril free acid in acetone solution.

[0044] Further, the molar ratio of acetone in the acetone solution of sacubitril free acid to (2R, 4S)-N-Boc-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (125-140): 1; preferably (128-136): 1; further preferably (130-134): 1.

[0045] In step (2), the molar concentration of sodium hydroxide in the sodium hydroxide aqueous solution is preferably 0.05-0.1 mol / mL.

[0046] Preferably, the molar concentration of sodium hydroxide in the sodium hydroxide aqueous solution is 0.05-0.1 mol / mL.

[0047] Preferably, the mass ratio of isopropyl alcohol in the mixed solution of acetone and isopropyl alcohol to water in the sodium hydroxide aqueous solution is (43-50): 1; preferably (45-48): 1.

[0048] Preferably, the mass ratio of acetone and isopropyl alcohol in the mixed solution of acetone and isopropyl alcohol is (3.5-4.5): 1; preferably (3.7-4): 1.

[0049] According to a specific and preferred embodiment, the acetone solution of sacubitril free acid in step (1) is added with isopropyl alcohol and mixed with valsartan at 20-30°C, then the sodium hydroxide aqueous solution is added and stirred for 20-60 min, and then filtered after being warmed to 40-50°C, followed by cooling and crystallization, suction filtration, acetone leaching and drying to obtain sacubitril valsartan sodium.

[0050] Further, the cooling and crystallization specifically refers to slowly cooling the filtered filtrate to 20-30°C for crystallization, then adding acetone, slowly cooling to -5-5°C, and continuing to crystallize for 24-72 h.

[0051] Further, the drying temperature is 45-65°C, preferably 50-60°C.

[0052] Further, the moisture content of the product after drying is 3-8%, preferably 4-6%.

[0053] By means of the technical solutions, the present application has the following advantages compared with the prior art:

[0054] The present application avoids the centrifugation, drying and other processes of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, avoids the use of isopropyl acetate, further avoids the by-products generated by the transesterification reaction of the isopropyl acetate system, avoids the introduction of calcium ions by purifying the free acid of sacubitril by means of acid-base adjustment with citric acid and the like, and finally avoids the risk of producing hydrolysis impurities due to the local over-concentration of the sodium hydroxide aqueous solution by adding isopropyl alcohol in the system, so that the preparation method of sacubitril valsartan sodium has high purity and high yield, is safe and environmentally friendly, reduces the cost, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0055] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative effort.

[0056] Figure 1 : HPLC spectrum of the toluene suspension of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride in Example 1;

[0057] Figure 2 : System suitability HPLC spectrum of the free acid of sacubitril;

[0058] Figure 3 : HPLC spectrum of the acetone solution of the free acid of sacubitril in Example 1;

[0059] Figure 4 : System suitability HPLC spectrum of sacubitril valsartan sodium;

[0060] Figure 5 : HPLC spectrum of the blank solvent in the system suitability solution;

[0061] Figure 6 : HPLC spectrum of sacubitril valsartan sodium in Example 1. DETAILED DESCRIPTION

[0062] All features disclosed in this specification, or all steps of any method or process specified in this specification, can be combined in any combination, except where such combinations are mutually exclusive.

[0063] In view of the deficiencies in the prior art, the present inventors have long studied and practiced to propose the technical solution of the present application. The technical solution, its implementation process and principles will be further explained as follows.

[0064] The present application uses (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid as a starting material, which is stable in quality and raw material is easy to obtain. After Boc protection group and esterification reaction are carried out in anhydrous ethanol using thionyl chloride, ethanol and thionyl chloride are removed by distillation under reduced pressure, and then toluene is added to remove ethanol and acidic substances to obtain intermediate (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride. Then, toluene is added to obtain toluene suspension of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride. Then, amidation reaction is carried out in toluene system with succinic anhydride and triethylamine to obtain sacubitril free acid. After citric acid is added, sodium hydroxide is added to form a salt into an aqueous phase, toluene is used for washing and impurity removal to obtain sacubitril sodium aqueous solution. Then, hydrochloric acid is used for acidification, dichloromethane is used for extraction, concentration, acetone distillation, and acetone dissolution to obtain sacubitril free acid acetone solution. Finally, sacubitril free acid and valsartan are added in a mixed solution of acetone and isopropanol, and sodium hydroxide aqueous solution is added to form a salt. Slow crystallization is first adopted, and then crystallization time is prolonged to improve yield. Sacubitril valsartan sodium raw material with single impurity less than 0.10% and purity greater than 99.9% is obtained.

[0065] The synthesis route of sacubitril valsartan sodium in the present application is shown in the following formula:

[0066]

[0067] Further, in the present application, ethanol and thionyl chloride are removed by distillation under reduced pressure, and then toluene is added for distillation to remove ethanol and acidic substances. Finally, toluene is added according to a certain feeding ratio to form toluene suspension of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, which can be directly used for the next reaction, avoiding centrifugation, drying and other processes, being safe, environmentally friendly and reducing cost.

[0068] Further, the toluene suspension of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride is used for the amidation reaction of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride with succinic anhydride and triethylamine in toluene system, avoiding the use of isopropyl acetate solvent, and further avoiding the by-product produced by ester exchange reaction in isopropyl acetate system, and avoiding the repeated distillation operation required by the use of isopropyl acetate, simplifying the preparation process.

[0069] Further, the free acid of sacubitril is obtained by adjusting the acid with citric acid to obtain a toluene solution of sacubitril free acid, adjusting the base with sodium hydroxide to obtain a sodium sacubitril aqueous solution, and then adjusting the acid with hydrochloric acid, extracting and concentrating with dichloromethane, drying and filtering with anhydrous sodium sulfate, adding acetone for continuous distillation, and dissolving with acetone to obtain a high-purity sacubitril free acid acetone solution, which is directly used for the next reaction, avoiding the introduction of calcium ions and chloride ions, avoiding the processes of centrifugation and drying, and reducing the cost.

[0070] Further, in the reaction process of the sacubitril free acid acetone solution, isopropyl alcohol is selected to be added, sodium hydroxide is added in the form of an aqueous solution, the molar concentration of the feed is 0.05-0.2 mol / mL, and the mass ratio of isopropyl alcohol and water in the sodium hydroxide aqueous solution is (43-50):1; preferably (45-48):1, which avoids the risk of producing hydrolysis impurities due to the local high concentration of sodium hydroxide aqueous solution, and improves the yield.

[0071] The application will be further described below in conjunction with examples. However, the application is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the application can be combined with each other as long as there is no conflict between them.

[0072] In the following examples, the experimental methods are described, the hydrochloric acid is commercially available with a concentration of 36%-38% concentrated hydrochloric acid; and the water is purified water.

[0073] In the following examples, the experimental methods are described, the experimental materials used are commercially available from conventional biochemical reagent manufacturers unless otherwise specified.

[0074] Example 1

[0075] (1) Preparation of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene suspension Into a reaction flask was added 150.0 g of (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid (0.39 mol), 750 g of anhydrous ethanol (16.28 mol), and stirred until homogeneous. The reaction was cooled to 0-5 °C. While maintaining the temperature at 0-5 °C, 70.0 g of sulfurous chloride (0.59 mol) was slowly added over a period of 0.5-1 h. After the addition of sulfurous chloride was complete, the temperature was increased to 70-75 °C and the reaction was stirred for 1 h. TLC was performed to monitor the reaction using dichloromethane / methanol (10:1) as the developing solvent until the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride spot was the only spot present. The reaction was distilled under reduced pressure until no distillate was obtained. 750 g of toluene was added and stirred until homogeneous. The reaction was distilled under reduced pressure until no distillate was obtained. The distillation was continued for an additional 1 h. 750.0 g of toluene was added and stirred until homogeneous to obtain (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene suspension.

[0076] (2) Preparation of sacubitril free acid in acetone

[0077] The (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene suspension obtained in step (1) was cooled to 8-10°C, 43.0 g succinic anhydride (0.43 mol) was added, stirred uniformly, and cooled to -5 to -2°C; 51.6 g triethylamine (0.51 mol) was slowly added while maintaining the temperature at -5 to -2°C; after the addition of triethylamine, the temperature was raised to 24-26°C, and the reaction was carried out for 1 h; the sample was analyzed by TLC with dichloromethane / methanol = 10:1 as the developing agent until the spot of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride disappeared; the reaction bottle was washed with an aqueous citric acid solution (42.0 g citric acid monohydrate (0.20 mol) and 600.0 g water), the reaction system was clarified, and the organic phase was retained while the aqueous phase was discarded; the organic phase was washed once more with 600.0 g water, the organic phase was retained while the aqueous phase was discarded; 900.0 g water was added to the reaction bottle, and 9.0 g sodium hydroxide (0.23 mol) in 300.0 g water was added to adjust the pH of the system to 10, the mixture was stirred for 20 min, the aqueous phase was separated, and the organic phase was discarded; 750.0 g toluene was added to the reaction bottle, the mixture was stirred for 5 min, and the mixture was allowed to stand for 0.5 h, the aqueous phase was separated, and the organic phase was discarded; 900.0 g dichloromethane was added to the aqueous phase, 39.0 g hydrochloric acid (0.39 mol) was added with stirring, and the mixture was stirred for 1 h; the organic phase was separated, and the organic phase was washed once with 150.0 g water; 15.0 g anhydrous sodium sulfate was added to the organic phase, the mixture was stirred for 0.5 h, the mixture was filtered, and the filter cake was washed with 150.0 g dichloromethane; the filtrate was concentrated under reduced pressure until no distillate was obtained, 150.0 g acetone was added, and the distillation was continued until no distillate was obtained; 150.0 g acetone was added again, and the distillation was continued until no distillate was obtained; 3000.0 g acetone was added, and the mixture was stirred to dissolve; and the solution of sacubitril free acid in acetone was obtained.

[0078] (3) Preparation of sacubitril valsartan sodium

[0079] To the solution of sacubitril free acid in acetone obtained in step (2), 170.0 g valsartan (0.39 mol) and 750.0 g isopropyl alcohol were added, and the mixture was stirred to dissolve at 24-26°C; sodium hydroxide solution (46.8 g sodium hydroxide (1.17 mol) and 16.0 g water) was slowly added, the mixture was continuously stirred for 0.5 h after the addition was completed, the temperature was raised to 44-46°C, and the mixture was filtered; the filtrate was slowly cooled to 24-26°C to crystallize; 3000.0 g acetone was added, and the mixture was slowly cooled to 0-3°C to continue crystallization for 48 h; the mixture was suction filtered, and the filter cake was washed once with 300.0 g acetone to obtain a white solid; the white solid was vacuum dried at 55-57°C until the moisture content was 4-6%, and the drying was considered to be completed; otherwise, the moisture content was detected again after 2 h; and about 340.0 g of the product was obtained.

[0080] The (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene suspension was dissolved in anhydrous ethanol and subjected to HPLC detection. The HPLC detection results are shown in Table 1. Figure 1

[0081] A system suitability solution containing sacubitril was prepared and subjected to system suitability testing using a system suitability solution containing sacubitril free acid. The HPLC detection results are shown in Table 2. Figure 2 Figure 3 The sacubitril free acid prepared in Example 1 was subjected to HPLC detection. The HPLC detection results are shown in Table 3.

[0082] The system suitability solution containing sacubitril was prepared as follows: an appropriate amount of impurity E, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity U, intermediate III, and sacubitril calcium reference substance were weighed, respectively, dissolved and diluted with 50% acetonitrile to prepare a mixed solution containing about 1.0 mg of sacubitril, about 2 μg of intermediate III and other impurities per 1 mL.

[0083] The chemical name of impurity E is (2R,4S)-5-(1,1-biphenyl)-4-amino-2-methylpentanoic acid, and the structural formula is as follows:

[0084] The chemical name of impurity I is (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(4-ethoxy-4-oxobutanaminyl)-2-methylpentanoic acid ethyl ester, and the structural formula is as follows:

[0085] The chemical name of impurity J is (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one, and the structural formula is as follows:

[0086] The chemical name of impurity K is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, and the structural formula is as follows:

[0087] The chemical name of impurity L is (2R,4S)-5-(biphenyl-4-yl)-4-[(butanediyI)amino]-2-methylpentanoic acid ethyl ester, and the structural formula is as follows:

[0088] ​​The chemical name of impurity M is (2R, 4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid methyl ester calcium salt, and the structural formula is:

[0089] The chemical name of impurity N is (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-acetamido-2-methylpentanoic acid ethyl ester, and the structural formula is:

[0090] The chemical name of impurity O is (E)-4-(((2S, 4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid-2-enoic acid, and the structural formula is:

[0091] The chemical name of impurity U is 4-(((2S, 4R)-1-([1,1'-biphenyl]-4-yl)-5-isopropoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid calcium salt, and the structural formula is:

[0092] The chemical name of intermediate III is (2R, 4S)-5-([1,1-biphenyl]-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, and the structural formula is:

[0093] The system suitability solution containing sacubitril valsartan sodium, the blank solvent were prepared, and the system suitability test was carried out by using the system suitability solution containing sacubitril valsartan sodium and the blank solvent respectively, and the HPLC detection results are shown in Table 1. Figure 4 and 5 The sacubitril valsartan sodium obtained in Example 1 was detected by HPLC, and the HPLC detection results are shown in Table 1. Figure 6 The yield of sacubitril valsartan sodium was 90.8%, and the purity was 99.93%.

[0094] The specific preparation method of the system suitability solution containing sacubitril valsartan sodium is as follows: an appropriate amount of impurity E, impurity F, impurity J, impurity K, impurity L, impurity U, intermediate III, sacubitril calcium and valsartan reference substance were respectively taken, dissolved and diluted with 50% acetonitrile solution to prepare a mixed solution containing about 1.0 mg of sacubitril and valsartan in each 1 mL, and about 2 μg of intermediate III and other impurities; the blank solvent refers to 50% volume fraction acetonitrile aqueous solution.

[0095] The chemical name of impurity F is 4-(((2S, 4S)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, and the structural formula is:

[0096] HPLC detection method: Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512), octadecylsilane bonded silica gel was used as the filler; mobile phase A was water-acetonitrile-trifluoroacetic acid (1900:100:1), and mobile phase B was water-acetonitrile-trifluoroacetic acid (100:1900:1); gradient elution (see Table 1), and the detection wavelength was 254 nm.

[0097] Table 1 Gradient elution parameters of HPLC detection method

[0098] Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 30 55 45 45 10 90 55 10 90 60 70 30

[0099] Comparative Example 1

[0100] This comparative example provides a method for preparing sacubitril-valsartan sodium, which is substantially the same as that of Example 1, except that in step (2), in the preparation of the acetone solution of sacubitril free acid, the sacubitril free acid is extracted with citric acid without further purification with sodium hydroxide or hydrochloric acid. Specifically:

[0101] The toluene suspension of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride obtained in step (1) was cooled to 8-10°C, 43.0 g of succinic anhydride (0.43 mol) was added, stirred evenly, and cooled to -5--2°C; 51.6 g of triethylamine (0.51 mol) was slowly added at a temperature of -5--2°C; after the addition of triethylamine, the temperature was raised to 24-26°C, the reaction was carried out for 1 hour, and a sample was taken for mid-control and TLC was performed. Central control, developing solvent: dichloromethane / methanol = 10:1, until the spots of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride disappear; add citric acid aqueous solution (42.0 g of citric acid monohydrate (0.20 mol) and 600.0 g of water) to the reaction flask for washing, clarify the reaction system, separate the liquids, and retain the organic phase; add 3000.0 g of acetone, stir and dissolve to obtain an acetone solution of sacubitril free acid.

[0102] TLC (silica gel GF254, developing solvent: dichloromethane / methanol = 10:1) detection showed that a small amount of impurities were still visible in addition to the main spot, while the toluene suspension of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride obtained in Example 1 showed no other impurities except the main spot. It can be seen that the purity of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride is significantly lower than that in Example 1.

[0103] Comparative Example 2

[0104] This comparative example provides a preparation method of sacubitril valsartan sodium, which is basically the same as that of Example 1, except that the volume ratio of acetone and isopropyl alcohol in the preparation of sacubitril valsartan sodium in step (3) is changed. Specifically:

[0105] To the acetone solution of sacubitril free acid obtained in step (2), 170.0 g of valsartan (0.39 mol) and 900.0 g of isopropyl alcohol were added and dissolved by stirring at 24-26°C; sodium hydroxide solution (46.8 g of sodium hydroxide (1.17 mol) and 16.0 g of water) was slowly added, and after the addition was completed, stirring was continued for 0.5 h, and the temperature was raised to 44-46°C, and then filtered; the filtrate was slowly cooled to 24-26°C to crystallize; 3000.0 g of acetone was added, and the temperature was slowly cooled to 0-3°C, and the crystallization was continued for 48 h; suction filtration was performed, and the white solid was obtained, and then 300.0 g of acetone was used for elution once, and the product was obtained as a white solid, which was dried in a vacuum at 55-57°C until the moisture content was 4-6%, which was considered as the end of drying, otherwise the product was detected again after 2 h interval, and about 300.0 g of product was obtained.

[0106] Compared with Example 1, the yield of Comparative Example 2 is obviously low.

[0107] Comparative Example 3

[0108] This comparative example provides a preparation method of sacubitril valsartan sodium, which is basically the same as that of Example 1, except that in steps (1) and (2), (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene suspension is not used. Specifically:

[0109] In step (1), after sampling and TLC control, vacuum distillation was performed until no distillate was obtained; 750 g of isopropyl acetate was added and stirred uniformly, vacuum distillation was performed until no distillate was obtained, and distillation was continued for 1 h to obtain (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride;

[0110] In step (2), (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride obtained in step (1) was dissolved in 750 g of isopropyl acetate.

[0111] After TLC (silica gel GF254, developing agent: dichloromethane / methanol = 10:1) detection, the impurity spots were more than those of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride toluene solution obtained in Example 1, which was speculated to be ester exchange by-products, and the effect of toluene with ethanol was better than that of isopropyl acetate, and the yield was more secure.

[0112] The above examples are only for illustrating the technical concept and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes made according to the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A method for preparing sacubitril-valsartan sodium, characterized in that: The steps include: (1) reacting (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid with anhydrous ethanol under the action of thionyl chloride, adding toluene and distilling to obtain (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, and dissolving the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride in toluene to obtain a toluene suspension of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride; (2) reacting a toluene suspension of the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride with succinic anhydride to obtain a crude product of sacubitril, adding a citric acid aqueous solution for washing, separating the liquids, washing the obtained organic phase with water, and separating the liquids to retain the organic phase. Add water and sodium hydroxide aqueous solution to the obtained organic phase to adjust the pH of the system, stir, separate and add toluene to the aqueous phase, stir again, let stand, separate and retain the aqueous phase. Dichloromethane and hydrochloric acid were added to the obtained aqueous phase, stirred for reaction, and the organic phase was washed with water after separation. The organic phase was retained, and anhydrous sodium sulfate was added, stirred again, and filtered. The filter cake was then washed with dichloromethane. The filtrate was concentrated under reduced pressure, and acetone was added and distilled continuously to form an acetone solution of sacubitril free acid; (3) adding isopropyl alcohol to the acetone solution of sacubitril free acid described in step (2), mixing the mixture with valsartan at 20-30° C., adding sodium hydroxide aqueous solution, stirring and reacting for 20-60 min, heating to 40-50° C., filtering, then slowly cooling the filtered filtrate to 20-30° C. for crystallization, adding acetone, slowly cooling to -5-5° C., continuing crystallization for 24-72 h, and finally filtering, rinsing with acetone, and drying to obtain sacubitril valsartan sodium. The molar concentration of sodium hydroxide in the sodium hydroxide aqueous solution described in step (3) is 0.05-0.2 mol / mL, and the mass ratio of acetone to isopropanol in the acetone solution of sacubitril free acid described in step (3) is (3.5-4.5):

1.

2. The method for preparing sacubitril / valsartan sodium according to claim 1, wherein: The molar ratio of citric acid in the citric acid aqueous solution in step (2) to the (2R,4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (0.3-0.8):1; And / or, the molar concentration of citric acid in the citric acid aqueous solution in step (2) is 0.2-0.5M.

3. The method for preparing sacubitril / valsartan sodium according to claim 1, wherein: The molar ratio of the sodium hydroxide in the sodium hydroxide aqueous solution described in step (2) to the (2R, 4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (0.4-0.7):1; And / or, in step (2), the pH of the system is adjusted to 9-11 using the sodium hydroxide aqueous solution.

4. The method for preparing sacubitril / valsartan sodium according to claim 1, wherein: The molar ratio of the hydrogen chloride in the hydrochloric acid to the (2R, 4S)-N-Boc-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid in step (2) is (0.7-1.5):

1.

5. The method for preparing sacubitril-valsartan sodium according to claim 1, wherein: In step (2), a toluene suspension of the (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride is stirred and reacted with succinic anhydride at 0-10°C, followed by addition of triethylamine at -5-5°C, heating to 20-30°C, and reacting for 0.5-2h to obtain a crude product of sacubitril.

6. The method for preparing sacubitril-valsartan sodium according to claim 5, wherein: The molar ratio of succinic anhydride, triethylamine and (2R, 4S)-N-Boc-5-([1, 1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid in step (2) is (1.0-1.4): (1.0-1.5): 1; and / or, the molar ratio of acetone in the acetone solution of sacubitril free acid in step (2) to the (2R, 4S)-N-Boc-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid is (125-140):1; And / or, the acetone solution of sacubitril free acid in step (2) is formed by dissolving sacubitril free acid in acetone solution.

7. The method for preparing sacubitril / valsartan sodium according to claim 1, wherein: In step (3), the mass ratio of isopropyl alcohol to water in the sodium hydroxide aqueous solution is (43-50):1.

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