A process for the preparation of a key intermediate of sacubitril

Abstract

The application provides a preparation method of a sacubitril intermediate compound III, which comprises the following steps: performing ring opening reaction on a compound of formula IV and a compound of formula V under the action of CuX, and the reaction formula is shown in the following formula: wherein X and X1 are independently selected from Cl, Br and I; the chiral 2-methyl pentanoic acid group is directly introduced into the chiral raw material compound of formula IV, the reaction route is short, time is saved, the purity of the chiral isomer is improved, and the post-treatment operation is simple; and the method has obvious technical advantages compared with the prior art.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for preparing (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butyloxycarbonyl)amino]-2-methylpentanoic acid, a key intermediate of sacubitril. Background Technology

[0002] Sacubitril, an enkephalinase inhibitor, has the chemical name 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopropane-2-yl)amino)-4-oxobutyric acid, and its structure is as follows:

[0003]

[0004] Entresto, a combination preparation of sacubitril / valsartan sodium tablets, is a dual-action angiotensin receptor-neprilysin inhibitor developed by Novartis. It is used to treat hypertension and heart failure. It effectively reduces the risk of hospitalization and death due to heart failure in patients with chronic heart failure (NYHA class II–IV).

[0005] When the key intermediate amino group of sacubitril is protected by a Boc group, the structural formula of (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (CAS:1012341-50-2) is as follows:

[0006]

[0007] Currently, the main process for compound I is the synthesis via routes WO2008031567A1 and WO2014032627A1. Using 4-bromobiphenyl as the biphenyl introducer, it reacts with S-epoxychloropropane via a Grignard reaction to form a biphenyl compound, which is then converted to a chiral amino alcohol via a Mitsunobu reaction. This alcohol is oxidized to an aldehyde group, followed by a Wittling reaction to form an alkene bond, and then the ester group is hydrolyzed. Metal hydrogenation catalysis yields the product (2R,4S)-5-([1,1-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid. This method has a long route, low overall yield, and high synthesis cost. The reaction formula is shown below:

[0008]

[0009] Patent WO2008083967A3 discloses a method using L-pyroglutamic acid as a starting material. After condensation to form an amide bond, a biphenyl group is constructed from the substrate using a biphenyl-based Grignard reagent. Following reduction and amino protection, a methyl group is selectively formed at the α-position of the pentacyclic carbonyl group. Further deprotection, ring-opening, and Boc amino protection result in the product (2R,4S)-5-([l,1-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid. This method requires low temperatures, has low yields, and is costly. The reaction formula is shown below:

[0010]

[0011] In summary, the preparation of the key chiral intermediate I of sacubitril using existing reported processes is unfavorable for industrial production due to harsh reaction conditions, long synthetic routes, low yields, high production costs, and cumbersome operations. Therefore, it is necessary to develop a simpler, more economical, and industrially feasible production route for the key chiral intermediate I, which is of great industrial significance. Summary of the Invention

[0012] This application addresses the problems of lengthy routes, low yields, low purity of chiral isomers, and high costs in the preparation of sacubitril intermediates in existing technologies by developing a novel synthetic route for sacubitril intermediates. This route is simple to operate, has a high reaction yield, avoids the use of costly catalysts and ligands, and produces products with high chiral purity, making it suitable for industrial application.

[0013] The first aspect of this application provides a method for preparing a compound of formula III, comprising reacting a compound of formula IV with a compound of formula V in the presence of CuX to carry out a ring-opening reaction, the reaction formula of which is shown below:

[0014]

[0015] Among them, X and X1 are independently selected from Cl, Br, and I, respectively;

[0016] As a further improvement to this application, the molar ratio of the compound of formula IV to the compound of formula V is 1:(1-5), for example 1:(1-3);

[0017] As a further improvement to this application, the molar ratio of compound IV to CuX is 1:(0.03-0.3), for example 1:(0.03-0.2), or even 1:0.045;

[0018] As a further improvement to this application, the compound of formula V, 1,1'-biphenyl-4-methyl magnesium halide, may be selected from any one of 1,1'-biphenyl-4-methyl magnesium chloride, 1,1'-biphenyl-4-methyl magnesium bromide, or 1,1'-biphenyl-4-methyl magnesium iodide, for example, 1,1'-biphenyl-4-methyl magnesium bromide.

[0019] As a further improvement to this application, the CuX is selected from any one of CuI, CuBr, and CuCl, such as CuI;

[0020] As a further improvement of this application, the ring-opening reaction is carried out in an organic solvent, wherein the organic solvent is selected from at least one of ethers and aromatic hydrocarbons, wherein the ether is any one of cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, propyl ether, isopropyl ether, diethyl ether, ethylene glycol dimethyl ether or anisole, and the aromatic hydrocarbon is any one of toluene or xylene;

[0021] As a further improvement of this application, the volume (mL) of the organic solvent used is 1 to 10 times, for example 5 to 8 times, the mass (g) of the compound of formula IV; in some specific embodiments of this application, the volume (mL) of the organic solvent used is 5 times the mass (g) of the compound of formula IV.

[0022] As a further improvement of this application, the ring-opening reaction temperature is -30 to 0°C, for example -25 to -15°C; the reaction time is 1 to 24 hours, for example 1 to 12 hours; in some specific embodiments of this application, the reaction temperature is -25 to -15°C and the reaction time is 1 hour.

[0023] In some specific embodiments of this application, a method for preparing compound III is provided, comprising:

[0024] 1) Under an inert atmosphere, add bromoethane and magnesium shavings, and add about 1 / 20 of the tetrahydrofuran solution of 4-bromomethylbiphenyl at 45-55°C. After confirming initiation, continue to add the remaining tetrahydrofuran solution of about 19 / 20 of the total amount of 4-bromomethylbiphenyl at 45-55°C.

[0025] 2) After the addition is complete, continue stirring for 1 hour, cool to -15 to -25°C, add cuprous iodide, and continue adding tetrahydrofuran solution of compound IV. After the addition is complete, keep the temperature at -15 to -25°C and stir for 1 hour to prepare compound III.

[0026] As a further improvement to this application, the ring-opening reaction yields compound III by simple separation;

[0027] This application does not specifically limit the separation steps; any separation steps known in the art can be used, as long as they achieve the purpose of this invention. For example, the separation steps may include, but are not limited to: quenching, extraction, washing, drying, concentration, recrystallization, and filtration. The solvents used in the separation steps can be conventional solvents known in the art.

[0028] In some specific embodiments of this application, the compound of formula III may be selectively post-treated, including slowly pouring the reaction solution into dilute hydrochloric acid after the ring-opening reaction is completed, and stirring at 10-30°C for 0.5 h. Then, ethyl acetate is added to the reaction flask for extraction, and the aqueous phase is extracted again with ethyl acetate. The organic phases are combined, concentrated under reduced pressure to 1 / 5 to 1 / 2 volume, cooled to 0-10°C, filtered, and dried to obtain solid compound III.

[0029] The biphenyl compounds of this application are obtained by conventional preparation methods in the prior art, such as the method described in the Journal of the American Chemical Society (2017), 139(37), 13126-13140, or by the method described in Example 1 of this invention.

[0030] The second aspect of this application provides a method for preparing a compound of formula I, comprising using a compound of formula III obtained in the first aspect of this application as a raw material, and subjecting it to an asymmetric reductive amination reaction and an amino protecting group addition reaction to obtain a compound of formula I;

[0031]

[0032] R is an amino protecting group, such as any one of tert-butoxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, p-methoxybenzyl, benzyl, or allyloxycarbonyl.

[0033] As a further improvement to this application, under the action of a chiral ruthenium catalyst, compound III reacts with an ammonia source and hydrogen gas through an asymmetric reductive amination reaction to obtain compound II.

[0034] As a further improvement of this application, the ammonia source is selected from one or more of ammonia gas, ammonia water, ammonia gas solution, ammonium acetate, ammonium formate, ammonium chloride, ammonium sulfate, and ammonium carbonate;

[0035] As a further improvement of this application, when the ammonia source is selected from ammonia solution, it can be any one of ammonia in methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1,4-dioxane, ethyl acetate solution (e.g., ammonia methanol solution with a molar concentration of 4 mol / L to 7 mol / L).

[0036] The molar ratio of compound III to the ammonia source is 1:1 to 20;

[0037] As a further improvement to this application, the chiral ruthenium catalyst is, for example, Ru(OAc)2[(S)-MeO-BIPHEP] or (S)-Ru(OAc)2(BINAP);

[0038] As a further improvement to this application, the molar ratio of the compound of formula III to the ruthenium catalyst is selected from 1:0.0001 to 0.001; for example, 1:0.0003 to 0.001, and even more for example, 1:0.00035;

[0039] As a further improvement to this application, the hydrogen pressure range is selected from 0.5 to 10 MPa, preferably 1.5 to 2.5 MPa;

[0040] As a further improvement of this application, the reaction temperature of the asymmetric reductive amination is selected from 45 to 70°C, for example 55 to 65°C;

[0041] As a further improvement of this application, the reaction time of the asymmetric reductive amination is selected from 12 to 48 hours, for example, 48 hours;

[0042] As a further improvement of this application, the reaction solvent for the asymmetric reductive amination is selected from any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, and ethyl acetate, for example, methanol;

[0043] As a further improvement of this application, after the asymmetric reductive amination reaction is completed, the reaction solution can be selectively cooled to room temperature, replaced with nitrogen, and then hydrogen chloride methanol solution is added dropwise until the pH is 2-3. The mixture is stirred for 1 hour, cooled to 0-10°C, filtered, washed, and dried to obtain the compound solid hydrochloride.

[0044] As a further improvement of this application, the reaction of the amino protecting group can be carried out under reasonable reaction conditions depending on the requirements of the protecting group; for example, compound II or its salt reacts with the amino protecting group reagent under the action of a base.

[0045] As a further improvement of this application, in the above-amino protecting group reaction, the molar ratio of compound II or salt to amino protecting group reagent is 1:1 to 1.2; the reaction temperature is 50 to 60°C; and the reaction time is 2 to 12 hours.

[0046] As a further improvement of this application, the solvent for the reaction of the amino protecting group is selected from one or any combination of water, methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, for example, methanol and water.

[0047] As a further improvement of this application, the base is selected from organic or inorganic bases. The organic base is selected from any one of triethylamine, diethylamine, pyridine, and diisopropylethylamine, such as diisopropylethylamine. The inorganic base is selected from one or more of potassium phosphate, potassium acetate, potassium carbonate, potassium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, and hydrated lithium hydroxide, such as sodium hydroxide.

[0048] As a further improvement of this application, the molar ratio of compound II to base in the reaction is 1:1.1 to 5, for example 1:2;

[0049] In some specific embodiments of this application, for example, R is a Boc protecting group. When R is a Boc amino protecting group, the amino protecting group reagent is selected from di-tert-butyl dicarbonate. This invention provides a method for preparing a compound of formula Ia, comprising:

[0050]

[0051] Compound II hydrochloride was added to methanol and water, followed by the addition of an alkali (e.g., sodium hydroxide). Di-tert-butyl dicarbonate was added dropwise at 50–60 °C. After the addition was complete, the temperature was maintained for another 2 hours. The mixture was then concentrated by distillation, filtered, and dried under reduced pressure to obtain compound Ia.

[0052] The third aspect of this application provides a method for preparing Sacubitril, comprising obtaining a compound of formula III by the preparation method described in the first aspect of this invention, and then preparing Sacubitril from the compound of formula III.

[0053] The fourth aspect of this application provides a method for preparing Sacubitril, comprising obtaining a compound of formula I by the preparation method described in the second aspect of this invention, and then preparing Sacubitril from the compound of formula I.

[0054] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0055] (1) The present invention introduces a chiral 2-methylpentanoic acid group directly through a chiral raw material compound of formula IV. The reaction route is short, saving time, while improving the purity of the chiral isomer and simplifying the post-processing operation.

[0056] (2) The present invention optimizes the process, is simple to operate, has high raw material availability, significantly reduces costs, and is suitable for industrial production.

[0057] (3) The inventors unexpectedly discovered that the addition of substances such as tBuXphos ligands made it difficult to separate the product, increasing the difficulty of separating the ligand and the substrate. Without the special introduction of ligands such as triphenylphosphine or Xphos, the present invention can achieve high yield and high quality of ring-opening compounds. The ring-opening reaction yield of the present invention reaches 73%, which can effectively avoid the generation of ring-opening impurities at other positions.

[0058] (4) The inventors also unexpectedly discovered that the addition of CuX-type catalysts to the ring-opening reaction significantly improved both the conversion rate and the reaction rate, while the reaction rate of the ring-opening reaction without the addition of CuX-type catalysts was significantly reduced and the conversion rate was insufficient. Attached Figure Description

[0059] Figure 1 The hydrogen NMR spectrum of compound III described in this invention;

[0060] Figure 2 The 1H NMR spectrum of compound II described in this invention;

[0061] Figure 3 The 1H NMR spectrum of compound Ia described in this invention;

[0062] Figure 4 This is the HPLC spectrum of compound Ia described in this invention. Detailed Implementation

[0063] To facilitate understanding of the invention by those skilled in the art, the technical solution of the present invention is further described below with reference to specific embodiments. It should be understood that these embodiments are not intended to limit the scope and spirit of the claims. Unless otherwise specified, all raw materials, reagents, and solvents used in this invention are commercially available, and experimental methods without specific conditions are generally performed under conventional conditions in the art.

[0064] Example 1

[0065] Preparation of Compound III

[0066]

[0067] Under a nitrogen atmosphere, 0.2 mL of bromoethane and 5.04 g (0.21 mol) of magnesium shavings were added to the reaction flask. A portion of a tetrahydrofuran solution (250 mL) of 4-bromomethylbiphenyl (49.4 g, 0.2 mol) was added dropwise at 45–55 °C. After confirming initiation, the remaining amount was added dropwise while maintaining the temperature at 45–55 °C. After the addition was complete, the reaction was stirred for 1 hour. The temperature was then lowered to -15–-25 °C, and 1.9 g (0.01 mol) of cuprous iodide was added. A tetrahydrofuran solution (125 mL) of compound IV (25.1 g, 0.22 mol) was then added dropwise. After the addition was complete, the mixture was kept at -15–-25 °C with stirring for 1 hour. The reaction solution was then slowly poured into dilute hydrochloric acid (6 N, 100 mL), and stirred at 10–30 °C for 0.5 h. Then, ethyl acetate was added to the reaction flask for extraction twice, each time using 200 mL. The aqueous phase was then extracted once more with 100 mL of ethyl acetate. The organic phases were combined and washed with 200 mL of water until neutral. The organic phase was then concentrated under reduced pressure to 100–150 mL, cooled to 0–10 °C, filtered, and dried to obtain 41.8 g of white powder of compound III, with a yield of 73%.

[0068] NMR data for Compound III: 1 H NMR (400MHz, CDCl3) δ7.60-7.55(m,4H),7.44(t,J=7.6Hz,2H),7.35(d,J=7.3Hz,1H),7.29-7. 27(d,2H),3.74(s,2H),3.13–2.88(m,2H),2.55(dd,J=17.1,5.0Hz,1H),1.20(d,J=7.0Hz,3H).

[0069] Example 2

[0070] Preparation of Compound II Hydrochloride

[0071]

[0072] Compound III (15 g, 53.1 mmol) obtained in Example 1 and 120 mL of ammonia-methanol (7 mol / L) solution were added to a pressure vessel to purge the air inside. Then, 15 mg of Ru(OAc)2[(S)-MeO-BIPHEP] was added, and the gas inside the reaction vessel was purged with hydrogen to 2 ± 0.5 MPa. The temperature was raised to 60 ± 5 °C and reacted for 48 hours. After cooling to room temperature and purging with nitrogen, the reaction solution was transferred to a flask, and hydrogen chloride methanol solution was added dropwise until the pH was 2–3. The mixture was stirred for 1 hour, cooled to 0–10 °C, and filtered. The filter cake was washed with a small amount of methanol and dried to obtain 14.7 g of compound II hydrochloride as an off-white solid, with a yield of 86.5%.

[0073] NMR data for Compound II:1 H NMR(400MHz,MeOD)δ7.62(t,J=7.9Hz,4H),7.44(t,J=10.3,4.8Hz,2H),7.39–7.31(m,3H),3.60(m,J=13.6,6.3Hz,1H),3.00 (d,J=6.9Hz,2H),2.69(m,J=8.9,7.1,5.3Hz,1H),2.05(m,J=14.4,9.1,5.2Hz,1H),1.73–1.63(m,1H),1.20(t,J=6.3Hz,3H).

[0074] Example 3

[0075] Preparation of compound Ia

[0076]

[0077] The compound II hydrochloride (10 g, 31.3 mmol) obtained in Example 2 was added to a three-necked flask, followed by 50 mL of methanol and 50 mL of water. Then, sodium hydroxide (2.63 g, 65.7 mmol) was added, and di-tert-butyl dicarbonate (7.46 g, 34.2 mmol) was added dropwise at 50–60 °C. After the addition was complete, the temperature was maintained for another 2 hours. Most of the methanol was concentrated off, filtered, and dried under reduced pressure to obtain 11.7 g of compound Ia as an off-white powder, with a yield of 97.5% and a purity of 99.87%.

[0078] NMR data for compound I: 1 H NMR(400MHz,DMSO)δ11.98(s,1H),7.63(d,J=7.5Hz,2H),7.56(d,J=8.2Hz,2H), 7.44(t,J=7.6Hz,2H),7.33(t,J=7.3Hz,1H),7.24(d,J=8.1Hz,2H),6.71(d,J=8. 7Hz,1H),3.72–3.62(m,1H),2.68(d,J=6.8Hz,2H),2.47–2.37(m,1H),1.74(ddd ,J=13.5,9.4,4.1Hz,1H),1.42–1.29(m,8H),1.21(s,2H),1.07(t,J=7.6Hz,3H).

Claims

1. A method for preparing a sacubitril intermediate compound III, comprising performing a ring-opening reaction of a compound of formula IV with a compound of formula V in the presence of CuX, as shown in the following reaction formula: wherein X and X1 are independently selected from Cl, Br or I, and CuX is selected from any one of CuI, CuBr and CuCl; the molar ratio of the compound of formula IV to the compound of formula V is 1: (1-5); the molar ratio of the compound of formula IV to CuX is 1: (0.03-0.3); and the ring-opening reaction is performed at a temperature of -30-0℃. wherein In the ring-opening reaction, the ring-opening reaction of the compound of formula IV with the compound of formula V satisfies one or more of the following conditions: 1) the molar ratio of the compound of formula IV to the compound of formula V is 1: (1-3); 2. The production method according to claim 1, characterized by, 2) the molar ratio of the compound of formula IV to CuX is 1: (0.03-0.2); 3) the ring-opening reaction is performed in an organic solvent; 4) the ring-opening reaction is performed at a temperature of -25--15℃; 5) the reaction time is 1-24 h. The organic solvent is selected from at least one of ethers and aromatic hydrocarbons, the ethers being any one of cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, propyl ether, isopropyl ether, diethyl ether, ethylene glycol dimethyl ether or anisole, and the aromatic hydrocarbons being any one of toluene or xylene; and / or, the volume of the organic solvent is 1-10 times the mass of the compound of formula IV.

3. The method of claim 2, wherein, In the ring-opening reaction, the ring-opening reaction of the compound of formula IV with the compound of formula V satisfies one or more of the following conditions: 1) the molar ratio of the compound of formula IV to CuX is 1:0.045; 4. The preparation method according to claim 2, characterized in that, 2) the volume of the organic solvent is 5-8 times the mass of the compound of formula IV; 3) the reaction time is 1-12 h. The compound of formula III is used as a raw material to obtain a compound of formula I through an asymmetric reductive amination reaction and an amino protecting group reaction. R is an amino protecting group.

5. The method of any one of claims 1-4, wherein the method further comprises, The asymmetric reductive amination reaction of the compound of formula III comprises performing an asymmetric reductive amination reaction of compound III with an ammonia source and hydrogen in the presence of a chiral ruthenium catalyst to obtain a compound of formula II, and further satisfies one or more of the following conditions: 1) the ammonia source is selected from one or more of ammonia, an ammonia solution, ammonium acetate, ammonium formate, ammonium chloride, ammonium sulfate and ammonium carbonate; 6. The production method according to claim 5, wherein 2) the molar ratio of compound III to the ammonia source is 1:1-20; 3) the chiral ruthenium catalyst is selected from Ru(OAc)2[(S)-MeO-BIPHEP] or (S)-Ru(OAc)2(BINAP); 4) the molar ratio of the compound of formula III to the ruthenium catalyst is selected from 1:0.0001-0.001; 5) the hydrogen pressure is selected from 0.5-10 MPa; 6) the reaction temperature of the asymmetric reductive amination is 45-70℃; 7) the reaction time of the asymmetric reductive amination is 12-48 h; 8) the reaction solvent of the asymmetric reductive amination is selected from any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane and ethyl acetate. ​ ​ 7. The production method according to claim 6, wherein When the ammonia source is an ammonia gas solution, the ammonia gas solution is selected from any one of aqueous ammonia or a methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane or ethyl acetate solution of ammonia gas.

8. The preparation method according to claim 6, characterized in that, The asymmetric reductive amination reaction of the compound of formula III satisfies one or more of the following conditions: 1) the ammonia source is an ammonium methanol solution, and the ammonium methanol solution has a molar concentration of 4 mol / L to 7 mol / L; 2) the molar ratio of the compound of formula III to the chiral ruthenium catalyst is 1:0.0003 to 0.001; 3) the hydrogen pressure is in the range of 1.5 to 2.5 MPa; 4) the reaction temperature of the asymmetric reductive amination is 55 to 65°C; 5) the reaction time of the asymmetric reductive amination is 48 h; 6) the reaction solvent of the asymmetric reductive amination is methanol.

9. The production method according to claim 8, characterized by, The molar ratio of the compound of formula III to the chiral ruthenium catalyst is 0.00035.

10. The method of claim 5, wherein, The upper amino protecting group reaction is a compound of formula II, which is reacted with an amino protecting group reagent under the action of a base.

11. The method of claim 10, wherein, The upper amino protecting group reaction satisfies one or more of the following conditions: 1) the molar ratio of the compound II or a salt thereof to the amino protecting group reagent is 1:1 to 1.2; 2) the reaction temperature is 50 to 60°C; 3) the reaction time is 2 to 12 h; 4) the solvent for the upper amino protecting group reaction is selected from one or any combination of water, methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, and ethyl acetate.

12. The method of claim 10, wherein, The solvent for the upper amino protecting group reaction is methanol and water.

13. The preparation method according to claim 10, characterized in that, When R is a Boc amino protecting group and the amino protecting group reagent is di-tert-butyl dicarbonate, the preparation method of the compound of formula Ia comprises: The hydrochloride salt of the compound of formula II is added with methanol and water, then a base is added, di-tert-butyl dicarbonate is added dropwise while controlling the temperature at 50 to 60°C, and after the dropwise addition is completed, the temperature is maintained for 2 hours, then distillation and concentration are performed, filtration is performed, and drying is performed under reduced pressure to obtain the compound of formula Ia.

14. The method of any one of claims 10-13, wherein, The base is selected from an organic base or an inorganic base, the organic base is selected from any one of triethylamine, diethylamine, pyridine, and diisopropylethylamine, and the inorganic base is selected from one or more of potassium phosphate, potassium acetate, potassium carbonate, potassium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, and lithium hydroxide; And / or, the molar ratio of the compound II to the base in the reaction is 1:1.1 to 5.

15. The preparation method according to claim 14, characterized in that, The organic base is diisopropylethylamine, and the inorganic base is sodium hydroxide; And / or, the molar ratio of the compound II to the base in this reaction is 1:

2.

16. A preparation method of sacubitril, comprising obtaining the compound of formula III according to any one of the preparation methods of claims 1 to 4, and then preparing sacubitril from the compound of formula III.

17. A preparation method of sacubitril, comprising obtaining the compound of formula I according to any one of the preparation methods of claims 5 to 15, and then preparing sacubitril from the compound of formula I.

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