A method for synthesizing a saperconazole intermediate

Abstract

The present application relates to the technical field of drug intermediate synthesis, in particular to a synthesis method of a sacubitril intermediate.The synthesis method of the sacubitril intermediate of the present application obtains compound (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxo-pent-2-enoic acid ethyl ester through multi-step reactions after taking 4-halogenated biphenyl and epichlorohydrin as starting materials.The synthesis method of the sacubitril intermediate of the present application has the characteristics of high yield, few by-products and impurities, and high conversion rate without the need to construct or introduce a chiral group, can greatly improve production efficiency, increase benefits, effectively reduce the generation of three wastes, reduce the pressure of pollution discharge, and has a mild reaction process, is safe and controllable, and has low production process risk.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for synthesizing sacubitril intermediate. Background Technology

[0002] LCZ696 is a Class 1 ARNi (angiotensin receptor neprilysin inhibitor), composed of the anionic group of the angiotensin receptor (AR) inhibitor valsartan and the prodrug AHU377, a neprilysin inhibitor used for heart failure and hypertension, in a 1:1 ratio. It possesses a unique mode of action and is believed to reduce the strain on a failing heart. This drug was approved by the FDA on July 7, 2015, for the treatment of heart failure patients with reduced ejection fraction. LCZ696 is composed of sacubitril and valsartan. Sacubitril blocks the action of the two peptides responsible for lowering blood pressure, while valsartan improves vasodilation and stimulates the body to excrete sodium and water. Cardiovascular drugs have extremely high safety thresholds, and LCZ696 has even demonstrated a higher safety profile than conventional drugs. The industry considers LCZ696's outstanding performance to be one of the most important advances in cardiology over the past decade. Furthermore, LCZ696 is expected to remain unparalleled in the cardiovascular field for the next few years, thus its pharmaceutical prospects are very promising.

[0003] The chemical name of sacubitril is 4-((2S,3R)-1-(1,1'-biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxopentane-2-yl)amino)-4-oxobutyric acid (1), and its structural formula is shown in Formula 1.

[0004]

[0005] (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester is a key intermediate in the synthesis of sacubitril, and its structure is shown in the compound in Formula 2.

[0006]

[0007] The intermediate is used to construct a chiral amine intermediate via transaminase, and then the product sacubitril can be prepared by metal-catalyzed hydrogenation and docking coupling reaction.

[0008]

[0009] Patent document CN105924355 discloses a method for preparing a sacubitril intermediate, the synthetic route of which is as follows (Equation 3).

[0010]

[0011] Route 3 constructs chiral centers by preparing branched compounds, but it suffers from high costs for branched raw materials and even higher costs for sodium iodide used in the preparation of branched compounds. In addition, the process of combining the main branch with the branched compound requires hydrogen-removing materials such as sodium hydrogen, which makes the process difficult and results in low yield, thereby increasing the production and processing costs for enterprises.

[0012] Patent document CN113121342A discloses a method for preparing a sacubitril intermediate, the synthetic route of which is as follows (Equation 4).

[0013]

[0014] Route 4 uses itaconic anhydride to selectively obtain chiral atoms via hydrogenation with noble metals. Although this route is shorter, reaction initiation is difficult to control, there are many impurities, and post-processing is complex. Furthermore, the noble metal selectivity during chiral reduction is low, easily leading to yield reduction. The lipase reduction process used also has low yield and poor enzyme selectivity, indicating that the process is not yet mature.

[0015] Analysis of the synthetic routes for preparing sacubitril reported in the aforementioned literature reveals that constructing the chiral group is a crucial core step and also the source of high costs in the preparation route. There are two main methods for constructing the chiral center: the first method uses hydrogenation reduction to select chirality, and the second method directly introduces a chiral source. However, both methods are currently either costly, pose safety risks, or have difficulty obtaining the intermediates used directly in the preparation process. Furthermore, they suffer from high excipient costs, cumbersome routes, troublesome post-processing, and the generation of numerous impurities, all of which hinder the economical preparation of compound formula 2. Therefore, a new preparation method is urgently needed to solve the aforementioned production problems. Summary of the Invention

[0016] In view of this, the purpose of this invention is to propose a method for synthesizing sacubitril intermediates, which can improve product yield while ensuring safe production and reducing production costs.

[0017] To achieve the above objectives, this invention provides a method for synthesizing a sacubitril intermediate, wherein the (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester, i.e., the sacubitril intermediate, is synthesized via the following reaction mechanism as shown in Formula II: S1: Using 4-halobiphenyl as the starting material, react with metallic magnesium under anhydrous and oxygen-free conditions to obtain 4-biphenyl magnesium halo, which is then reacted with halopropylene oxide to obtain compound (2). S2: Compound (2) is oxidized with an oxidizing agent to obtain compound (3); S3: React compound (3) with ethylene glycol and trimethyl orthoformate to generate compound (4); S4: Hydrolyze compound (4) under alkaline conditions to generate compound (5); S5: Oxidize compound (5) to obtain compound (6); S6: Compound (6) is reacted with phosphorus ylide to obtain compound (7); S7: Remove ethylene glycol from compound (7) to obtain compound (8) (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester, which is the intermediate of sacubitril.

[0018] Preferably, the halogens in the 4-halobiphenyl and halopropylene oxide in step S1 are one of chlorine, bromine, and iodine.

[0019] Preferably, the oxidation reaction in step S2 is performed by one of TEMPO oxidation, Swern oxidation, or direct oxidation with hydrogen peroxide.

[0020] More preferably, the oxidant in the TEMPO oxidation reaction can be sodium hypochlorite, sodium hypobromite, or sodium hypoiodide; in the Swern oxidation reaction, dimethyl sulfoxide is used as a solvent, and the Swern reaction occurs synergistically with oxaloyl chloride or trifluoroacetic anhydride under alkaline and low-temperature conditions; the hydrogen peroxide reaction is carried out by the strong oxidizing property of hydrogen peroxide; and the reaction solvent is generally a solvent such as DCM, ethyl acetate, toluene, DMF, or DMSO.

[0021] Preferably, a catalyst is required during the reaction in step S3, and the catalyst is one of sulfuric acid, p-toluenesulfonic acid, and hydrochloric acid.

[0022] Preferably, the alkali used in the alkaline conditions described in step S4 is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, and triethylamine.

[0023] Preferably, the oxidation reaction in step S5 is performed by one of TEMPO oxidation, Swern oxidation, or direct oxidation with hydrogen peroxide.

[0024] Preferably, the acid-binding agent used in the reaction in step S6 is one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, and triethylamine.

[0025] Preferably, the reagent added in step S7 to remove ethylene glycol protection is one of p-toluenesulfonic acid, sulfuric acid, and hydrochloric acid, and the solvent is methanol, ethanol, tetrahydrofuran, toluene, or other solvents.

[0026] The beneficial effects of this invention are: (1) Reduce costs. Epichlorohydrin can be used in the reaction, and there is no need to construct or introduce chiral groups. The materials used are inexpensive, such as sodium hypochlorite and sodium hydroxide, which can reduce costs and reduce the generation of by-products, thereby increasing the yield.

[0027] (2) High yield, high yield of each step of the reaction, low by-products and impurities, high conversion rate, good effect, can greatly improve production efficiency and increase benefits.

[0028] (3) Green and safe, with no high phosphorus and high nitrogen reactions used throughout the process, which can effectively reduce the generation of three wastes and reduce the pressure of sewage discharge (phosphorus, nitrogen and chlorine).

[0029] (4) The reaction process is mild, safe and controllable, and the production process has low risk. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0031] Figure 1 This is a schematic diagram of the synthetic reaction process for the sacubitril intermediate prepared according to the present invention; Figure 2 This is a schematic diagram of the preparation of compound (2) in Example 1 of the present invention; Figure 3 This is a schematic diagram of the preparation of compound (2) in Example 2 of the present invention; Figure 4 This is a schematic diagram of the preparation of compound (2) in Example 3 of the present invention; Figure 5 This is a schematic diagram of the preparation of compound (3) in Example 4 of the present invention; Figure 6 This is a schematic diagram of the preparation of compound (3) in Example 5 of the present invention; Figure 7 This is a schematic diagram of the preparation of compound (3) in Example 6 of the present invention; Figure 8 This is a schematic diagram of the preparation of compound (4) in Examples 7-9 of the present invention; Figure 9 This is a schematic diagram of the preparation of compound (5) in Examples 10-12 of the present invention; Figure 10 This is a schematic diagram illustrating the preparation of compound (6) in Examples 13-15 of the present invention; Figure 11 This is a schematic diagram illustrating the preparation of compound (7) in Examples 16-18 of the present invention; Figure 12 This is a schematic diagram of the preparation of compound (8) in Examples 19-21 of the present invention. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0033] Example 1: The specific preparation steps of compound (2) are as follows:

[0034] Magnesium powder (34.7 g, 1.35 mol), tetrahydrofuran (500 ml), and 6 iodine grains were added sequentially to a 3 L reaction flask. After stirring thoroughly, the mixture was purged with nitrogen three times. Then, 4-chlorobiphenyl (200 g, 1.06 mol) was added dropwise. The temperature was raised to 50 °C, and after the addition was complete, the temperature was lowered to 0-5 °C. Cuprous iodide (20.2 g, 0.10 mol) was added, and the reaction was stirred for 0.5 h. Then, the temperature was lowered to -10 °C, and epichlorohydrin (117.6 g, 1.2 mol) was added dropwise. The reaction was allowed to proceed for 9 h. After the reaction was completed, 200 ml of 6N hydrochloric acid was added dropwise to quench the reaction. The tetrahydrofuran was evaporated, and the mixture was extracted twice with 1000 ml of DCM. The solid was then dried by rotary evaporation to obtain 236.3 g of a white solid (molar yield 89.9%).

[0035] Compound (2) was analyzed and characterized: Mass spectrometry: ESI-MS m / z: 247.7 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 7.75 (2H, m), 7.62 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 7.32 (2H, m), 5.02 (1H, -OH), 4.29 (1H, m), 3.63 (2H, m), 2.81 (2H, m), correct structure.

[0036] Example 2: The specific preparation steps of compound (2) are as follows: Magnesium powder (31.2 g, 1.28 mol), DMSO (500 ml), and 6 iodine grains were added sequentially to a 3 L reaction flask. After stirring thoroughly, the mixture was purged with nitrogen three times. Then, 4-bromobiphenyl (200 g, 0.858 mol) was added dropwise. The temperature was raised to 50 °C, and after the addition was complete, the temperature was lowered to 0-5 °C. Cuprous iodide (16.3 g, 0.085 mol) was added, and the reaction was stirred for 0.5 h. Then, the temperature was lowered to 10 °C, and epichlorohydrin (141.1 g, 1.03 mol) was added dropwise. The reaction was allowed to proceed for 6 h. After the reaction was completed, 200 ml of 6N hydrochloric acid was added dropwise to quench the reaction. Tetrahydrofuran was evaporated, and the mixture was extracted twice with 1000 ml of DCM and once with water. After drying by rotary evaporation, 225.3 g of a white solid (molar yield 90.2%) was obtained.

[0037] Example 3: The specific preparation steps of compound (2) are as follows: Magnesium powder (23.4 g, 0.96 mol), DMF (500 ml), and 6 iodine grains were added sequentially to a 3 L reaction flask. After stirring thoroughly, the mixture was purged with nitrogen three times. Then, 4-iodobiphenyl (200 g, 0.714 mol) was added dropwise. The temperature was raised to 50 °C, and after the addition was complete, the temperature was lowered to 0-5 °C. Cuprous iodide (13.6 g, 0.07 mol) was added, and the reaction was stirred for 0.5 h. The temperature was then lowered to 10 °C, and epichlorohydrin (79.2 g, 0.856 mol) was added dropwise. The reaction was allowed to proceed for 3 h. After the reaction was completed, 200 ml of 6N hydrochloric acid was added dropwise to quench the reaction. Tetrahydrofuran was evaporated, and the mixture was extracted twice with 1000 ml of DCM and once with water. After drying by rotary evaporation, 160.6 g of a white solid (molar yield 91.1%) was obtained.

[0038] Example 4: The specific preparation steps of compound (3) are as follows: Compound (2) (200 g, 0.876 mol), sodium bicarbonate (117.6 g, 1.39 mol), sodium bromide (54.1 g, 0.52 mol), DCM (1000 ml), and water (800 ml) were added sequentially to a 3 L reaction flask. After stirring thoroughly, the mixture was cooled to 0 °C, and TEMPO (8.7 g, 0.052 mol) was added. Sodium hypochlorite solution (effective amount: 10%) (1691 g, 2.26 mol) was added dropwise. After the TEMPO reaction was complete, sodium bisulfite was added to quench the reaction until potassium iodide paper was colorless. The mixture was extracted twice with 1000 ml of DCM and once with water. The organic phases were combined and dried by rotary evaporation to obtain 184.5 g of a white solid (molar yield 94.9%).

[0039] Compound (3) was analyzed and characterized: Mass spectrometry: ESI-MS m / z: 245.7 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 7.75 (2H, m), 7.63 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 7.38 (2H, m), 4.54 (2H, m), 3.45 (2H, m), structure correct.

[0040] Example 5: The specific preparation steps of compound (3) are as follows: Compound (2) (200 g, 0.687 mol), sodium bicarbonate (117.6 g, 1.39 mol), sodium bromide (54.1 g, 0.52 mol), toluene (1000 ml), and water (800 ml) were added sequentially to a 3 L reaction flask. After stirring thoroughly, the mixture was cooled to 0 °C, and TEMPO (8.7 g, 0.052 mol) was added. Sodium hypobromite solution (effective amount: 10%) (1070 g, 2.26 mol) was added dropwise. After the TEMPO reaction was complete, sodium bisulfite was added to quench the reaction until potassium iodide paper was colorless. The mixture was extracted twice with 1000 ml of DCM and once with water. The organic phases were combined and dried by rotary evaporation to obtain 184.5 g of a white solid (molar yield 93%).

[0041] Example 6: The specific preparation steps of compound (3) are as follows: A DCM solution of oxaloyl chloride (166 g, 1.3 mol) was cooled to -80 °C, and a DCM solution of DMSO (75.2 g, 0.97 mol) was added dropwise, producing a large amount of gas. After reacting for 10 min, a DCM solution of compound (2) (200 g, 0.81 mol) was slowly added dropwise, and the mixture was stirred for 15 min. Then, triethylamine (295 g, 2.9 mol) was slowly added, and the mixture was stirred for 15 min. The mixture was then slowly raised to room temperature, and the reaction was completed after 1 h. The solution was quenched with ammonia, DCM, and brine, and then extracted with DCM. The solid was then evaporated to dryness to obtain 186.5 g of off-white solid (molar yield 94%).

[0042] Example 7: The specific preparation steps of compound (4) are as follows: A DCM solution of compound (3) (100 g, 0.408 mol) was added to ethylene glycol and stirred until homogeneous. Trimethyl orthoformate was then added dropwise at 15-20 °C, followed by concentrated sulfuric acid (3 g). After the addition was complete, the temperature was raised to 25 °C and kept at that temperature for 1 h. Once the reaction was complete, sodium bicarbonate was added and stirred to quench the reaction. The insoluble matter was removed by filtration. The organic layer was washed twice with water, evaporated to dryness, and then dissolved in anhydrous ethanol under reflux. The mixture was cooled to 0-5 °C and stirred for 1 h. After centrifugation and drying, 105 g of white solid was obtained (molar yield 90.1%).

[0043] Compound (4) was analyzed and characterized: Mass spectrometry: ESI-MS m / z: 289.7 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 7.75 (2H, m), 7.62 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 7.32 (2H, m), 3.85 (4H, m), 3.62 (2H, m), 2.79 (2H, m), correct structure.

[0044] Example 8: The specific preparation steps of compound (4) are as follows: A toluene solution of compound (3) (100 g, 0.408 mol) was added to ethylene glycol and stirred until homogeneous. Trimethyl orthoformate was then added dropwise at 15-20 °C, followed by p-toluenesulfonic acid (3 g). After the addition was complete, the temperature was raised to 25 °C and kept at that temperature for 1 h. Once the reaction was complete, sodium bicarbonate was added and stirred to quench the reaction. The insoluble matter was removed by filtration. The organic layer was washed twice with water, evaporated to dryness, and then dissolved in anhydrous ethanol under reflux. The mixture was cooled to 0-5 °C and stirred for 1 h. After centrifugation and drying, 99 g of white solid was obtained (molar yield 86.5%).

[0045] Example 9: The specific preparation steps of compound (4) are as follows: An EA solution of compound (3) (100 g, 0.408 mol) was added to ethylene glycol and stirred until homogeneous. Trimethyl orthoformate (108 g, 1.46 mol) was added dropwise at 15-20 °C, followed by hydrochloric acid (3 g). After the addition was complete, the temperature was raised to 25 °C and kept at that temperature for 1 h. After the reaction was complete, sodium bicarbonate was added and stirred to quench the reaction. The insoluble matter was removed by filtration. The organic layer was washed twice with water, evaporated to dryness, and then dissolved in anhydrous ethanol under reflux. The temperature was lowered to 0-5 °C and stirred for 1 h. The mixture was then centrifuged and dried to obtain 97 g of white solid (molar yield 85.4%).

[0046] Example 10: The specific preparation steps of compound (5) are as follows: Compound (4) (80 g, 0.277 mol) and an aqueous solution of sodium hydroxide (44 g, 1.1 mol) (220 ml) were added to a reaction flask and heated to 35 °C for 3 h. After the reaction was complete, 200 ml of DCM was added for extraction twice, followed by washing with water once. The organic layers were combined and evaporated to dryness to give 68.1 g of a pale yellow solid (molar yield 91%).

[0047] Compound (5) was analyzed and characterized: Mass spectrometry: ESI-MS m / z: 271.3 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 7.75 (2H, m), 7.62 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 7.32 (2H, m), 4.95 (1H, -OH), 3.85 (4H, m), 3.77 (2H, m), 2.79 (2H, m), correct structure.

[0048] Example 11: The specific preparation steps of compound (5) are as follows: Compound (4) (80 g, 0.277 mol) and an aqueous solution of lithium hydroxide (26.4 g, 1.1 mol) (180 ml) were added to a reaction flask and heated to 30 °C for 2 h. After the reaction was complete, 200 ml of DCM was added for extraction twice, followed by washing with water once. The organic layers were combined and evaporated to dryness to give 69.6 g of a pale yellow solid (molar yield 93%).

[0049] Example 12: The specific preparation steps of compound (5) are as follows: Compound (4) (80 g, 0.277 mol) and an aqueous solution of potassium hydroxide (62.1 g, 1.1 mol) (300 ml) were added to a reaction flask and heated to 30 °C for 3 h. After the reaction was complete, 200 ml of DCM was added for extraction twice, followed by washing with water once. The organic layers were combined and evaporated to dryness to give 66.1 g of a pale yellow solid (molar yield 88.4%).

[0050] Example 13: The specific preparation steps of compound (6) are as follows: Compound (5) (50 g, 0.185 mol), sodium bicarbonate (46.6 g, 0.55 mol), sodium bromide (44.1 g, 0.52 mol), DCM (500 ml), and water (500 ml) were added sequentially to a 2 L reaction flask. After stirring thoroughly, the mixture was cooled to 0 °C, and TEMPO (1.84 g, 0.012 mol) was added. Sodium hypochlorite solution (effective amount: 10%) (322 g, 0.22 mol) was added dropwise. After the TEMPO reaction was complete, sodium bisulfite was added to quench the reaction until potassium iodide paper was colorless. The mixture was extracted twice with 500 ml of DCM and once with water. The organic phases were combined and dried by rotary evaporation to obtain 45.6 g of a white solid (molar yield 92.1%).

[0051] Compound (6) was analyzed and characterized: Mass spectrometry: ESI-MS m / z: 269.3 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 9.72 (1H, m), 7.75 (2H, m), 7.62 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 3.85 (4H, m), 3.14 (2H, m), correct structure.

[0052] Example 14: The specific preparation steps of compound (6) are as follows: Compound (5) (50 g, 0.185 mol), sodium bicarbonate (117.6 g, 1.39 mol), sodium bromide (54.1 g, 0.52 mol), toluene (500 ml), and water (500 ml) were added sequentially to a 2 L reaction flask. After stirring thoroughly, the mixture was cooled to 0 °C, and TEMPO (1.84 g, 0.01 mol) was added. Sodium hypobromite solution (effective amount: 10%) (256 g, 0.23 mol) was added dropwise. After the TEMPO reaction was complete, sodium bisulfite was added to quench the reaction until potassium iodide paper was colorless. The mixture was extracted twice with 500 ml of DCM and once with water. The organic phases were combined and dried by rotary evaporation to obtain 43.6 g of a white solid (molar yield 88%).

[0053] Example 15: The specific preparation steps of compound (6) are as follows: A DCM solution of oxalyl chloride (41.5 g, 0.32 mol) was cooled to -80 °C, and a DCM solution of DMSO (18.8 g, 0.24 mol) was added dropwise, producing a large amount of gas. After reacting for 10 min, a DCM solution of compound (5) (50 g, 0.21 mol) was slowly added dropwise, and the mixture was stirred for 15 min. Then, triethylamine (74 g, 0.73 mol) was slowly added, and the mixture was stirred for 15 min. The mixture was then slowly raised to room temperature, and the reaction was completed after 1 h. The solution was quenched with ammonia, DCM, and brine, and then extracted with DCM. The solid was then evaporated to dryness to obtain 46.5 g of off-white solid (molar yield 94%).

[0054] Example 16: The specific preparation steps of compound (7) are as follows: A DCM solution of compound (7) (20 g, 0.075 mol), phosphine ylide bromide (52.8 g, 0.14 mol), and an aqueous solution of potassium carbonate (20.8 g, 0.17 mol) were added to a 500 mL reaction flask to carry out the substitution reaction. The reaction was stirred at 0-5 °C for 1 h until the reaction was complete. Water was added to the solution, and the aqueous phase was extracted twice with DCM. The organic phases were combined, evaporated to dryness, and dried to obtain 23.1 g of white solid (molar yield 87.2%).

[0055] The compound (7) was analyzed and characterized as follows: Mass spectrometry: ESI-MS m / z: 353 [M+H]+; Nuclear magnetic resonance (NMR) spectrum: 1H NMR (600MHz, CDCl3), δ: 7.75 (2H, m), 7.62 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 6.79 (1H, m), 4.08 (2H, m), 3.85 (4H, m), 2.34 (3H, m), 1.15 (3H, m), and the structure was correct.

[0056] Example 17: The specific preparation steps of compound (7) are as follows: A DCM solution of compound (7) (20 g, 0.075 mol), a solution of phosphorus ylide bromide (52.8 g, 0.14 mol), and a solution of triethylamine (16.18 g, 0.18 mol) were added to a 500 mL reaction flask to carry out the substitution reaction. The reaction was stirred at 0-5 °C for 1 h until the reaction was complete. Water was added to the solution, and the aqueous phase was extracted twice with DCM. The organic phases were combined, evaporated to dryness, and dried to obtain 24.3 g of white solid (molar yield 90.4%).

[0057] Example 18: The specific preparation steps of compound (7) are as follows: A DCM solution of compound (7) (20 g, 0.075 mol), phosphine ylide bromide (52.8 g, 0.14 mol), and an aqueous solution of sodium hydroxide (5.3 g, 0.15 mol) were added to a 500 mL reaction flask to carry out the substitution reaction. The reaction was stirred at 0-5 °C for 1 h until the reaction was complete. Water was added to the solution, and the aqueous phase was extracted twice with DCM. The organic phases were combined, evaporated to dryness, and dried to obtain 22.1 g of white solid (molar yield 82.4%).

[0058] Example 19: The specific preparation steps of compound (8) (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester are as follows: Compound (7) (20g, 0.056mol) was added to 160ml of acetone and 10ml of water, and p-toluenesulfonic acid (0.8g, 0.042mol) was added. The mixture was heated to reflux. After the reaction was completed, the temperature was lowered to 40-45℃, and the acetone was removed by vacuum distillation. The mixture was then dissolved in 80ml of ethyl acetate, washed with 20ml of sodium bicarbonate solution and 20ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40-45℃. 40ml of methanol was added and refluxed to dissolve the crystals. The mixture was slowly cooled to crystallize, stirred overnight in an ice salt solution (-10 to -15℃), filtered, and rinsed to obtain 21g of wet product. Secondary purification: 60 ml of methanol was added, 21 g of wet product was added, the temperature was raised to reflux and dissolved, the temperature was slowly lowered to crystallize, the product was cooled with ice salt for more than 2 hours, filtered, rinsed, and dried under reduced pressure at 45 °C to obtain 15.1 g (molar yield 87.3%) of off-white solid product.

[0059] Compound (8) was analyzed and characterized as follows: Mass spectrometry: ESI-MS m / z: 309.4 [M+H]+; 1H NMR: 600MHz, CDCl3, δ: 7.75 (2H, m), 7.63 (2H, m), 7.49 (2H, m), 7.41 (1H, m), 7.04 (1H, m), 4.20 (2H, m), 4.08 (2H, m), 2.34 (3H, m), 1.16 (3H, m), and the structure is correct.

[0060] Example 20: The specific preparation steps of compound (8) (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester are as follows: Compound (7) (20g, 0.056mol) was added to 160ml of acetone and 10ml of water, and concentrated sulfuric acid (0.8g, 0.083mol) was added dropwise. The mixture was heated to reflux. After the reaction was completed, the temperature was lowered to 40-45℃, and the acetone was removed by vacuum distillation. The mixture was then dissolved in 80ml of ethyl acetate, washed with 20ml of sodium bicarbonate solution and 20ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40-45℃. 40ml of methanol was added and refluxed to dissolve the crystals. The mixture was slowly cooled to crystallize, stirred overnight in an ice salt solution (-10 to -15℃), filtered, and rinsed to obtain 21g of wet product. Secondary purification: 60 ml of methanol was pumped in, 21 g of wet product was added, the temperature was raised to reflux and dissolved, the temperature was slowly lowered to crystallize, the product was cooled with ice salt for more than 2 hours, filtered, rinsed, and dried under reduced pressure at 45 °C to obtain 14.9 g (molar yield 86.3%) of off-white solid product.

[0061] Example 21: The specific preparation steps of compound (8) (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester are as follows: Compound (7) (20g, 0.056mol) was added to 160ml of acetone and 10ml of water, and concentrated hydrochloric acid (2.1g, 0.22mol) was added dropwise. The mixture was heated to reflux. After the reaction was completed, the temperature was lowered to 40-45℃, and the acetone was removed by vacuum distillation. The mixture was then dissolved in 80ml of ethyl acetate, washed with 20ml of sodium bicarbonate solution and 20ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40-45℃. 40ml of methanol was added and refluxed to dissolve the crystals. The mixture was slowly cooled to crystallize, stirred overnight in an ice salt solution (-10 to -15℃), filtered, and rinsed to obtain 21g of wet product. Secondary purification: 60 ml of methanol was pumped in, 21 g of wet product was added, the temperature was raised to reflux and dissolved, the temperature was slowly lowered to crystallize, the product was cooled with ice salt for more than 2 hours, filtered, rinsed, and dried under reduced pressure at 45 °C to obtain 14.8 g (molar yield 86.1%) of off-white solid product.

[0062] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0063] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A method for synthesizing a sacubitril intermediate, characterized in that, The sacubitril intermediate, namely (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester, is shown in Formula I, and its synthetic reaction mechanism is shown in Formula II, namely: ； S1: Using compound (1) 4-halobiphenyl as the starting material, react with metallic magnesium under anhydrous and oxygen-free conditions to obtain 4-biphenyl halomagnesium, and then react with halopropylene oxide to obtain compound (2). S2: Compound (2) is oxidized with an oxidizing agent to obtain compound (3); S3: Compound (3) is reacted with ethylene glycol and trimethyl orthoformate to generate compound (4), where EG refers to ethylene glycol solvent; S4: Hydrolyze compound (4) under alkaline conditions to generate compound (5); S5: Oxidize compound (5) to obtain compound (6); S6: Compound (6) is reacted with phosphorus ylide to obtain compound (7); S7: Remove ethylene glycol from compound (7) to obtain compound (8) (E)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopent-2-enoic acid ethyl ester, which is the intermediate of sacubitril.

2. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The halogens in the 4-halobiphenyl and halopropylene oxide mentioned in step S1 are all one of chlorine, bromine, and iodine.

3. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The oxidation reaction described in step S2 is one of TEMPO oxidation, Swern oxidation, or direct oxidation with hydrogen peroxide.

4. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The reaction described in step S3 requires the addition of a catalyst, which is one of sulfuric acid, p-toluenesulfonic acid, or hydrochloric acid.

5. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The type of alkali used in the alkaline conditions described in step S4 is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, and potassium tert-butoxide.

6. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The oxidation reaction described in step S5 is one of TEMPO oxidation, Swern oxidation, or direct oxidation with hydrogen peroxide.

7. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The acid-binding agent used in the reaction described in step S6 is one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, and triethylamine.

8. The method for synthesizing the sacubitril intermediate according to claim 1, characterized in that, The reagent added in step S7 to remove ethylene glycol protection is one of p-toluenesulfonic acid, sulfuric acid, or hydrochloric acid.

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