A method for preparing a sacubitril intermediate

Abstract

This invention provides a method for preparing a sacubitril intermediate, relating to the field of pharmaceutical synthesis technology. Using (2R)-4-nitro-2-methyl-butyrate ethyl ester and 4-bromomethylbiphenyl as initial raw materials, the method involves condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salt formation and resolution reaction with R(+)-α-methylbenzylamine, and acidification to liberate the sacubitril intermediate. The preparation method provided by this invention is simple, easy to operate, has a high yield of the target product (36.5% overall yield in Example 1), high purity, low raw material cost, low production cost, and generates minimal waste, making it suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine synthesis, and particularly relates to a preparation method of a sacubitril intermediate. BACKGROUND

[0002] Sacubitril valsartan sodium (LCZ696) is a drug developed by Novartis, the first angiotensin receptor neprilysin inhibitor drug approved worldwide, which has a definite curative effect and good safety in the treatment of heart failure and hypertension. Data shows that in 2022, Novartis' sacubitril valsartan sodium tablets had a global sales of 4.644 billion US dollars, and the market is huge. The structure of each molecule of sacubitril valsartan sodium is composed of one molecule of sodium salt of sacubitril (structural formula as follows), one molecule of disodium salt of valsartan sodium, and two molecules of hemihydrate.

[0003]

[0004] The conventional synthesis method of sacubitril is to use compound (2R, 4S)-5-[(1, 1'-biphenyl)-4-yl]-4-tert-butoxycarbonyl-2-methylpentanoic acid (2) as a raw material, and obtain by two-step reaction (Chen, Zhijun; et al, Optimization and process improvement for LCZ696 by employing quality by design (QbD) principles, Tetrahedron (2020), 76 (46), 131558; patent WO2017009784A1), and the reaction process is as follows:

[0005]

[0006]

[0007] Among them, compound 2 is a key intermediate for synthesizing sacubitril. At present, patents WO2014032627A1 and WO2008031567A1 disclose the synthesis of sacubitril intermediate compound 2, and the steps are as follows:

[0008]

[0009] However, the above synthesis method has a long process route, uses expensive Wittig reagent and chiral auxiliary catalyst, has high raw material cost and large three-waste discharge. SUMMARY

[0010] Therefore, the purpose of the present application is to provide a preparation method of a sacubitril intermediate. The preparation method provided by the present application has simple process steps, low preparation cost and less three-waste.

[0011] To achieve the above-mentioned object, the present application provides the following technical solutions.

[0012] The present application provides a preparation method of a sacubitril intermediate, comprising the following steps:

[0013] (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl are subjected to condensation reaction to obtain an intermediate 1;

[0014] The intermediate 1 is subjected to hydrogenation reduction reaction and acidification to obtain an intermediate 2;

[0015] The intermediate 2 and BOC anhydride are subjected to amino protection reaction and hydrolysis to obtain an intermediate 3;

[0016] The intermediate 3 and R(+)-α-methylbenzylamine are subjected to salt formation resolution reaction to obtain an intermediate 4;

[0017] The intermediate 4 is subjected to acidification and free treatment to obtain a sacubitril intermediate;

[0018]

[0019] Preferably, the molar ratio of (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl is 0.95-1.05:1.

[0020] Preferably, the condensation reaction is carried out in the presence of a basic reagent and an organic solvent;

[0021] The basic reagent comprises one or more of potassium carbonate, sodium carbonate and triethylamine;

[0022] The molar ratio of (2R)-4-nitro-2-methyl-butyric acid ethyl ester and the basic reagent is 1:1-1.1;

[0023] The organic solvent comprises N,N-dimethylformamide and / or acetonitrile;

[0024] The temperature of the condensation reaction is 50-60°C, and the time is 5-7h.

[0025] Preferably, the hydrogenation reduction reaction is carried out in the presence of a catalyst and hydrogen; the catalyst comprises Raney nickel and / or palladium-carbon;

[0026] The hydrogenation reduction reaction is carried out in the presence of an organic solvent, and the organic solvent comprises ethanol and / or methanol.

[0027] Preferably, the temperature of the hydrogenation reduction reaction is 35-45°C, the time is 13-17h, and the hydrogen pressure is 0.85-1.15MPa.

[0028] Preferably, the pH value of the acidified system is 3-4.

[0029] Preferably, the molar ratio of the intermediate 2 and BOC anhydride is 1:1.05-1.15.

[0030] The temperature of the amino protection reaction is 45-55℃, and the time is 2-4h.

[0031] Preferably, the hydrolysis is carried out under acidic conditions, and the pH value of the acidic conditions is 5-6.

[0032] Preferably, the molar ratio of the intermediate 3 and R(+)-α-methylbenzylamine is 1:0.8-1.3.

[0033] The temperature of the salt-forming resolution reaction is 45-55℃, and the time is 0.5-2h.

[0034] Preferably, the acid used in the acidification and free treatment includes one or more of acetic acid, hydrochloric acid and sulfuric acid.

[0035] The molar ratio of the intermediate 4 and the acid is 1:1.1-1.3.

[0036] The present application uses (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethyl biphenyl as initial raw materials, and through condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salt-forming resolution reaction with R(+)-α-methylbenzylamine and acidification and free treatment, a sacubitril intermediate can be prepared. The preparation method provided by the present application has simple process, simple operation, high yield of target product (the total yield of example 1 is 36.5%), high purity, low raw material cost, low production cost, less waste, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 It is the nuclear collision resonance hydrogen spectrum of the intermediate 4;

[0038] Figure 2 It is the infrared spectrum of the intermediate 4;

[0039] Figure 3 It is the nuclear collision resonance hydrogen spectrum of the sacubitril intermediate;

[0040] Figure 4 It is the infrared spectrum of the sacubitril intermediate;

[0041] Figure 5 It is the mass spectrum of the sacubitril intermediate. DETAILED DESCRIPTION

[0042] The present application provides a preparation method of a sacubitril intermediate, which comprises the following steps:

[0043] condensation reaction of (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl to obtain intermediate 1;

[0044] acidification after hydrogenation reduction reaction of the intermediate 1 to obtain intermediate 2;

[0045] hydrolysis after amino protection reaction of the intermediate 2 and BOC anhydride to obtain intermediate 3;

[0046] salt separation reaction of the intermediate 3 and R(+)-α-methylbenzylamine to obtain intermediate 4;

[0047] acidification free treatment of the intermediate 4 to obtain sacubitril intermediate;

[0048]

[0049] Unless otherwise specified, the materials and equipment used in the present application are commercially available in the art.

[0050] The present application condenses (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl to obtain intermediate 1.

[0051] In the present application, the molar ratio of (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl is preferably 0.95-1.05:1, more preferably 1-1.02:1.

[0052] In the present application, the condensation reaction is preferably carried out in the presence of a basic reagent and an organic solvent. In the present application, the basic reagent preferably includes one or more of potassium carbonate, sodium carbonate and triethylamine; the molar ratio of (2R)-4-nitro-2-methyl-butyric acid ethyl ester and the basic reagent is preferably 1:1-1.1, more preferably 1:1.02-1.05. In the present application, the organic solvent preferably includes N,N-dimethylformamide and / or acetonitrile, more preferably N,N-dimethylformamide; the amount ratio of (2R)-4-nitro-2-methyl-butyric acid ethyl ester to the organic solvent is preferably 1 mol:1800-2200 g, more preferably 1 mol:1900-2100 g, further preferably 1 mol:2000 g.

[0053] In the present application, the temperature of the condensation reaction is preferably 50-60°C, more preferably 55°C; the time of the condensation reaction is preferably 5-7 h, more preferably 6 h.

[0054] After the condensation reaction is completed, the present application concentrates the condensation reaction liquid obtained from the condensation reaction to no solvent effluent, cools to 27-33°C (more preferably 30°C), adds dichloromethane and water, performs dichloromethane extraction, and concentrates the obtained organic phase to constant weight to obtain intermediate 1. In the present application, the number of times of water washing is preferably 1-3 times, and more preferably 2 times.

[0055] After obtaining intermediate 1, the present application performs hydrogenation reduction reaction on the intermediate 1 and acidifies to obtain intermediate 2.

[0056] In the present application, the hydrogenation reduction reaction is preferably performed in the presence of a catalyst and hydrogen; the catalyst preferably includes Raney nickel and / or palladium-carbon, and more preferably Raney nickel. In the present application, the use amount ratio of intermediate 1 to catalyst is preferably 1 mol: 45-55 g, more preferably 1 mol: 48-52 g, and further preferably 1 mol: 50 g.

[0057] In the present application, the hydrogenation reduction reaction is preferably performed in the presence of an organic solvent, and the organic solvent preferably includes ethanol and / or methanol, and more preferably ethanol. In the present application, the use amount ratio of intermediate 1 to organic solvent is preferably 1 mol: 1800-2200 g, more preferably 1 mol: 1900-2100 g, and further preferably 1 mol: 2000 g.

[0058] In the present application, the temperature of the hydrogenation reduction reaction is preferably 35-45°C, and more preferably 40°C; the time of the hydrogenation reduction reaction is preferably 13-17 h, and more preferably 14-15 h; and the hydrogen pressure of the hydrogenation reduction reaction is preferably 0.85-1.15 MPa, and more preferably 1 MPa.

[0059] After the hydrogenation reduction reaction is completed, the present application preferably further includes performing solid-liquid separation on the hydrogenation reduction reaction liquid obtained from the hydrogenation reduction reaction and concentrating the obtained liquid component to constant weight. The present application does not have special limitations on the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as filtration, suction filtration, or centrifugal separation.

[0060] In the present application, the pH value of the acidification system is preferably 3-4, and more preferably 3.5; and a solid product is precipitated during the acidification. In the present application, the acid used for acidification preferably includes hydrochloric acid or sulfuric acid; and the present application does not have special limitations on the concentration of the acid, and any acid known to those skilled in the art can be used to adjust the pH value of the system to 3-4, such as concentrated hydrochloric acid or 70 wt% sulfuric acid aqueous solution.

[0061] After the acidification, the present application preferably further comprises: performing solid-liquid separation on the acidification system obtained by the acidification, and drying the obtained solid product to constant weight to obtain intermediate 2. The present application does not have special limitations on the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation.

[0062] After obtaining the intermediate 2, the present application performs an amino protection reaction on the intermediate 2 and BOC anhydride, and then hydrolyzes to obtain intermediate 3.

[0063] In the present application, the molar ratio of the intermediate 2 to BOC anhydride is preferably 1:1.05-1.15, and more preferably 1:1.1.

[0064] In the present application, the amino protection reaction is preferably performed in the presence of a basic reagent. In the present application, the basic reagent preferably includes sodium hydroxide and / or potassium hydroxide, and more preferably sodium hydroxide; the basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the concentration of the aqueous solution of the basic reagent is preferably 35-40 wt%, and more preferably 40 wt%. In the present application, the molar ratio of the intermediate 2 to the basic reagent is preferably 1:1.9-2.1, and more preferably 1:2.

[0065] In the present application, the solvent used in the amino protection reaction is preferably water, and the usage ratio of the intermediate 2 to water is preferably 1 mol:80-120 g, more preferably 1 mol:90-110 g, and further preferably 1 mol:100 g.

[0066] In the present application, the amino protection reaction of the intermediate 2 and BOC anhydride preferably comprises: stirring and mixing the intermediate with water, and then adding an aqueous solution of the basic reagent dropwise. In the present application, the temperature of the stirring and mixing is preferably 15-25°C, and more preferably 20°C; and the time of the stirring and mixing is preferably 25-40 min, and more preferably 30-35 min.

[0067] In the present application, the temperature of the amino protection reaction is preferably 45-55°C, more preferably 48-52°C, and further preferably 50°C; and the time of the amino protection reaction is preferably 2-4 h, more preferably 2.5-3.5 h, and further preferably 3 h.

[0068] In the present application, the hydrolysis is preferably performed under acidic conditions, and the pH value of the acidic conditions is preferably 5-6, and more preferably 5.5. In the present application, the acid used in the acidic conditions preferably includes one or more of acetic acid, hydrochloric acid and sulfuric acid; and the acid is preferably used in the form of an aqueous acid solution, and the present application does not have special limitations on the concentration of the aqueous acid solution, which can only adjust the pH value of the system to 5-6.

[0069] After the hydrolysis, the present application preferably further comprises: concentrating the hydrolysis solution obtained by the hydrolysis to a constant weight, adding water to stir and pulp, solid-liquid separation, drying the obtained solid product to a constant weight to obtain intermediate 3. The present application does not have special limitations for the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation. In the present application, the ratio of the use amount of intermediate 2 to the water for stirring and pulping is preferably 1 mol: 900-1100 g, more preferably 1 mol: 950-1050 g, and further preferably 1 mol: 1000 g.

[0070] After obtaining intermediate 3, the present application carries out a salt-forming resolution reaction of intermediate 3 with R(+)-α-methylbenzylamine to obtain intermediate 4.

[0071] In the present application, the molar ratio of intermediate 3 to R(+)-α-methylbenzylamine is preferably 1:0.8-1.3, more preferably 1:1.1-1.3, and further preferably 1:1.2.

[0072] In the present application, the salt-forming resolution reaction of intermediate 3 with R(+)-α-methylbenzylamine preferably comprises: dissolving intermediate 3 in an organic solvent, and adding a solution of R(+)-α-methylbenzylamine dropwise to carry out the salt-forming resolution reaction. In the present application, the organic solvent preferably comprises ethyl acetate (EA) and / or isopropyl alcohol, and more preferably ethyl acetate; the ratio of the use amount of intermediate 3 to the organic solvent is preferably 1 mol: 320-350 g, more preferably 1 mol: 340-350 g, and further preferably 1 mol: 350 g. In the present application, the solvent in the solution of R(+)-α-methylbenzylamine preferably comprises ethyl acetate (EA) and / or isopropyl alcohol, and more preferably ethyl acetate; the ratio of the use amount of R(+)-α-methylbenzylamine to the solvent in the solution of R(+)-α-methylbenzylamine is preferably 1 mol: 350-400 g, more preferably 1 mol: 360-390 g, and further preferably 1 mol: 375 g.

[0073] In the present application, the temperature of the salt-forming resolution reaction is preferably 45-55°C, and more preferably 50°C; the salt-forming resolution reaction time is preferably 0.5-2 h, and more preferably 1-1.5 h.

[0074] After the salt-forming resolution reaction is completed, the present application preferably further comprises: crystallizing the salt-forming resolution reaction liquid obtained from the salt-forming resolution reaction to obtain intermediate 4. The solid-liquid separation is performed, and the obtained solid product is washed with ethyl acetate and dried to constant weight to obtain intermediate 4. In the present application, the crystallization is preferably cooling crystallization, and the cooling crystallization is preferably natural cooling of the temperature of the salt-forming resolution reaction to -5-5°C (more preferably 0°C). The present application is not particularly limited to the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as filtration, suction filtration, or centrifugal separation.

[0075] After obtaining intermediate 4, the present application performs acidification and free treatment on the intermediate 4 to obtain a sacubitril intermediate.

[0076] In the present application, the acid used in the acidification and free treatment preferably comprises one or more of acetic acid, hydrochloric acid, and sulfuric acid, and more preferably acetic acid. In the present application, the molar ratio of the intermediate 4 to the acid is preferably 1:1.1-1.3, and more preferably 1:1.2.

[0077] In the present application, the acidification and free treatment of the intermediate 4 preferably comprises: dissolving the intermediate 4 in an organic solvent and adding acid dropwise for acidification and free treatment. In the present application, the organic solvent preferably comprises dichloromethane and / or toluene, and more preferably dichloromethane; and the use amount ratio of the intermediate 4 to the organic solvent is preferably 1 mol: 3500-4500 g, more preferably 1 mol: 3800-4200 g, and further preferably 1 mol: 4000 g.

[0078] In the present application, the temperature of the acidification and free treatment is preferably 15-25°C, and more preferably 20-25°C; and the time of the acidification and free treatment is preferably 0.2-1 h, and more preferably 0.5 h, starting from the completion of the acid addition.

[0079] After the acidification and free treatment, the application preferably further comprises: mixing and separating the acidification and free treatment liquid obtained by the acidification and free treatment with water to obtain a separated water phase and an organic phase, respectively, washing the organic phase with water to obtain a washed water phase and a washed organic phase, respectively, combining the separated water phase and the washed water phase, and then back-extracting with dichloromethane to obtain a dichloromethane back-extraction phase, combining the dichloromethane back-extraction phase and the washed organic phase, and then concentrating to a constant weight, adding a beating reagent to beat, solid-liquid separating, washing the obtained solid product with n-hexane, and then drying to a constant weight to obtain the sacubitril intermediate. In the application, the number of times of washing with water is preferably 2-4, and more preferably 3. In the application, the ratio of the amount of the intermediate 4 to the amount of dichloromethane used for back-extraction is preferably 1 mol: 900-1100 g, and more preferably 1 mol: 1000 g. In the application, the beating reagent preferably comprises n-hexane and dichloromethane, and the ratio of the amounts of the intermediate 4, n-hexane and dichloromethane is preferably 1 mol: 1400-1600 g: 140-160 g, and more preferably 1 mol: 1500 g: 150 g. In the application, the temperature of beating is preferably -5-5°C, and more preferably 0°C; and the time of beating is preferably 0.4-1 h, and more preferably 0.5 h. The application does not have special limitations on the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation.

[0080] In order to further illustrate the application, the preparation method of the sacubitril intermediate is described in detail below with examples, but they should not be understood as limiting the scope of protection of the application.

[0081] Example 1

[0082] Step 1: Synthesis of (2R)-5-([1,1'-biphenyl]-4-yl)-4-nitro-2-methylpentanoic acid ethyl ester (intermediate 1).

[0083] (2R)-4-nitro-2-methyl-butyric acid ethyl ester (175 g, 1 mol), 4-bromomethylbiphenyl (247 g, 1 mol), DMF 2000 g, potassium carbonate (145 g, 1.05 mol) were mixed, warmed to 55°C, and reacted for 6 h. The HPLC content of 4-bromomethylbiphenyl was less than 0.3 wt%. The reaction was stopped, concentrated under reduced pressure to no effluent, cooled to 30°C, stirred with dichloromethane 2500 g and water 1000 g to separate layers. The obtained organic phase was washed with water twice (500 g of water was used each time), and the combined organic phase was concentrated to a constant weight to obtain (2R)-5-([1,1'-biphenyl]-4-yl)-4-nitro-2-methylpentanoic acid ethyl ester (intermediate 1).

[0084] Step 2: Synthesis of (2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (intermediate 2).

[0085] The intermediate 1 was dissolved in 2000 g of ethanol, 50 g of Raney nickel was added, the air was replaced by nitrogen, and then the nitrogen was replaced by hydrogen. After the pressure reached 1 MPa, the temperature was raised to 40°C, and the reaction was carried out for 15 h. The HPLC content of the intermediate 1 was less than 0.3 wt%. The reaction was stopped, the Raney nickel was removed by filtration, and the filtrate was concentrated to distill off the ethanol. 1500 g of dichloromethane was added to dissolve the mixture. The pH of the system was adjusted to 3-4 with concentrated hydrochloric acid. A yellowish solid compound was precipitated, which was filtered and dried to constant weight to obtain the intermediate 2 (308 g, based on 4-bromomethylbiphenyl, the yield was 88.5%, and the HPLC purity was 99.52%).

[0086] Step 3: Synthesis of (2R)-N-tert-butoxycarbonyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid (intermediate 3).

[0087] The intermediate 2 (174 g, 0.5 mol), 500 g of ethanol, and 100 g of a 40 wt% aqueous sodium hydroxide solution were stirred at 20°C for 0.5 h. Then, 120 g (0.55 mol) of BOC anhydride was added dropwise while the temperature was raised to 50°C. The HPLC tracking showed that the residual amount of the intermediate 2 was less than 0.2 wt% after the reaction was carried out for 3 h. The pH was adjusted to 5-6 with hydrochloric acid, and the ethanol was distilled off. 500 g of water was added to disperse the mixture by stirring. The solid product was obtained by filtration and dried to constant weight to obtain the intermediate 3, which was directly used in the next step without purification.

[0088] Step 4: Synthesis of the R-α-methylbenzylamine salt of (2R,4S)-5-[(1,1'-biphenyl]-4-yl]-4-tert-butoxycarbonyl-2-methylpentanoic acid (intermediate 4).

[0089] The intermediate 3 and 1750 g of ethyl acetate were stirred to dissolve at 50°C. Then, a mixed solution of R(+)-α-methylbenzylamine (48.5 g, 0.4 mol) and 150 g of ethyl acetate was added dropwise. After the addition was completed, the mixture was stirred for 1 h, and then naturally cooled to 0°C. The solid product was obtained by filtration and dried to constant weight to obtain the intermediate 4 (white solid, 106.5 g, based on the intermediate 2, the yield was 42.3%, the HPLC purity was 99.68%, and the melting point was 141.5-142.1°C).

[0090] Figure 1 The nuclear magnetic resonance spectrum of the intermediate 4 is shown in FIG. 1. 1H-NMR (CDCl3, 600MHz): δ1.04(d,3H,CH3),1.29(d,3H,CH3),1.32(s,3,CH3),1.34(s,6H,2CH3),1.37(m,1,1 / 2CH2),1.7 4(m,1H,1 / 2CH2),2.38(m,1H,CH),2.68(d,2H,CH2),3.65(m,1H,CH),4.01(q,1H,CH),7.18~7.64(m,14H,Ph-Ph-H,Ph-H).

[0091] Figure 2 Infrared spectrum (IR, KBr, cm⁻¹) of intermediate 4: 3372 (ν) NH2 ), 2971(δ CH3 ), 2933(ν OH ), 1682 (ν C＝O ), 1517(ν CONH ), 1458(δ CH2 ), 1399(δ CH ), 1247(ν COC ), 1175(δ Ph-H ), 1077(δ Ph-H ), 731(г) Ph-H ),698(ν CH ).

[0092] Elemental analysis of intermediate 4 (C 23 H 29 NO4.C8H 11 N, % (measured / calculated): C 73.69 / 73.78 H 8.05 / 7.99 N 5.57 / 5.55.

[0093] Step 5: Synthesis of Sakubaqu intermediate.

[0094] Intermediate 4 (50.4 g, 0.1 mol) and 400 g of dichloromethane were mixed evenly. Glacial acetic acid (7.2 g, 0.12 mol) was added dropwise at 20 °C. After the addition was complete, the mixture was stirred for 0.5 h. 100 g of water was added, and the mixture was allowed to separate into two phases: an aqueous phase and an organic phase. The organic phase was washed with water three times (100 g each time) to obtain a water-washed organic phase and a water-washed aqueous phase. All aqueous phases were combined, and 100 g of dichloromethane was added for back-extraction to obtain a dichloromethane back-extracted phase. The water-washed organic phase and the dichloromethane back-extracted phase were combined and concentrated to constant weight. Add 150g of n-hexane and 15g of dichloromethane, slurry for 0.5h, filter, wash the obtained solid product with 5g of n-hexane and dry to obtain sacubitril intermediate (white solid, 37.3g, yield 97.5%, HPLC purity 99.76%, melting point 148.5~148.6℃, specific rotation (2% methanol, i.e. compound to methanol ratio 2g:100mL): -7.2°).

[0095] Figure 3 The nuclear collision resonance proton spectrum of the sakubaqu intermediate. 1 H-NMR (CDCl3, 600MHz): δ1.20(d,3H,CH3),1.29(s,3H,CH3),1.41(s,6H,CH3),1.49(q,1H,CH),1.9(m,1H,CH),2.58~2.67(d d,1H,1 / 2CH2),2.8(m,2H,CH2),3.92~4.01(dd,1H,1 / 2CH2),4.56(d,1H,NH),6.37(s,1H,COOH),7.23~7.58(m,9H,Ph-Ph-H).

[0096] Figure 4 Infrared spectrum (IR, KBr, cm⁻¹) of the intermediate of sacubitril -1 ): 3221(ν OH ), 2974(δ CH3 ), 1705 (ν C＝O ), 1647 (ν CONH ), 1487(δ CH2 ), 1431(δ CH ), 1241(ν COC ), 1171(δ Ph-H ), 1049(δ Ph-H ),764(г Ph-H ), 696(ν CH ).

[0097] Figure 5 The mass spectrum of the Sakubaqu intermediate is shown, M-1 = 382 (M = 383).

[0098] Elemental analysis of the intermediate of Sakubaqu (C 23 H 29 NO4, % (Measured / Calculated): C 72.10 / 72.04 H 7.68 / 7.62 N 3.57 / 3.65.

[0099] Example 2

[0100] The sacubitril intermediate was prepared according to the method of Example 1, with the only difference from Example 1 being:

[0101] In step 1, replace DMF with acetonitrile;

[0102] In step 2, ethanol was replaced with methanol and Raney nickel was replaced with 5% palladium on carbon; based on 4-bromomethylbiphenyl, the yield of intermediate 2 was 86.7% and the HPLC purity was 99.48%.

[0103] In step 4, the amount of R(+)-α-methylbenzylamine used was 0.55 mol (1.1 equivalents); based on intermediate 2, the yield of intermediate 4 was 42.8%, and the HPLC purity was 99.32%.

[0104] In step 5, 400g of dichloromethane was replaced with 800g of toluene; the yield of sacubitril intermediate was 96.6%, and the HPLC purity was 99.73%.

[0105] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of a sacubitril intermediate, characterized by, The method comprises the following steps: condensing (2R)-4-nitro-2-methyl-butyric acid ethyl ester and 4-bromomethylbiphenyl to obtain an intermediate 1; the condensation is carried out in the presence of a basic reagent and an organic solvent; carrying out hydrogenation reduction on the intermediate 1 and then acidizing to obtain an intermediate 2; the hydrogenation reduction is carried out in the presence of a catalyst and hydrogen; the hydrogenation reduction is carried out in the presence of an organic solvent; carrying out an amino protection reaction on the intermediate 2 and BOC anhydride and then hydrolyzing to obtain an intermediate 3; carrying out a salt-forming resolution reaction on the intermediate 3 and R(+)-α-methylbenzylamine to obtain an intermediate 4; carrying out acidification free treatment on the intermediate 4 to obtain a sacubitril intermediate; 2. The production method according to claim 1, characterized by, the molar ratio of the (2R)-4-nitro-2-methyl-butyric acid ethyl ester and the 4-bromomethylbiphenyl is 0.95-1.05:

1.

3. The production method according to claim 1 or 2, characterized by, the basic reagent is one or more of potassium carbonate, sodium carbonate and triethylamine; the molar ratio of the (2R)-4-nitro-2-methyl-butyric acid ethyl ester and the basic reagent is 1:1-1.1; the organic solvent is N,N-dimethylformamide and / or acetonitrile; the condensation is carried out at a temperature of 50-60℃ for 5-7h.

4. The method of claim 1, wherein, the catalyst is Raney nickel and / or palladium-carbon; the organic solvent is ethanol and / or methanol.

5. The preparation method according to claim 1, characterized in that, the hydrogenation reduction is carried out at a temperature of 35-45℃ for 13-17h under a hydrogen pressure of 0.85-1.15MPa.

6. The method of claim 1, wherein, the pH value of the acidification system is 3-4.

7. The preparation method according to claim 1, characterized in that, the molar ratio of the intermediate 2 and the BOC anhydride is 1:1.05-1.15; the amino protection reaction is carried out at a temperature of 45-55℃ for 2-4h.

8. The method of claim 1, wherein, the hydrolysis is carried out under acidic conditions with a pH value of 5-6.

9. The method of claim 1, wherein, the molar ratio of the intermediate 3 and the R(+)-α-methylbenzylamine is 1:0.8-1.3; the salt-forming resolution reaction is carried out at a temperature of 45-55℃ for 0.5-2h.

10. The method of claim 1, wherein, the acid used in the acidification free treatment is one or more of acetic acid, hydrochloric acid and sulfuric acid; the molar ratio of the intermediate 4 and the acid is 1:1.1-1.3.

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