A method of synthesizing sacubitrilat

Abstract

The application provides a synthesis method of sacubitril sodium, which is prepared from compound IX through a multi-step reaction. The synthesis method has the advantages of simple preparation process, cheap and easily available raw materials, short synthesis route, mild reaction condition, high safety, simple operation, high reaction yield, high purity of the target compound and the like, has better application value and economic benefits, and is suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for synthesizing sacubitril sodium. Background Technology

[0002] Sacubitril, chemically named 4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutyric acid, has the following structural formula:

[0003] .

[0004] Chronic heart failure (CHF), also known as chronic congestive heart failure, is the end stage of various heart diseases. Currently, there are still relatively few medications available for treating heart failure, and patients continue to face a high risk of death and a poor quality of life.

[0005] Sacubitril is an enkephalinase inhibitor that blocks the degradation of two peptides responsible for vasodilation, thus alleviating heart failure. Its complex with valsartan is a first-line drug for the clinical treatment of chronic heart failure. The complex, Entresto (sacubitril / valsartan sodium, also known as Enresto), is a salt complex crystal composed of sacubitril and valsartan in a 1:1 molar ratio. It received marketing approval in the United States and the European Union in 2015. In 2016, Enresto was included in the priority review program by the CDE (Center for Drug Evaluation) and received approval from the CFDA (China Food and Drug Administration) for marketing in China on July 28, 2017.

[0006] Sacubitril exists primarily as its sodium salt (CAS: 149690-05-1) during synthesis. Containing two chiral centers, its synthesis presents certain challenges. The key to synthesizing sacubitril sodium lies in constructing these two chiral centers. The main reported synthetic methods are as follows:

[0007] The following method is reported in the literature J. Med. Chem., 1995, Vol. 38, pp. 1689-1700:

[0008] .

[0009] This route uses D-Boc-tyrosine methyl ester as the starting material and employs expensive reagents such as trifluoromethanesulfonic anhydride to protect the phenolic hydroxyl groups. The coupling reaction requires expensive palladium catalysts and ligands, the reduction reaction uses palladium on carbon, and the condensation reaction uses EDCI, HOBT, etc. These reagents are generally expensive, and the synthetic route is also too long, resulting in high production costs and a large amount of hazardous waste. It faces the dual challenges of price and environmental protection, which is not conducive to large-scale production.

[0010] Patent WO2008031567 reports the synthesis of sodium sacubitril from 4-bromobiphenyl and S-epimylochloropropane via multiple reaction steps including Grignard, Mitsunobu, hydrolysis, Boc protection, oxidation, Wittig, hydrolysis, and asymmetric hydrogenation. The reaction route is as follows:

[0011] .

[0012] This is the current mainstream synthetic route. However, this method is lengthy, leading to a significant increase in production costs. Asymmetric catalysis uses expensive metal catalysts and chiral ligands, which cannot be recycled, resulting in high costs. Furthermore, production requires high-pressure hydrogenation equipment, increasing safety risks. The Wittig reaction generates a large amount of triphenylphosphine oxygenate waste, and the steps of Boc protection and deprotection result in low atom utilization. Post-processing uses large amounts of strong acid, generating significant amounts of hazardous waste, which is detrimental to large-scale commercial production.

[0013] Patent CN107382779 reports a method for constructing the first chiral center by asymmetric alkylation of glycine with 4-bromomethylbiphenyl as the starting material in the presence of a chiral catalyst (R)-(-)-2-amino-2'-hydroxy-1,1'-binaphthylene. Subsequent synthetic steps, including reduction with lithium aluminum hydride and Boc protection, are largely consistent with those reported in WO2008031567. The reaction route is as follows:

[0014] .

[0015] The chiral catalyst used in this route is expensive, resulting in high production costs. The lithium aluminum hydride reduction ester group used is not only expensive but also poses significant safety risks during process scale-up, leading to a low overall yield. Subsequent steps also use expensive metal catalysts, which is not conducive to industrial production.

[0016] In summary, existing synthetic methods are constrained by the cost of raw materials, reagents, and prices, and fail to adequately consider atom economy, resulting in long synthetic routes, high production costs, and difficulties in industrialization of sacubitril. Therefore, there is an urgent need to design and develop a more economical and concise synthetic route to meet the needs of industrial-scale sacubitril production. Summary of the Invention

[0017] To address the problems existing in the prior art, this invention provides a synthesis method with low raw material costs, a simple synthesis route, and high yield, in order to meet the requirements of the current industrialization of Sakubaqu.

[0018] First, this invention provides a method for synthesizing sacubitril sodium intermediate compound II, which is prepared from compound III via an esterification reaction, as shown in the following reaction formula:

[0019] ,

[0020] Among them, R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + .

[0021] The reagents for the above esterification reaction are diethyl sulfate, bromoethane, or diethyl carbonate.

[0022] The reaction temperature of the above esterification reaction is 20-60℃, with 50-55℃ being more preferred.

[0023] The reaction solvent for the above esterification reaction is isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate, or anhydrous acetone.

[0024] This invention provides a method for synthesizing compound III, which is prepared from compound IV via a hydrolysis ring-opening reaction, as shown in the following reaction formula:

[0025] ,

[0026] Among them, R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + .

[0027] The above-mentioned hydrolysis ring-opening reaction is carried out in the presence of an alkali, which is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and DBU, with potassium hydroxide being the preferred choice.

[0028] The reaction solvent for the above hydrolysis ring-opening reaction is isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate, or toluene.

[0029] This invention provides a method for synthesizing sodium sacubitril, chemically named sodium 4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutyrate. The synthetic route is as follows:

[0030] ,

[0031] Wherein, R1 is Cl, Br, I, OTs or OMs; R2 is cyano or -COOR4; R4 is C1~C4 alkyl; R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + .

[0032] The specific reaction steps are as follows:

[0033] (1) Compound VI was prepared from compound IX by a one-pot method via epoxidation, ring-opening-lactoneation and hydrolysis.

[0034] (2) Compound VI obtained in step (1) is reacted with Mannich to obtain compound V;

[0035] (3) Compound V obtained in step (2) is reduced to obtain compound IV;

[0036] (4) Compound IV obtained in step (3) undergoes a ring-opening hydrolysis reaction to yield compound III;

[0037] (5) Compound III obtained in step (4) is subjected to esterification and Mitsunobu reaction to obtain compound I;

[0038] (6) Compound I obtained in step (5) is hydrolyzed to obtain compound 10.

[0039] Steps (1) and (2) are carried out in the presence of an alkali, wherein the alkali is one or more of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium tert-pentoxide, sodium tert-pentoxide, triethylamine, diisopropylethylamine, morpholine, pyridine, and DBU.

[0040] In step (1), the molar ratio of the base to compound IⅩ is in the range of 1.0 to 2.0:1, with a preferred ratio of 1.2 to 1.5:1.

[0041] The reaction solvent in step (1) is isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate or toluene.

[0042] In step (2), the reduction reaction is carried out in the presence of acetic acid, N-methylaniline and sodium acetate, wherein the reducing agent is formaldehyde, and the formaldehyde is an aqueous solution of formaldehyde with a mass fraction of 35% to 38%. The molar ratio of formaldehyde to compound VI is in the range of 1:1.0 to 2.0, and more preferably 1:1.1 to 1.5.

[0043] The solvent for the reduction reaction in step (3) is dichloromethane, tetrahydrofuran, acetone, toluene, ethyl acetate, ethanol, isopropanol or acetic acid.

[0044] The reagents for the reduction reaction in step (3) can be one or more of palladium on carbon, Raney Ni, Ru catalyst, sodium borohydride, potassium borohydride, pyridine borane, and 9-BBN, with sodium borohydride being preferred.

[0045] Step (4) is carried out in the presence of an alkali, which is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and DBU, with potassium hydroxide being preferred.

[0046] The reaction solvent for the hydrolysis ring-opening reaction in step (4) is isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate or toluene.

[0047] In step (5), the esterification reaction reagents are diethyl sulfate, bromoethane, or diethyl carbonate.

[0048] In step (5), the compound II obtained after the esterification reaction is not separated, but directly reacted in a one-pot process to obtain compound I.

[0049] The esterification reaction temperature in step (5) is 20~60℃, with 50-55℃ being more preferred.

[0050] The reaction solvent for the esterification reaction in step (5) is isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate or anhydrous acetone.

[0051] The reaction reagents for the Mitsunobu reaction in step (5) are triphenylphosphine and diisopropyl azodicarbonate.

[0052] The solvent for the Mitsunobu reaction in step (5) includes, but is not limited to, one or more of toluene, tetrahydrofuran, ethyl acetate, dioxane, and acetonitrile, with toluene being preferred.

[0053] Step (6) is carried out in the presence of an alkali, wherein the alkali is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, and sodium acetate, preferably sodium carbonate.

[0054] In step (6), the solvent is an organic solvent, with ethanol being a preferred choice.

[0055] The technical effects of this invention are as follows:

[0056] The method for synthesizing sacubitril sodium provided in this invention application can easily and effectively construct a second chiral center using relatively inexpensive reducing reagents such as sodium borohydride. It has the advantages of simple preparation process, inexpensive and readily available raw materials, short synthesis route, mild reaction conditions, high safety, simple operation, high reaction yield, and high purity of target compound. It has good application value and economic benefits and is suitable for industrial production. Attached Figure Description

[0057] Figure 1 Compound V obtained in Example 2 1 H-NMR spectrum.

[0058] Figure 2 Compound 10 obtained in Example 7 1 H-NMR spectrum.

[0059] Figure 3 Compound 10 obtained in Example 7 13 C-NMR spectrum. Detailed Implementation

[0060] To further understand the present invention, a method for synthesizing sacubitril sodium provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0061] Example 1: Preparation of compound VI

[0062]

[0063] Add 100g of compound IX-1 solid to a 500mL reaction flask, add 300mL of 2-butanol, add 44.6g of sodium tert-amyloxide, stir and heat to 50-55℃, keep warm and stir for 2h, the reaction is completed, intermediate VIII is obtained, filter, wash the filter cake with 100mL of 2-butanol to obtain the filtrate of intermediate VIII, which is ready for use.

[0064] Add 69.6 g of dimethyl malonate, 300 mL of 2-butanol, and 58 g of sodium tert-amyloxide to another 2 L reaction flask. Heat the reaction solution to 70 °C. Slowly add the filtrate of compound VIII dropwise. After the addition is complete, maintain the temperature for 4 h. Once the reaction is complete, compound VII is obtained. Cool the reaction solution to 50 °C, add 230 mL of 10% potassium hydroxide solution, and stir for 30 min. Stop stirring and separate the phases. Wash the organic phase twice with 200 mL of 10% potassium hydroxide solution, and combine the aqueous phases. Wash the aqueous phase once with 300 mL of 2-butanol, and then adjust the pH to 2-3 with 125 mL of 37% hydrochloric acid. Add 1000 mL of ethyl acetate, stir for 3 min, separate the phases, and concentrate under reduced pressure at 45-55 °C to remove the solvent, giving 108.7 g of compound VI, with a yield of 90.5%. LC-MS (M+H) + =297.1.

[0065] Example 2: Preparation of Compound V

[0066]

[0067] Add 50 mL of acetic acid, 35 mL of 37% formaldehyde solution, 13 mL of N-methylaniline, and 1.5 g of sodium acetate to a reaction flask. After stirring for 10–30 min, add 14.4 g of compound VI and stir the mixture at 20–30 °C for 3 h. After the reaction is complete, transfer the reaction mixture to a separatory funnel, add 150 mL of ethyl acetate and 60 mL of 2 mol / L hydrochloric acid, and extract. Extract the aqueous phase with 100 mL of ethyl acetate. Combine the organic phases, wash successively with 100 mL of water and 100 mL of 10% sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Recrystallize the concentrate from 220 mL of isopropyl acetate, filter, and give 10.9 g of compound V, yield 85.1%. LC-MS (M+H) + =265.3.

[0068] Example 3: Preparation of Compound IV a

[0069]

[0070] 20 g of compound VI and 200 mL of THF were added to a reaction flask. The mixture was stirred and cooled to 0-10 °C. 2.3 g of solid NaBH4 was added in portions, and the reaction was maintained at this temperature for 4 h. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. After concentrating to remove most of the solvent, 140 mL of ethyl acetate was added, and the organic phase was separated. The organic phase was washed successively with 140 mL of water and 140 mL of 10% sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was recrystallized from the concentrate using a toluene:n-heptane = 4:7 system, filtered, and yielded 13.9 g of compound IV, with a yield of 69.0%. LC-MS (M+H) +=267.3.

[0071] Example 4: Preparation of Compound IV

[0072]

[0073] 20 g of compound VI and 200 mL of ethyl acetate were added to a reaction flask, followed by 4 g of 10% Pd / C solid. The mixture was heated to 30-60 °C and reacted for 4 h. After the reaction was complete, the mixture was filtered. The organic phase was washed successively with 140 mL of water and 140 mL of 10% sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was recrystallized from the concentrate using a toluene:n-heptane = 4:7 system, filtered, and yielded 18.3 g of compound IV, with a yield of 90.8%. LC-MS (M+H) + =267.3.

[0074] Example 5: Preparation of Compound III

[0075]

[0076] 10 g of compound IV and 100 mL of THF were added to a reaction flask. Then, 20 mL of a 2.53 g aqueous solution of potassium hydroxide was slowly added dropwise. The reaction was maintained at 20-30 °C for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain 11.9 g of compound III-1, with a yield of 98.3%. LC-MS (M+H) + =285.3.

[0077] Example 6: Preparation of Compound I

[0078]

[0079] Add 1.0 g of compound III-1 to a reaction flask, add 10 mL of anhydrous acetone, stir and heat to 50-55 °C, then slowly add 526 mg of diethyl sulfate dropwise. After the addition is complete, maintain the temperature and stir for 2 hours to complete the reaction. Cool the reaction solution to 20-25 °C, add 10 mL of 10% potassium carbonate solution. Extract with 20 mL of toluene, separate the layers, wash the organic phase with 10 mL of water, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure to remove most of the solvent, giving approximately 8 mL of a toluene solution of compound II.

[0080] To a toluene solution of compound II, 338 mg of compound XI and 1.10 g of triphenylphosphine were added, and the mixture was cooled to -10°C. 845 mg of diisopropyl azodicarbonate was slowly added dropwise over approximately one hour. The reaction was maintained at -10°C for 30 minutes. After the reaction was complete, the temperature was raised to 25°C, and 5 mL of toluene was added with stirring. The mixture was washed with 10 mL of 10% sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was recrystallized from ethyl acetate / n-heptane to give 859 mg of compound I, in 78% yield. LC-MS (M+H) + =394.2.

[0081] Example 7: Preparation of Compound 10

[0082]

[0083] 10 g of compound I was added to a reaction flask, followed by 60 mL of ethanol. The mixture was stirred until dissolved, then 1 mL of water was added. The temperature was lowered to 0–10 °C, and 2.69 g of sodium carbonate was added. After the addition was complete, the mixture was stirred at this temperature for 8 hours until the reaction was complete. The mixture was filtered, and the filtrate was heated to 40–60 °C. 120 mL of n-heptane was added dropwise while maintaining the temperature. Seed crystals were added, and the mixture was stirred at this temperature for 2 hours. The mixture was then cooled to 10–20 °C to allow crystals to crystallize for 2 hours. The crystals were filtered, and the filter cake was washed with 30 mL of n-heptane to give 9.8 g of compound 10, with a yield of 89.1%. LC-MS (M+H) + =412.2.

Claims

1. A method for synthesizing sacubitril sodium intermediate compound II, characterized in that, It was prepared by esterification of compound III, as shown in the following reaction formula: ， Among them, R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + .

2. The synthesis method according to claim 1, characterized in that, Compound III was prepared from compound IV via a hydrolytic ring-opening reaction, as shown in the following reaction formula: ， Among them, R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + .

3. A method for synthesizing sacubitril sodium, characterized in that, The synthesis route is as follows: ， Wherein, R1 is Cl, Br, I, OTs or OMs; R2 is cyano or -COOR4; R4 is C1~C4 alkyl; R3 is Na, K, Ca, 1 / 2Mg, NH4 + Et3NH + or i-Pr2EtNH + ; The specific reaction steps are as follows: (1) Compound VI was prepared from compound IX by a one-pot method via epoxidation, ring-opening-lactoneation and hydrolysis. (2) Compound VI obtained in step (1) is reacted with Mannich to obtain compound V; (3) Compound V obtained in step (2) is reduced to obtain compound IV; (4) Compound IV obtained in step (3) undergoes a ring-opening hydrolysis reaction to yield compound III; (5) Compound II was prepared by esterification of compound III obtained in step (4), and then compound I was obtained by Mitsunobu reaction; (6) Compound I obtained in step (5) is hydrolyzed to obtain compound 10.

4. The synthesis method according to claim 3, characterized in that, Steps (1) and (2) are carried out in the presence of an alkali, wherein the alkali is one or more of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, and sodium acetate.

5. The synthesis method according to claim 4, characterized in that, In step (1), the molar ratio of the base to compound IⅩ is in the range of 1.0 to 2.0:

1.

6. The synthesis method according to claim 3, characterized in that, The reaction solvents in steps (1) and (4) are isopropanol, n-butanol, 2-butanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate or toluene.

7. The synthesis method according to claim 3, characterized in that, In step (2), the Mannich reaction reagent is formaldehyde, which is a formaldehyde aqueous solution with a mass fraction of 35% to 38%, and the molar ratio of formaldehyde to compound VI is in the range of 1:1.0 to 2.

0.

8. The synthesis method according to claim 3, characterized in that, The solvent for the reduction reaction in step (3) is dichloromethane, tetrahydrofuran, acetone, toluene, ethyl acetate, ethanol, isopropanol, or acetic acid.

9. The synthesis method according to claim 3, characterized in that, The reagents that can be selected for the reduction reaction in step (3) are one or more of palladium on carbon, Raney Ni, sodium borohydride, and potassium borohydride.

10. The synthesis method according to claim 3, characterized in that, The hydrolysis ring-opening reaction in step (4) is carried out in the presence of an alkali, which is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and DBU.

11. The synthesis method according to claim 3, characterized in that, In step (5), after the esterification reaction, compound II is obtained and directly reacted in a one-pot process to obtain compound I without separation.

12. The synthesis method according to claim 3, characterized in that, The reaction reagents for the esterification reaction in step (5) are diethyl sulfate, bromoethane, or diethyl carbonate.

13. The synthesis method according to claim 3, characterized in that, The esterification reaction temperature in step (5) is 20~60℃.

14. The synthesis method according to claim 3, characterized in that, The reaction reagents for the Mitsunobu reaction in step (5) are triphenylphosphine and diisopropyl azodicarbonate, and the reaction solvent is one or more of toluene, tetrahydrofuran, ethyl acetate, dioxane, and acetonitrile.

15. The synthesis method according to claim 3, characterized in that, Step (6) is carried out in the presence of an alkali, wherein the alkali is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, and sodium acetate.

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