A preparation method of sacubitril calcium

Abstract

The present invention discloses a preparation method of sacubitril calcium. The preparation method comprises the following steps: adding compound 1 into a pre-prepared mixed solution for esterification and deprotection reactions; after the esterification and deprotection reactions are completed, concentrating under reduced pressure to dryness, adding a non-polar solvent and stirring to dissolve, then adding succinic anhydride and triethylamine for acylation reaction; after the acylation reaction ends, adding water for quenching, acid washing, and water washing in sequence, and standing to collect the organic layer; adding an aqueous solution of alkali metal weak acid salt to the obtained organic layer for sodium salt formation reaction, separating the organic layer, adding a co-crystallization solvent to the aqueous layer and then dropping an aqueous calcium chloride solution, and centrifuging, washing, and drying to obtain sacubitril calcium. The preparation method of the present invention can effectively avoid the generation of amide impurities and disodium salt impurities, effectively improve the difficulties of centrifugation and drying caused by the too fine crystallization of sacubitril calcium salt, and has the characteristics of simple process, low production cost, controllable quality, and suitability for industrial scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical processes, and particularly relates to a method for preparing sacubitril calcium. Background Art

[0002] The cardiovascular therapeutic drug sacubitril valsartan sodium developed by Novartis was approved by the FDA for marketing in July 2015 and is used to treat heart failure patients with reduced ejection fraction, which can effectively reduce the risk of cardiovascular death and hospitalization for heart failure. Given its excellent performance in reducing key cardiovascular risks, in the coming years, no drug in the cardiovascular field will be able to compete with it, and sacubitril valsartan sodium will lead the cardiovascular treatment into a new era with great strides.

[0003] Currently, the method for synthesizing sacubitril valsartan sodium is basically prepared by co-crystallization of sacubitril with valsartan and an aqueous solution of sodium hydroxide. The process of the sacubitril valsartan sodium co-crystal is relatively mature. Sacubitril is a liquid oily substance, which is not convenient for purification, storage and transportation. Usually, it is salted with calcium ions to obtain white solid sacubitril calcium, and then co-crystallized with valsartan to prepare sacubitril valsartan sodium.

[0004]

[0005] The literature "Synthesis of Related Substances of Sacubitril" (Chinese Journal of Pharmaceuticals, 2018, 49(10), 1392 - 1398) reported that (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid (Compound 1) and thionyl chloride were subjected to esterification and deprotection reactions in an ethanol solvent to obtain Intermediate II - (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride, and then subjected to acylation reaction with succinic anhydride to obtain Intermediate III (sacubitril), reacted with sodium hydroxide to form Intermediate IV (sacubitril sodium salt), and salted with calcium chloride to prepare sacubitril calcium. The following problems exist in the industrialized large-scale production of this process: A large amount of hydrogen chloride and sulfur dioxide are released during the esterification and deprotection reaction of Compound 1 with thionyl chloride. Sulfur dioxide is a Class 3 carcinogen and is highly toxic to the respiratory system of operators; under the action of thionyl chloride, Compound 1 first reacts with thionyl chloride to form an acyl chloride, which is prone to intramolecular amidation condensation reaction with the deprotected amino group in the molecular structure to form amide impurities; during the process of forming sacubitril sodium salt with sodium hydroxide, due to the strong alkalinity, hydrolysis reaction is prone to occur to produce disodium salt impurities; during the process of salting with calcium chloride to prepare sacubitril calcium, the product is wrapped with calcium hydroxide, resulting in a low content; the sacubitril calcium particles prepared are extremely fine and are not easy to centrifuge and dry. Its synthetic route is as follows:

[0006]

[0007] During the preparation of Intermediate II, Compound 1 reacts with thionyl chloride, generating amide impurities. The reaction process is as follows:

[0008]

[0009] During the preparation of Intermediate IV (sacubitril sodium), Intermediate III (sacubitril) is prone to hydrolysis reaction under the strong base of sodium hydroxide to produce disodium salt impurities. The reaction process is as follows:

[0010]

[0011] Chinese Patent CN 113135836 A discloses a method for preparing sacubitril calcium salt. Using (2R)-1-((1,1'-biphenyl)-4-yl)-3-hydroxypropan-2-yl-aminofluorene methoxycarbonyl ester as the starting material, through TEMPO-catalyzed oxidation, Wittig reaction with tert-butoxycarbonyl ethylidene triphenylphosphine, catalytic hydrogenation with noble metal palladium catalyst, esterification reaction with ethanol under the action of thionyl chloride, acylation reaction with succinic anhydride, and successively salifying with sodium hydroxide and calcium chloride to prepare sacubitril calcium salt. This process route requires expensive catalysts such as TEMPO, palladium-containing catalyst, and tert-butoxycarbonyl ethylidene triphenylphosphine. Catalytic hydrogenation needs to be carried out under a pressure of 4 - 6 MPa, which requires high equipment requirements. The sacubitril calcium salt prepared by salifying with calcium chloride is not easy to centrifugate and dry due to extremely fine particles. The whole route has the defects of high production cost and large safety risks, which is not conducive to large-scale application.

[0012] Chinese Patent CN110845349 B discloses a method for preparing Intermediate II. Using a large excess of thionyl chloride, the reaction process will produce more than 1% of amide impurities. A large amount of ethyl acetate needs to be added during post-treatment to remove acids and amide impurities to meet the quality requirements, resulting in a low yield. And the use of a large amount of thionyl chloride, absolute ethanol, ethyl acetate, etc. leads to too high costs of reagents and solvents, with obvious process defects.

[0013] Chinese Patent CN110818581 A discloses a method for purifying Intermediate II. By adding an acid-binding agent during the post-treatment process, reacting with acidic substances such as excess thionyl chloride and hydrochloric acid to form acid salts, concentrating the reaction solution, and then removing the insoluble substances therein with ethyl acetate, the post-treatment steps are increased, which is not conducive to industrial production applications.

[0014] Chinese Patent CN115677521A discloses a method for preparing sacubitril calcium with high purity. It still conducts esterification and deprotection reactions under the action of thionyl chloride. After the acylation reaction with succinic anhydride, it still forms sodium salt with sodium hydroxide and then forms calcium salt with calcium chloride to prepare sacubitril calcium salt. This process route cannot avoid the generation of amide impurities under the action of thionyl chloride, the generation of disodium salt impurities under the action of strong base sodium hydroxide, and the problems of difficult centrifugation and drying when forming calcium salt with calcium chloride.

[0015] The above-mentioned methods for preparing sacubitril calcium all carry out esterification and deprotection reactions under the action of thionyl chloride, and after the acylation reaction with succinic anhydride, they form sodium salt with sodium hydroxide and then form calcium salt with calcium chloride for preparation. They cannot effectively solve the problems of generating amide impurities, disodium salt impurities, and the difficult centrifugation and drying of sacubitril calcium salt in the process route. Summary of the Invention

[0016] Aiming at the defects and deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing sacubitril calcium. The preparation method of the present invention can effectively avoid the generation of amide impurities and disodium salt impurities, effectively improve the difficulties of fine crystallization, easy centrifugation and drying of sacubitril calcium salt, and has the characteristics of simple process, low production cost, controllable quality, and suitability for industrial scale production.

[0017] The synthetic route of sacubitril calcium of the present invention is as follows:

[0018]

[0019] The purpose of the present invention is achieved through the following technical solutions:

[0020] A method for preparing sacubitril calcium, comprising the following steps:

[0021] (1) First, cool anhydrous ethanol, maintain the temperature at 10 - 15 °C under stirring conditions, add acetyl chloride, and after adding, continue to stir at 10 - 15 °C to obtain a mixed solution; then add (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid to the mixed solution for esterification and deprotection reactions. After the esterification and deprotection reactions are completed, concentrate to dryness under reduced pressure, add a non-polar solvent and stir to dissolve, then add succinic anhydride and triethylamine for acylation reaction. After the acylation reaction, perform water quenching and washing in sequence, and let it stand to collect the organic layer;

[0022] (2) Add an aqueous solution of alkali metal weak acid salt to the organic layer obtained in step (1) for sodium salt formation reaction, separate the organic layer, add a crystal growth assisting solvent to the aqueous layer, then add an aqueous solution of calcium chloride, and finally obtain the sacubitril calcium after centrifugation, washing and drying.

[0023] Preferably, in step (1), the absolute ethanol is cooled to 10°C.

[0024] Preferably, in step (1), the time for continuous stirring at 10 - 15°C is 15 min.

[0025] Preferably, in step (1), the dosage ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: acetyl chloride: absolute ethanol is 1 kg: 0.225 - 0.300 kg: 3 - 10 L.

[0026] Preferably, in step (1), the esterification and deprotection reactions are carried out as follows: first, the temperature is raised to 35 - 40°C and the reaction is carried out for 2 h, and then the temperature is further raised to 70 - 75°C and the reaction is carried out for 2 h.

[0027] Preferably, in step (1), the non-polar solvent is dichloromethane or ethyl acetate.

[0028] Preferably, in step (1), the dosage ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: non-polar solvent: succinic anhydride: triethylamine is 1 kg: 5 - 10 L: 0.28 - 0.32 kg: 0.66 - 0.80 kg.

[0029] Preferably, in step (1), the temperature of the acylation reaction is 10 - 20°C and the reaction time is 1 h.

[0030] Preferably, in step (1), the washing method is: first acid washing and then water washing.

[0031] Preferably, the acid washing is carried out with an aqueous hydrochloric acid solution with a concentration of 0.8 - 1.2 mol / L.

[0032] Preferably, in step (2), the sodium salt reaction is carried out as follows: stirring reaction is carried out at 15 - 20°C for 30 min.

[0033] Preferably, in step (2), the alkali metal weak acid salt is sodium carbonate or potassium carbonate.

[0034] Preferably, in step (2), the concentration of the aqueous solution of the alkali metal weak acid salt is 8 - 12 wt%.

[0035] Preferably, in step (2), the crystallization aid solvent is ethyl acetate.

[0036] Preferably, in step (2), the concentration of the calcium chloride aqueous solution is 8 - 12 wt%.

[0037] Preferably, the dosage ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: alkali metal weak acid salt: co-crystallization solvent: calcium chloride is 1 kg: 0.40 - 0.80 kg: 0.80 - 1.20 kg: 0.30 - 0.48 kg.

[0038] Preferably, the drying method in step (2) is: drying at 45 - 50 °C for 6 h.

[0039] Compared with the prior art, the beneficial effects of the present invention include:

[0040] The present invention provides a preparation method of sacubitril calcium, and the obtained sacubitril calcium has a purity of not less than 99.95%, wherein the hydrolysis disodium salt impurity does not exceed 0.03%, and the amide impurity is not detected. In the method of the present invention, thionyl chloride is not used in the esterification and deprotection group reactions, thereby avoiding the formation of acyl chloride by compound 1 and thionyl chloride, and effectively avoiding the formation of amide impurities; sodium carbonate is used instead of sodium hydroxide in the sodium salt formation reaction, which can greatly reduce the formation of disodium salt impurities; by adding ethyl acetate during the calcium salt formation reaction, sacubitril calcium products with larger particles can be formed, which is convenient for greatly shortening the subsequent centrifugation and drying time. The method of the present invention has the advantages of simple process, low production cost, controllable quality, and being suitable for industrial scale production. Detailed implementation manners

[0041] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0042] Example 1

[0043] A preparation method of sacubitril calcium comprises the following steps:

[0044] Charge 120 L of absolute ethanol into the reaction kettle, stir and cool down to 10 °C, control the temperature at 10 - 15 °C under stirring and dropwise add 9 kg of acetyl chloride. After the dropping is completed, continue to stir at 10 - 15 °C for 15 minutes to obtain a standby mixed solution.

[0045] 40 kg of Compound 1 (i.e., (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid) was added to the above-prepared mixed solution, and the temperature was raised to 35 - 40 °C for reaction for 2 hours. Then the temperature was continuously raised to 70 - 75 °C for reaction for 2 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure, cooled to 20 °C, and 240 L of dichloromethane was added and stirred for 30 minutes. Then it was cooled to 10 °C, 27.0 kg of triethylamine was added, and 11.5 kg of succinic anhydride was added in portions at 10 - 20 °C. The succinic anhydride was added completely within 20 - 30 minutes. After addition, the reaction was continued at 10 - 20 °C for 1 hour. After the reaction ended, 60 kg of water was added to quench the reaction, and it was washed with 140 kg of 1.2 mol / L hydrochloric acid aqueous solution. The layers were allowed to stand and the aqueous layer was separated. 100 kg of water was added to the organic layer for washing, the layers were allowed to stand and the aqueous layer was separated, and the organic layer was collected;

[0046] 200 kg of an aqueous sodium carbonate solution with a mass percentage concentration of 8% was added to the organic layer, and it was stirred at 15 - 20 °C for 30 minutes. The layers were allowed to stand and separated, and the aqueous layer was collected. The organic layer was washed with 120 kg of water again. 48 kg of ethyl acetate was added to the combined aqueous layers (the previously collected aqueous layer and the aqueous layer after washing with water), and 106.5 kg of an aqueous calcium chloride solution with a mass percentage concentration of 12% was added dropwise with stirring at 20 - 25 °C. First, 42 kg of the calcium chloride aqueous solution was added dropwise, the addition and stirring were stopped, and it was allowed to stand for 30 minutes. Then the remaining 64.5 kg of the calcium chloride aqueous solution was added dropwise. After the addition was completed, it was stirred at 20 - 25 °C under a heat preservation condition for 3 hours, centrifuged, the centrifugation time was 4 hours, and it was dried at 45 - 50 °C for 6 hours to obtain 43.8 kg of sacubitrilat calcium. By HPLC detection, its purity was 99.97%, the disodium salt impurity was 0.02%, and the amide impurity was not detected.

[0047] Example 2

[0048] A preparation method of sacubitrilat calcium is as follows:

[0049] 400 L of absolute ethanol was put into a reaction kettle, and it was stirred and cooled to 10 °C. While stirring, the temperature was controlled to 10 - 15 °C and 12 kg of acetyl chloride was added dropwise. After the addition was completed, it was continuously stirred at 10 - 15 °C for 15 minutes to obtain a standby mixed solution.

[0050] Add 40 kg of compound 1 to the above-prepared mixed solution, heat to 35-40 ° C for 2 hours, and continue to heat to 70-75 ° C for 2 hours. After the reaction is completed, concentrate to dryness under reduced pressure, cool to 20 ° C, add 300 L of ethyl acetate and stir for 30 minutes. Cool to 10 ° C, add 31.7 kg of triethylamine, add 12.5 kg of succinic anhydride in portions at 10-20 ° C, and add succinic anhydride within 20 minutes to 30 minutes. After the addition, continue to react at 10-20 ° C for 1 hour. After the reaction is completed, add 60 kg of water to quench, wash with 250 kg of 0.8 mol / L hydrochloric acid aqueous solution, let stand to separate the water layer, add 100 kg of water to the organic layer to wash, let stand to separate the water layer, and collect the organic layer;

[0051] Add 200kg of 12% sodium carbonate aqueous solution by mass percentage concentration to the organic layer, stir for 30 minutes at 15-20°C, let stand for stratification, collect the water layer, wash the organic layer with 120kg of water, add 32kg of ethyl acetate to the combined water layer, add 239.1kg of 8% calcium chloride aqueous solution by mass percentage concentration at 20-25°C under stirring, first add 95kg of the calcium chloride aqueous solution, stop dropping and stop stirring and let stand for 30 minutes, and continue to drop the remaining 144.1kg of the calcium chloride aqueous solution. After the addition is completed, stir for 3 hours under 20-25°C insulation conditions, centrifuge, centrifuge for 4 hours, dry at 45-50°C, dry for 6 hours, and obtain 44.0kg of sacubitril calcium, which is detected by HPLC with a purity of 99.98%, a disodium salt impurity of 0.02%, and an amide impurity that is not detected.

[0052] Comparative Example 1

[0053] A method for preparing sacubitril calcium, comprising the following steps:

[0054] 120 L of anhydrous ethanol was added to the reaction kettle, and the temperature was cooled to 10°C with stirring. 12.5 kg of thionyl chloride was added dropwise while the temperature was controlled to 10-20°C with stirring. After the addition was completed, stirring was continued at 10-20°C for 30 minutes to obtain a mixed solution for standby use.

[0055] 40 kg of Compound 1 was added to the above-prepared mixed solution, and the temperature was raised to 60 °C and stirred for 3 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure, cooled to 20 °C, and 180 L of dichloromethane was added and stirred for 30 minutes. Then, 24.5 kg of triethylamine and 10.5 kg of succinic anhydride were added, and the reaction was carried out at 20 - 30 °C for 3 hours to obtain the sacubitril reaction solution. 95 kg of an aqueous acetic acid solution with a mass percentage concentration of 0.5% was added to the reaction solution, stirred for 10 minutes, and then layered. The organic phase was washed with 200 kg of water, and the aqueous layer was separated. 160 kg of an aqueous sodium hydroxide solution with a mass percentage concentration of 3% was added to the organic layer to adjust the pH to 7.5, and the aqueous layer was collected. The temperature of the aqueous layer was raised and controlled at 65 - 70 °C, and 87.4 kg of an aqueous calcium chloride solution with a mass percentage concentration of 8% was added dropwise. After the dropwise addition was completed, the temperature was lowered, and it was kept stirring at 20 - 25 °C for 3 hours, centrifuged for 10 hours, and dried at 45 - 50 °C for 24 hours to obtain 43.0 kg of sacubitril calcium. By HPLC detection, its purity was 99.50%, the disodium salt impurity was 0.15%, and the amide impurity was 0.20%.

[0056] In summary, we can know that through the preparation method described in the present invention, thionyl chloride was not used in the esterification and deprotection reaction processes, which can effectively avoid the generation of amide impurities. The amide impurities were not detected in the present invention, and the proportion in the comparative example was 0.20%; sodium carbonate was used instead of sodium hydroxide in the sodium salt formation reaction, which can greatly reduce the generation of disodium salt impurities. The disodium salt impurity in the present invention was 0.02%, and the proportion in the comparative example was 0.15%; by adding ethyl acetate in the calcium salt formation reaction process, a larger particle sacubitril calcium product can be formed, which is convenient for greatly shortening the subsequent centrifugation and drying time. The centrifugation time in the present invention was 4 h, and the drying time was 6 h. The centrifugation time in the comparative example was 10 h, and the drying time was 24 h. The preparation method provided by the present invention has significant progress.

[0057] The specific embodiments of the present invention described above do not constitute a limitation to the protection scope of the present invention. Any other corresponding changes and deformations made according to the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A preparation method of sacubitril calcium, characterized in that, it comprises the following steps: (1) First, cool anhydrous ethanol, maintain the temperature at 10 - 15 °C under stirring conditions, add acetyl chloride, and after the addition, continue to stir at 10 - 15 °C to obtain a mixed solution; then add (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid to the mixed solution for esterification and deprotection reactions. After the esterification and deprotection reactions are completed, concentrate to dryness under reduced pressure, add a non-polar solvent and stir to dissolve, then add succinic anhydride and triethylamine for acylation reaction. After the acylation reaction, carry out water quenching and washing in sequence, and let it stand to collect the organic layer; (2) Add an aqueous solution of alkali metal weak acid salt to the organic layer obtained in step (1) for sodium salt formation reaction, separate the organic layer, add a co-crystallization solvent to the aqueous layer, then add an aqueous calcium chloride solution, and finally obtain the sacubitril calcium after centrifugation, washing and drying; the alkali metal weak base salt is sodium carbonate; the co-crystallization solvent is ethyl acetate.

2. The preparation method of sacubitril calcium according to claim 1, characterized in that, the dosage ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: acetyl chloride: anhydrous ethanol in step (1) is 1 kg: 0.225 - 0.300 kg: 3 - 10 L.

3. The preparation method of sacubitril calcium according to claim 2, characterized in that, the dosage ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: non-polar solvent: succinic anhydride: triethylamine in step (1) is 1 kg: 5 - 10 L: 0.28 - 0.32 kg: 0.66 - 0.80 kg.

4. The preparation method of sacubitril calcium according to any one of claims 1 - 3, characterized in that, the mass ratio of (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpentanoic acid: alkali metal weak acid salt: co-crystallization solvent: calcium chloride is 1 kg: 0.40 - 0.80: 0.80 kg - 1.20 kg: 0.30 - 0.48 kg.

5. The preparation method of sacubitril calcium according to claim 4, characterized in that, the stirring time in step (1) for continuing to stir at 10 - 15 °C is 15 min; the way of the esterification and deprotection reactions in step (1) is: first raise the temperature to 35 - 40 °C and react for 2 h, then continue to raise the temperature to 70 - 75 °C and react for 2 h; cooling the anhydrous ethanol in step (1) to 10 °C.

6. The preparation method of sacubitril calcium according to claim 5, characterized in that, the temperature of the acylation reaction in step (1) is 10 - 20 °C, and the reaction time is 1 h; the way of the sodium salt reaction in step (2) is: stir and react at 15 - 20 °C for 30 min.

7. The preparation method of sacubitril calcium according to any one of claims 1 to 3, characterized in that, the washing method in step (1) is: pickling first and then water washing; the drying method in step (2) is: drying at 45-50 °C for 6 h.

8. The preparation method of sacubitril calcium according to claim 7, characterized in that, the pickling is carried out by washing with an aqueous hydrochloric acid solution with a concentration of 0.8-1.2 mol / L.

9. The preparation method of sacubitril calcium according to any one of claims 1 to 3, characterized in that, the concentration of the aqueous solution of alkali metal weak acid salt in step (2) is 8-12 wt%; the concentration of the aqueous calcium chloride solution in step (2) is 8-12 wt%.

10. The preparation method of sacubitril calcium according to any one of claims 1 to 3, characterized in that, the non-polar solvent in step (1) is dichloromethane or ethyl acetate.

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