Valsartan disodium intermediate

Abstract

This invention discloses a valsartan disodium intermediate, belonging to the field of pharmaceutical intermediate technology. First, valsartan is reacted with an alkaline solution in a separate system to form a salt. Unreacted raw materials and poorly soluble impurities are removed by filtration and washing, resulting in a salt solution with a high proportion of effective components and a low content of crystal-inhibiting impurities. Subsequently, a solvent-controlled crystallization process using ethyl acetate and petroleum ether is employed, and ordered nucleation and crystal growth are achieved through staged cooling to obtain valsartan disodium crystals and a mother liquor. Secondary crystallization of the mother liquor is then performed using seed induction to fully extract and recover residual effective components, thereby improving raw material utilization and overall yield. This invention effectively reduces solvent loss, minimizes impurity interference, and enhances the stability of the crystallization process. It has the advantages of strong process controllability, high yield, and suitability for large-scale application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates technology, specifically valsartan disodium intermediate. Background Technology

[0002] Valsartan is a widely used active pharmaceutical ingredient for the treatment of hypertension and cardiovascular diseases. Valsartan disodium, as an important intermediate in the development of subsequent valsartan formulations, plays a key role in the industrial production of many pharmaceutical products. In particular, in the synthesis of drugs with sodium salt structures, valsartan disodium can serve as an effective source of valsartan anions for compounding, salt formation, or further structural derivatization with other drug fragments. Therefore, its purity and the controllability of the production process directly affect the quality of downstream products.

[0003] Currently, the industrial preparation of valsartan disodium typically involves using an alkaline source to induce a salt-forming reaction of valsartan, followed by solvent treatment or crystallization to obtain solid valsartan disodium. Among existing technologies, Chinese patent CN118184537A discloses a method for preparing high-purity sacubitril / valsartan sodium. This method involves mixing sacubitril sodium, valsartan, sodium carbonate, water, and a solvent in the same system and heating it to fully dissolve the components and complete the salt-forming reaction. Subsequently, seed crystals are added to the system for crystal growth. The system is then cooled to allow further crystallization and growth at low temperatures. Finally, solid product is obtained through post-processing steps such as solid-liquid separation and drying.

[0004] In the above technical solution, salt formation, nucleation, and crystal growth are carried out continuously in the same system, causing key factors such as ionic strength, pH, and temperature to change simultaneously. This makes it difficult for the salt formation reaction between valsartan and inorganic base to be fully completed, resulting in a limited amount of effective components that can actually participate in crystallization. At the same time, the long-term coexistence of impurities and unreacted raw materials in the system inhibits the normal progress of the crystallization process, causing some valsartan disodium to remain in a dissolved state and unable to precipitate, thus reducing the utilization rate of raw materials. As a result, the crystallization mother liquor obtained not only contains a significant amount of residual valsartan disodium, but also contains unsalted valsartan, inorganic base, various organic solvents, and by-product impurities. The complex composition of the system makes it difficult to effectively recover and utilize, further resulting in a decrease in the utilization rate of raw materials and a low product yield. Summary of the Invention

[0005] The purpose of this invention is to provide a valsartan disodium intermediate. By constructing a synergistic process system of "salt formation and purification - solvent-controlled crystallization - seed-induced secondary crystallization", the salt formation reaction is made more complete, impurities are removed more thoroughly, and the crystallization process is completed under a controllable environment, thereby significantly improving the precipitation degree of effective components and the utilization rate of raw materials.

[0006] The objective of this invention can be achieved through the following technical solutions: Step 1: Using valsartan as raw material and sodium hydroxide solution as alkali source, a salt formation reaction is carried out under heating and constant temperature stirring. After post-treatment, valsartan disodium salt filtrate is obtained.

[0007] Step 2: Add a mixture of ethyl acetate and petroleum ether to the valsartan disodium salt filtrate to allow valsartan disodium to crystallize out. After cooling and crystal growth, centrifuge to obtain valsartan disodium crystals and mother liquor.

[0008] Step 3: Using the valsartan disodium crystals obtained in Step 2 as seed crystals, add them to the mother liquor for secondary crystallization. Combine the separated crystals with the crystals from Step 2, wash them, and dry them to constant weight to obtain the valsartan disodium intermediate.

[0009] Furthermore, the preparation process of the valsartan disodium intermediate is as follows: The mother liquor of crystallization was placed in a reaction vessel, and valsartan disodium crystals were added. After stirring at 25-35℃ for 20-40 min, the mixture was cooled to 0-10℃, ethyl acetate and petroleum ether were added, and the reaction was continued for 2-3 h. The reaction solution was centrifuged, and the solid and the remaining valsartan disodium crystals were combined and washed. The mixture was then vacuum dried at 40-50℃ for 2-3 h, and then transferred to a microwave vacuum drying oven to dry to constant weight to obtain valsartan disodium intermediate.

[0010] Furthermore, the ratio of valsartan disodium crystals, crystallization mother liquor, ethyl acetate, and petroleum ether used is 80-160g: 250-300mL: 120-160mL: 120-160mL.

[0011] Furthermore, the preparation process of valsartan disodium crystals and crystallization mother liquor is as follows: The filtrate of valsartan disodium salt was placed in a reaction vessel, and ethyl acetate and petroleum ether were added. The reaction was carried out at 25-35℃ for 1-2 hours. After crystals precipitated, the mixture was cooled to 0-10℃ and the reaction was continued for 4-6 hours. The reaction solution was centrifuged, and the solid phase and aqueous phase were collected to obtain valsartan disodium crystals and crystallization mother liquor.

[0012] Furthermore, the volume ratio of valsartan disodium salt filtrate, ethyl acetate, and petroleum ether is 150-250:80-100:80-100.

[0013] Furthermore, the preparation process of the valsartan disodium salt filtrate is as follows: Valsartan and acetone were placed in a reaction vessel, and a 10 mol / L sodium hydroxide solution was added to adjust the pH of the reaction solution to 10-12. The reaction was carried out at 30-40℃ for 6-8 hours. The mixture was filtered while hot, and the filter cake and filtrate were collected. The filter cake was washed, and a washing solution with an equal volume of the filter cake was added to wash the filter cake. The washing solution and filtrate were mixed to obtain the valsartan disodium salt filtrate.

[0014] Furthermore, the ratio of valsartan, sodium hydroxide solution, and acetone used is 100-200g: 30-50mL: 80-100mL.

[0015] The beneficial effects of this invention are: The valsartan disodium intermediate prepared by this invention, through controlled salt-forming reaction in an independent system, allows the carboxyl group in the valsartan molecule to fully react with the inorganic base to form a stable salt structure. Unreacted raw materials and insoluble impurities are removed by filtration and washing, constructing a reaction system with a more homogeneous ionic environment. This results in more complete salt-form conversion, increasing the proportion of effective components that can participate in subsequent crystallization. Simultaneously, by removing crystal-inhibiting impurities and foreign nuclei, the possibility of impurity-induced nucleation is reduced, establishing a continuous and stable nucleation environment for crystals. Furthermore, the purified salt-forming solution prevents impurities from competing with valsartan disodium for crystallization sites during subsequent crystallization, making the mother liquor obtained from the initial crystallization more homogeneous and free of interfering impurities. This lays the foundation for the enrichment of valsartan disodium in the mother liquor, the induced precipitation in the secondary crystallization stage, and the high recovery rate of effective components, achieving efficient utilization of the effective substances in the system.

[0016] 2. The valsartan disodium intermediate prepared by this invention, through a seed-induced secondary crystallization process, makes the precipitation of valsartan disodium in the mother liquor more directional and selective. The regular crystal faces in the seed crystal provide continuous coordination lattice adsorption sites for the effective components in the solution, so that crystal growth preferentially occurs on the existing crystal faces, thereby avoiding problems such as small particles and increased solubility caused by spontaneous nucleation. At the same time, the inorganic salts, unreacted components and by-product impurities in the washed mother liquor are significantly reduced, so that the secondary crystallization can achieve full recovery of residual effective components, ultimately improving the overall yield and reducing batch fluctuations, and constructing a stable crystallization system that can be scaled up industrially. Detailed Implementation

[0017] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0018] Example 1: This example provides a valsartan disodium intermediate, which is prepared through the following steps: S1: Place 100g valsartan and 30mL acetone in a reaction vessel, add 80mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 10, stir at 200r / min at 30℃ for 6h. After the reaction is completed, filter while hot, collect the filter cake and filtrate, add washing solution (a mixed solvent prepared by acetone and deionized water in a volume ratio of 10:1) to wash the filter cake, mix the washing solution and filtrate to obtain valsartan disodium salt filtrate.

[0019] S2: Place 150 mL of valsartan disodium salt filtrate in a reaction vessel, add 80 mL of ethyl acetate and 80 mL of petroleum ether, and stir at 100 r / min for 1 h at 25 °C. After crystals precipitate, cool to 10 °C and continue the reaction at the same stirring rate for 4 h. After the reaction is completed, centrifuge the reaction solution and collect the solid phase and aqueous phase to obtain valsartan disodium crystals and crystallization mother liquor.

[0020] S3: Place 250 mL of crystallization mother liquor in a reaction vessel, add 4 g of valsartan disodium crystals obtained in S2 as seed crystals, stir at 100 r / min for 20 min at 25 °C, cool to 0 °C, add 120 mL of ethyl acetate and 120 mL of petroleum ether, maintain the temperature and stirring rate for 2-3 h, after the reaction is completed, centrifuge the reaction solution, collect the solid, wash the filter cake and the remaining 76 g of valsartan disodium crystals in S2 twice with ethyl acetate, vacuum dry at 40 °C for 2 h to remove most of the surface solvent and free water, then transfer to a microwave vacuum drying oven, dry at 60 °C and 0.5 W / g microwave power to constant weight to obtain valsartan disodium intermediate.

[0021] Example 2: This example provides a valsartan disodium intermediate, which is prepared through the following steps: S1: Place 150g valsartan and 40mL acetone in a reaction vessel, add 90mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 11, and stir at 250r / min at 35℃ for 7h. After the reaction is completed, filter while hot, collect the filter cake and filtrate, add washing solution (a mixed solvent prepared by acetone and deionized water at a volume ratio of 10:1) to wash the filter cake, mix the washing solution and filtrate to obtain valsartan disodium salt filtrate.

[0022] S2: Place 200 mL of valsartan disodium salt filtrate in a reaction vessel, add 90 mL of ethyl acetate and 90 mL of petroleum ether, and stir at 150 r / min at 30 °C for 1-2 h. After crystals precipitate, cool to 5 °C and continue the reaction at the same stirring rate for 5 h. After the reaction is completed, centrifuge the reaction solution and collect the solid phase and aqueous phase to obtain valsartan disodium crystals and crystallization mother liquor.

[0023] S3: Place 280 mL of crystallization mother liquor in a reaction vessel, add 6 g of valsartan disodium crystals obtained in S2 as seed crystals, stir at 150 r / min for 30 min at 30 °C, cool to 5 °C, add 140 mL of ethyl acetate and 140 mL of petroleum ether, maintain the temperature and stirring rate for 2.5 h. After the reaction is completed, centrifuge the reaction solution, collect the solid, wash the filter cake and the remaining 114 g of valsartan disodium crystals in S2 three times with ethyl acetate, vacuum dry at 45 °C for 2.5 h to remove most of the surface solvent and free water, then transfer to a microwave vacuum drying oven and dry to constant weight at 70 °C and 0.8 W / g microwave power to obtain valsartan disodium intermediate.

[0024] Example 3: This example provides a valsartan disodium intermediate, which is prepared through the following steps: S1: Place 200g valsartan and 50mL acetone in a reaction vessel, add 100mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 12, stir at 300r / min at 40℃ for 8h. After the reaction is completed, filter while hot, collect the filter cake and filtrate, add washing solution (a mixed solvent prepared by acetone and deionized water at a volume ratio of 10:1) to wash the filter cake, mix the washing solution and filtrate to obtain valsartan disodium salt filtrate.

[0025] S2: Place 250 mL of valsartan disodium salt filtrate in a reaction vessel, add 100 mL of ethyl acetate and 100 mL of petroleum ether, and stir at 200 r / min at 35 °C for 2 h. After crystals precipitate, cool to 0 °C and continue the reaction at the same stirring rate for 6 h. After the reaction is completed, centrifuge the reaction solution and collect the solid phase and aqueous phase to obtain valsartan disodium crystals and crystallization mother liquor.

[0026] S3: Place 300 mL of crystallization mother liquor in a reaction vessel, add 8 g of valsartan disodium crystals obtained in S2 as seed crystals, stir at 200 r / min for 40 min at 35 °C, cool to 0 °C, add 160 mL of ethyl acetate and 160 mL of petroleum ether, maintain the temperature and stirring rate for 3 h. After the reaction is completed, centrifuge the reaction solution, collect the solid, wash the filter cake and the remaining 152 g of valsartan disodium crystals in S2 with ethyl acetate 4 times, vacuum dry at 50 °C for 3 h to remove most of the surface solvent and free water, and then transfer to a microwave vacuum drying oven and dry to constant weight at 80 °C and 1 W / g microwave power to obtain valsartan disodium intermediate.

[0027] The valsartan disodium intermediates prepared in Examples 1-3 above were obtained by neutralizing valsartan with sodium hydroxide in an alkaline environment to form a valsartan sodium salt with high solubility. After solid-liquid separation and washing with an acetone-water mixed solvent, hydrophobic impurities were removed by utilizing the polarity difference, resulting in a valsartan disodium salt filtrate containing the salt-forming product. Ethyl acetate and petroleum ether were then added to the filtrate to control the crystallization of valsartan disodium as the solvent polarity decreased. At a lower temperature, the nucleation rate decreased and the crystals grew further, thus obtaining valsartan disodium crystals and its crystallization mother liquor. A small amount of seed crystals was further added to the mother liquor to direct the nucleation process. With the reintroduction of ethyl acetate and petroleum ether, the polarity of the system was further adjusted, allowing valsartan disodium to precipitate better from the mother liquor, obtaining a solid product with uniform crystal form and suitable particle size. Finally, residual impurities on the crystal surface were replaced by organic solvents, and residual solvent and bound water were removed by the combined action of conventional drying and microwave vacuum drying to obtain the valsartan disodium intermediate.

[0028] Comparative Example 1: The difference from Example 2 is that valsartan disodium obtained from S2 was added to S3 as a seed crystal for removal.

[0029] S1: Place 150g valsartan and 40mL acetone in a reaction vessel, add 90mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 11, and stir at 250r / min at 35℃ for 7h. After the reaction is completed, filter while hot, collect the filter cake and filtrate, add washing solution (a mixed solvent prepared by acetone and deionized water at a volume ratio of 10:1) to wash the filter cake, mix the washing solution and filtrate to obtain valsartan disodium salt filtrate.

[0030] S2: Place 200 mL of valsartan disodium salt filtrate in a reaction vessel, add 90 mL of ethyl acetate and 90 mL of petroleum ether, and stir at 150 r / min at 30 °C for 1-2 h. After crystals precipitate, cool to 5 °C and continue the reaction at the same stirring rate for 5 h. After the reaction is completed, centrifuge the reaction solution and collect the solid phase and aqueous phase to obtain valsartan disodium crystals and crystallization mother liquor.

[0031] S3: Place 280 mL of the crystallization mother liquor in a reaction vessel, add 140 mL of ethyl acetate and 140 mL of petroleum ether, and maintain the temperature and stirring rate for 2.5 h. After the reaction is completed, centrifuge the reaction solution and collect the solid. Wash the filter cake and the remaining 118 g of valsartan disodium crystals in S2 three times with ethyl acetate, and vacuum dry at 45 °C for 2.5 h to remove most of the surface solvent and free water. Then transfer it to a microwave vacuum drying oven and dry it at 70 °C and 0.8 W / g microwave power to constant weight to obtain valsartan disodium intermediate.

[0032] Comparative Example 2: The difference from Example 2 is that the secondary crystallization step of the mother liquor in S3 is removed.

[0033] S1: Place 150g valsartan and 40mL acetone in a reaction vessel, add 90mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 11, and stir at 250r / min at 35℃ for 7h. After the reaction is completed, filter while hot, collect the filter cake and filtrate, add washing solution (a mixed solvent prepared by acetone and deionized water at a volume ratio of 10:1) to wash the filter cake, mix the washing solution and filtrate to obtain valsartan disodium salt filtrate.

[0034] S2: Place 200 mL of valsartan disodium salt filtrate in a reaction vessel, add 90 mL of ethyl acetate and 90 mL of petroleum ether, and stir at 150 r / min at 30 °C for 1-2 h. After crystals precipitate, cool to 5 °C and continue the reaction at the same stirring rate for 5 h. After the reaction is complete, centrifuge the reaction solution, collect the solid, wash the solid three times with ethyl acetate, and vacuum dry at 45 °C for 2.5 h to remove most of the surface solvent and free water. Then transfer it to a microwave vacuum drying oven and dry at 70 °C and 0.8 W / g microwave power to constant weight to obtain valsartan disodium intermediate.

[0035] Comparative Example 3: The difference from Example 2 is that the filtration operation of the reaction solution in S1 is removed, and the crystal precipitation reaction is carried out directly.

[0036] S1: Place 150g of valsartan and 40mL of acetone in a reaction vessel, add 90mL of 10mol / L sodium hydroxide solution to make the pH of the reaction solution 11, and stir at 250r / min at 35℃ for 7h. After the reaction is completed, the valsartan disodium salt formation reaction solution is obtained.

[0037] S2: Place 150 mL of valsartan disodium salt formation reaction solution in a reaction vessel, add 50 mL of ethyl acetate and 50 mL of petroleum ether, and stir at 150 r / min at 30 °C for 1-2 h. After crystals precipitate, cool to 5 °C and continue the reaction at the same stirring rate for 5 h. After the reaction is completed, centrifuge the reaction solution and collect the solid phase and aqueous phase to obtain valsartan disodium crystals and crystallization mother liquor.

[0038] S3: Place 200 mL of crystallization mother liquor in a reaction vessel, add 6 g of valsartan disodium crystals obtained in S2 as seed crystals, stir at 150 r / min for 30 min at 30 °C, cool to 5 °C, add 140 mL of ethyl acetate and 140 mL of petroleum ether, maintain the temperature and stirring rate for 2.5 h. After the reaction is completed, centrifuge the reaction solution, collect the solid, wash the filter cake and the remaining 80 g of valsartan disodium crystals in S2 three times with ethyl acetate, vacuum dry at 45 °C for 2.5 h to remove most of the surface solvent and free water, then transfer to a microwave vacuum drying oven and dry to constant weight at 70 °C and 0.8 W / g microwave power to obtain valsartan disodium intermediate.

[0039] In the above examples and comparative examples, the valsartan purchased was manufactured by Ningbo Minova Pharmaceutical Co., Ltd., with CAS number 137862-53-4 and a purity of 98%.

[0040] The yields and final yields of valsartan disodium obtained from the first crystallization and the second crystallization in the above examples and comparative examples are compared, as shown in Table 1: Table 1 Comparison of Yield and Final Yield for Each Group As shown in Table 1, the yields of Comparative Examples 1-3 were all lower than those of Examples 1-3, indicating that the stepwise process of "salt formation and purification - controlled nucleation - secondary crystallization" adopted in this invention can effectively reduce raw material loss and improve the controllability of the crystallization process. Specifically, by first forming salt and then filtering and washing, unreacted raw materials and insoluble components can be separated from the system, making the composition of the salt solution more uniform and avoiding the formation of foreign nucleation sites by impurities during the crystallization process, thereby increasing the proportion of effective materials participating in crystallization. Subsequently, ethyl acetate and petroleum ether are used to adjust the solubility and the temperature is reduced in stages, so that the system is under control during both the nucleation and growth stages, and a stable crystallization and sedimentation process is obtained. Finally, seed crystals are introduced into the mother liquor for induced crystallization and secondary crystallization, which can further precipitate and recover the residual valsartan disodium in the solution, improve the raw material utilization rate, reduce the loss of mother liquor, and thus obtain a higher yield and stable process performance with the same amount of raw material input.

[0041] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A valsartan disodium intermediate, characterized in that, Prepared by the following steps: Step 1: Using valsartan as raw material and sodium hydroxide solution as alkali source, a salt formation reaction is carried out under heating and constant temperature stirring. After post-treatment, valsartan disodium salt filtrate is obtained. Step 2: Add a mixed solvent of ethyl acetate and petroleum ether to the valsartan disodium salt filtrate to crystallize valsartan disodium. After cooling and crystal growth, centrifuge to obtain valsartan disodium crystals and crystallization mother liquor. Step 3: Using a portion of the valsartan disodium crystals from Step 2 as seed crystals, add them to the mother liquor for secondary crystallization. Combine the separated crystals with the remaining crystals from Step 2, wash them, and dry them to constant weight to obtain the valsartan disodium intermediate.

2. The valsartan disodium intermediate according to claim 1, characterized in that, The valsartan disodium intermediate described in step three is prepared through the following steps: The mother liquor of crystallization was placed in a reaction vessel, and valsartan disodium crystals were added. After stirring at 25-35℃ for 20-40 min, the mixture was cooled to 0-10℃, ethyl acetate and petroleum ether were added, and the reaction was continued for 2-3 h. The reaction solution was centrifuged, and the solid and the remaining valsartan disodium crystals were combined and washed. The mixture was then vacuum dried at 40-50℃ for 2-3 h, and then transferred to a microwave vacuum drying oven to dry to constant weight to obtain valsartan disodium intermediate.

3. The valsartan disodium intermediate according to claim 2, characterized in that, The ratio of valsartan disodium crystals, crystallization mother liquor, ethyl acetate, and petroleum ether is 80-160g: 250-300mL: 120-160mL: 120-160mL.

4. The valsartan disodium intermediate according to claim 2, characterized in that, The microwave vacuum drying temperature is 60-80℃, and the microwave power is 0.5-W / g.

5. The valsartan disodium intermediate according to claim 3, characterized in that, The valsartan disodium crystals and crystallization mother liquor are prepared by the following steps: The filtrate of valsartan disodium salt was placed in a reaction vessel, and ethyl acetate and petroleum ether were added. The reaction was carried out at 25-35℃ for 1-2 hours. After crystals precipitated, the mixture was cooled to 0-10℃ and the reaction was continued for 4-6 hours. The reaction solution was centrifuged, and the solid phase and aqueous phase were collected to obtain valsartan disodium crystals and crystallization mother liquor.

6. The valsartan disodium intermediate according to claim 5, characterized in that, The volume ratio of the valsartan disodium salt filtrate, ethyl acetate, and petroleum ether is 150-250:80-100:80-100.

7. The valsartan disodium intermediate according to claim 6, characterized in that, The valsartan disodium salt filtrate was prepared by the following steps: Valsartan and acetone were placed in a reaction vessel, and sodium hydroxide solution was added to adjust the pH of the reaction solution to 10-12. The reaction was carried out at 30-40℃ for 6-8 hours. The mixture was filtered while hot, and the filter cake and filtrate were collected. The filter cake was washed, and a washing solution with an equal volume of the filter cake was added to wash the filter cake. The washing solution and filtrate were mixed to obtain the valsartan disodium salt filtrate.

8. The valsartan disodium intermediate according to claim 7, characterized in that, The ratio of valsartan, sodium hydroxide solution, and acetone used is 100-200g: 30-50mL: 80-100mL.

9. The valsartan disodium intermediate according to claim 7, characterized in that, The washing solution is a mixed solvent prepared by acetone and deionized water in a volume ratio of 10:

1.

10. The valsartan disodium intermediate according to claim 7, characterized in that, The concentration of the sodium hydroxide solution is 10 mol / L.

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