Preparation method and production system of tolvaptan sodium phosphate

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method and a production system of tolvaptan sodium phosphate. The preparation method comprises the following steps: taking tolvaptan as a raw material, firstly carrying out phosphorus esterification reaction on the tolvaptan and a phosphorus reagent, then carrying out oxidation reaction on the tolvaptan and an oxidizing agent, and washing, extracting, salifying, freeze-drying or crystallizing the obtained reaction liquid to obtain tolvaptan sodium phosphate. When the method is used for preparing the tolvaptan sodium phosphate, alkaline substances such as triethylamine do not need to be added in the reaction process, side reactions are few, and steps such as recrystallization are not involved. The preparation method is simple in process, high in yield, high in purity, less in three wastes and more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method and a production system of tolvaptan sodium phosphate. Background Art

[0002] Tolvaptan is a selective vasopressin V2 receptor antagonist, mainly used to treat hypervolemic or isovolemic hyponatremia with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. The drug specifically antagonizes arginine vasopressin, thereby reducing the renal reabsorption of water, increasing urine volume, and raising blood sodium levels. As a prodrug of tolvaptan, tolvaptan sodium phosphate can be hydrolyzed by phosphatase in the body into the active drug tolvaptan, thereby exerting a therapeutic effect. Tolvaptan sodium phosphate introduces a phosphate group on the basis of tolvaptan, thereby improving the solubility and stability of tolvaptan in water, making it suitable for intravenous injection, providing a new treatment option for patients who cannot take tolvaptan orally. In March 2022, tolvaptan sodium phosphate was officially approved in Japan for the treatment of fluid retention in heart failure that is not adequately controlled by other diuretics. In a Phase 3 clinical trial conducted in Japan, tolvaptan sodium phosphate showed non-inferiority to tolvaptan tablets in the primary endpoint of weight change at the final dose, with no significant differences in key secondary endpoints.

[0003] Some prior art reports on the synthesis process of tolvaptan sodium phosphate. For example:

[0004] 1) The invention patent with publication number WO2020158548 discloses a method for preparing tolvaptan sodium phosphate, which comprises using tolvaptan as a raw material, reacting in 1,2-dimethoxyethane, triethylamine, and phosphorus oxychloride, and after the reaction, post-processing and crystallization to obtain tolvaptan sodium phosphate with a molar yield of 86%. In the patent, alkaline substances such as triethylamine are added during the reaction, resulting in more side reactions and affecting the purity of the product.

[0005] The process route is as follows:

[0006]

[0007] 2) The invention patent with publication number WO2020196814 discloses a method for preparing tolvaptan sodium phosphate, including dissolving tolvaptan and 1H-tetrazole in dichloromethane, reacting with dibenzyl diisopropyl phosphoramidite to obtain compound 1; compound 1 reacts with m-CPBA to obtain compound 2; compound 2 is reduced under palladium carbon catalysis, concentrated and crystallized to obtain tolvaptan phosphate with a molar yield of 86.02%; then salted with sodium hydroxide aqueous solution, crystallized in an acetone / water system, to obtain a finished tolvaptan phosphate with a molar yield of 76.03%. The total molar yield of the entire process is 65.40%, which is low and not suitable for industrial production.

[0008] The process route is as follows:

[0009]

[0010] 3) The invention patent with publication number WO2007074915 reports a method for preparing tolvaptan phosphorous acid, comprising adding phosphorus trichloride to tetrahydrofuran, cooling and stirring, dripping triethylamine and then adding a tetrahydrofuran solution of tolvaptan, washing, extracting and concentrating to obtain tolvaptan phosphorous acid solid, with a molar yield of 60%. The patent adds alkaline substances such as triethylamine during the reaction process, resulting in more side reactions, requiring the removal of by-products by recrystallization, etc., which easily causes the loss of the main product and affects the purity and yield of the product. The purpose of the patent inventor adding triethylamine is to promote the reaction by using alkaline substances such as triethylamine as an acid binding agent for the reaction, but the phosphorus chloride reagent itself is more active and can react completely without the addition of triethylamine.

[0011] The process route is as follows:

[0012]

[0013] The above-mentioned WO2007074915 patent, WO2020158548 patent and WO2020196814 patent are patents of the original research company of tolvaptan sodium phosphate at different times. The WO2007074915 patent discloses a method for preparing tolvaptan phosphite from phosphorus trichloride and tolvaptan, but due to the poor reaction purity after adding triethylamine, the single-step molar yield is only 60%, so the subsequent oxidation reaction to prepare tolvaptan sodium phosphate was abandoned, and the complex process of tolvaptan and dibenzyl diisopropyl phosphoramidite, oxidation, and hydrogenation in route 2 was used instead.

[0014] Therefore, it is necessary to develop a method for synthesizing tolvaptan sodium phosphate with simple process, environmental protection and higher product purity yield. Summary of the invention

[0015] In view of this, in order to overcome the problems of many side reactions and low yield purity in the existing process, the present invention proposes a preparation method and production system of tolvaptan sodium phosphate. The present invention uses tolvaptan as a raw material, first performs a phosphating reaction with a phosphorus reagent, and then performs an oxidation reaction with an oxidant to prepare tolvaptan sodium phosphate. During the reaction, there is no need to add alkaline substances such as triethylamine, there are few side reactions, and steps such as recrystallization are not involved. The process is simpler, the three wastes are less, and the product purity and yield are higher, which is more suitable for industrial production.

[0016] One of the objects of the present invention is to provide a method for preparing tolvaptan sodium phosphate.

[0017] To achieve the above object, the present invention adopts the following technical solutions:

[0018] The preparation method of tolvaptan sodium phosphate comprises the following steps:

[0019] (1) using tolvaptan as a raw material and conducting a phosphoesterification reaction with a phosphorus reagent to obtain a reaction solution A; the reaction solution A contains a compound represented by formula II;

[0020] (2) adding an oxidant to the reaction solution A obtained in step (1) to cause an oxidation reaction to obtain tolvaptan sodium phosphate;

[0021] In step (1), no alkaline substance needs to be added, and the alkaline substance includes triethylamine; the structural formula of tolvaptan is shown in Formula I; the structural formula of tolvaptan sodium phosphate is shown in Formula III;

[0022]

[0023] Furthermore, the phosphorus reagent includes any one or more of phosphorus pentachloride, phosphorus pentafluoride, phosphorus pentabromide, phosphorus pentaiodide, phosphorus trichloride, phosphorus trifluoride, phosphorus tribromide, and phosphorus triiodide.

[0024] Preferably, the phosphorus reagent is phosphorus pentachloride.

[0025] Furthermore, the molar ratio of the tolvaptan to the phosphorus reagent is 1:0.7-10.

[0026] Preferably, the molar ratio of the tolvaptan to the phosphorus reagent is 1:0.8-5.

[0027] Most preferably, the molar ratio of tolvaptan to the phosphorus reagent is 1:2.

[0028] Furthermore, the oxidant includes any one or more of Oxone, hydrogen peroxide, TCCA, sodium hypochlorite, m-CPBA, calcium hypochlorite, and potassium permanganate.

[0029] Preferably, the oxidant is Oxone.

[0030] Furthermore, the molar ratio of the tolvaptan to the oxidant is 1:0.7-20.

[0031] Preferably, the molar ratio of tolvaptan to the oxidant is 1:2.

[0032] Further, the reaction solution A obtained in step (1) is cooled to -30°C, and water is added dropwise. The temperature is controlled at -30 to -10°C during the addition. After the addition is completed, the reaction solution is heated to room temperature, the pH is adjusted to 7.0 to 9.0, and then an oxidant is added in batches to carry out an oxidation reaction.

[0033] Furthermore, the pH adjuster is a sodium hydroxide aqueous solution with a concentration of 20%.

[0034] Furthermore, in step (1), the solvent is any one or more mixed solvents of methyltetrahydrofuran, dichloromethane, tetrahydrofuran, and chloroform.

[0035] Furthermore, after step (2), the method further comprises step (3): washing, extracting, salifying, freeze-drying or crystallizing the reaction solution obtained by the oxidation reaction to obtain tolvaptan sodium phosphate.

[0036] Furthermore, the crystals are crystals of tolvaptan sodium phosphate in a non-aqueous system, and the crystallization solvents are organic solvents and ether solvents; the organic solvents include any one or more of methanol, ethanol, acetone, tetrahydrofuran, and dichloromethane; the ether solvents are any one or more of ethyl ether, isopropyl ether, methyl tert-butyl ether, and anisole.

[0037] Furthermore, the crystallization comprises the following steps: the ethyl acetate solution of tolvaptan phosphate obtained by extraction is concentrated under reduced pressure until the flow is cut off, and a mixed solution of an organic solvent and sodium hydroxide is added to react; after stirring to dissolve clearly, an ether solvent is added to crystallize, and the solution is filtered and dried to obtain tolvaptan sodium phosphate.

[0038] Preferably, the method comprises the following steps:

[0039] Step 1: Mix the phosphorus reagent and the solvent, stir evenly, add the tolvaptan methyltetrahydrofuran solution or tolvaptan solid, stir and react until the remaining raw material is less than 1.0% as detected by HPLC, and terminate the reaction to obtain a reaction solution A containing the compound of formula II;

[0040] Step 2: Cool the reaction solution A obtained in step 1 to 0° C., add water dropwise, adjust the pH to 7.0-9.0 using a 20% aqueous sodium hydroxide solution, add an oxidant in batches, and terminate the reaction when the residual intermediate is less than 0.5% by HPLC to obtain a reaction solution containing tolvaptan sodium phosphate;

[0041] Step 3: washing, extracting, salifying, freeze-drying or crystallizing the reaction solution containing tolvaptan sodium phosphate obtained in step 2 to obtain tolvaptan sodium phosphate.

[0042] Preferably, step (3) is as follows:

[0043] 1) adding ethyl acetate to the reaction solution obtained by the oxidation reaction, stirring, standing, separating, retaining the aqueous phase, and discharging the organic phase; adding ethyl acetate to the aqueous phase, adding concentrated hydrochloric acid to adjust the pH to 1-3, stirring, standing, separating, retaining the organic phase, and discharging the aqueous phase; adding water to the organic phase, stirring, standing, separating, retaining the organic phase, and discharging the aqueous phase to obtain an ethyl acetate solution of tolvaptan phosphoric acid;

[0044] Or first, the reaction solution containing tolvaptan sodium phosphate obtained in step 2 is allowed to stand, separated, the aqueous phase is retained, and the organic phase is discharged; ethyl acetate is added to the aqueous phase, stirred, allowed to stand, separated, the aqueous phase is retained, and the organic phase is discharged; 900 mL of ethyl acetate is added to the aqueous phase, concentrated hydrochloric acid is added to adjust the pH to 1-3, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discharged; water is added to the organic phase, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discharged to obtain an ethyl acetate solution of tolvaptan phosphate;

[0045] 2) adding an aqueous sodium hydroxide solution to the ethyl acetate solution of tolvaptan phosphate obtained in step 3, stirring, standing, and separating the liquids, adjusting the pH of the aqueous phase to 7.0-9.0 with a 10% aqueous sodium hydroxide solution, and freeze-drying in a freeze dryer to obtain a tolvaptan sodium phosphate solid;

[0046] Alternatively, the ethyl acetate solution of tolvaptan phosphate obtained in step 3 is concentrated under reduced pressure until the flow is cut off, a methanol solution of sodium hydroxide is added, and after stirring to dissolve, the obtained tolvaptan sodium phosphate solution is slowly added dropwise to a crystallization solvent for crystallization, filtered, and dried to obtain tolvaptan sodium phosphate solid.

[0047] A second object of the present invention is to provide a production system for preparing tolvaptan sodium phosphate.

[0048] To achieve the above object, the present invention adopts the following technical solutions:

[0049] A production system for preparing tolvaptan sodium phosphate, the production system comprising a production unit, a temperature control unit, an extraction unit, a salt-forming unit, a freeze-drying unit or a crystallization unit; the production unit is respectively connected to a stirring unit, a temperature control unit and an extraction unit, and the extraction unit is connected to a freeze-drying unit or a crystallization unit; the tolvaptan undergoes phosphoesterification reaction and oxidation reaction in the production unit, during which the temperature is controlled by the temperature control unit; after the reaction is completed, the tolvaptan is washed and extracted in the extraction unit, salt is formed in the salt-forming unit, and finally freeze-dried in the freeze-drying unit or crystallized in the crystallization unit to obtain tolvaptan sodium phosphate.

[0050] The beneficial effects of the present invention are:

[0051] 1. The present invention provides a preparation method and production system of tolvaptan sodium phosphate, comprising using tolvaptan as a raw material, undergoing phosphating reaction and oxidation reaction, and preparing tolvaptan sodium phosphate. In the first step of the reaction process (phosphating reaction), there is no need to add alkaline substances such as triethylamine, there are few side reactions, and the obtained reaction solution has high purity. The reaction solution obtained by the subsequent oxidation reaction only needs simple post-treatment to obtain tolvaptan sodium phosphate solid, which effectively avoids the loss of the main product caused by recrystallization to remove by-products. The preparation method provided by the present invention has simple process, high yield, less three wastes, and has strong industrial value.

[0052] 2. The method of the present invention is used to prepare tolvaptan sodium phosphate, and the product purity and yield are high. After the reaction is completed, a freeze-drying process is used, and the total molar yield of tolvaptan sodium phosphate is 92.36% to 93.73%, and the final optimized process total molar yield is 95.41%.

[0053] 3. The present invention also provides a recrystallization process for tolvaptan sodium phosphate. Considering that although the freeze-drying process has a high molar yield, the freeze dryer is used in production, and the production capacity is easily limited; and although the molar yield of the crystallization method is low, the output of a single batch of products is high. Tolvaptan sodium phosphate is a product with good water solubility. Patent WO2020196814 uses acetone and water for crystallization, and the single-step crystallization molar yield is only 76.03%. The present invention uses methanol and ether solvents of a non-aqueous system for crystallization, and the total molar yield of the reaction and finished product recrystallization is 87.10-87.80%. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 HPLC spectrum of the tolvaptan sodium phosphate solid prepared in Example 4;

[0055] Figure 2 The solid tolvaptan sodium phosphate prepared in Example 4 1 H-NMR spectrum;

[0056] Figure 3 The solid tolvaptan sodium phosphate prepared in Example 4 31 P-NMR spectrum. DETAILED DESCRIPTION

[0057] The technical solution of the present invention will be further described clearly and completely in conjunction with specific embodiments below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work belong to the protection scope of the present invention.

[0058] In the embodiment of the present invention, the synthesis reaction formula of tolvaptan sodium phosphate is as follows:

[0059]

[0060] The present invention uses tolvaptan as a raw material, and a phosphorus halide reagent (such as PCl 3 etc.) to carry out phosphating reaction to obtain a reaction solution containing a compound of formula II; an oxidant (such as Oxone, etc.) is further added to carry out oxidation reaction to obtain tolvaptan sodium phosphate; the structural formula of tolvaptan sodium phosphate is shown in formula III.

[0061] In the embodiment of the present invention, the methanolic sodium hydroxide solution is prepared from 16.0 g of sodium hydroxide and 720 mL of methanol.

[0062] In the embodiments of the present invention, the chromatographic conditions of HPLC detection are shown in Table 1 and Table 2.

[0063] Table 1. Chromatographic conditions

[0064] Detection wavelength 254nm Column temperature 30℃ Flow rate 1.0mL / min Injection volume 10uL Chromatographic columns YMCHydrosphereC18, 4.6mm×250mm, 5μm Mobile phase A Phosphate buffer solution: acetonitrile = 8:92 Mobile phase B Phosphate buffer solution: acetonitrile = 80:20 Elution gradient

[0065] Table 2. Gradient elution schedule

[0066] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 25 40 60 35 0 100 45 0 100 45.1 100 0 50 100 0

[0067] Example 1

[0068] (1) 83.29 g (0.4 mmol, 2.0 eq) of phosphorus pentachloride and 180 mL of methyltetrahydrofuran were added to a clean three-necked flask, stirred evenly, and then a tolvaptan methyltetrahydrofuran solution (tolvaptan: 89.79 g, 0.2 mol, 1.0 eq; methyltetrahydrofuran: 900 mL) was added. After the addition was completed, the reaction was stirred until the residual raw material was less than 1.0% as detected by HPLC. The reaction was terminated to obtain a reaction solution A containing the compound of formula II.

[0069] (2) The qualified reaction solution A obtained in step (1) was cooled to 0° C., 180 mL of water was added dropwise, and after the addition, 20% aqueous sodium hydroxide solution was used to adjust the pH to 7.0-9.0, and 245.88 g (0.4 mol, 2.0 eq) of Oxone was added in batches. The residual intermediate was <0.5% by HPLC, and the reaction was terminated to obtain a reaction solution containing tolvaptan sodium phosphate with a purity of 95.5%.

[0070] (3) Post-treatment: Add 900 mL of ethyl acetate to the qualified reaction solution, stir, stand, separate, retain the aqueous phase, and discard the organic phase. Add 900 mL of ethyl acetate to the aqueous phase, add concentrated hydrochloric acid to adjust the pH to 1-3, stir, stand, separate, retain the organic phase, and discard the aqueous phase. Add 450 mL of water to the organic phase, stir, stand, separate, retain the organic phase, and discard the aqueous phase to obtain an ethyl acetate solution of tolvaptan phosphoric acid.

[0071] (4) Lyophilization: A sodium hydroxide aqueous solution (sodium hydroxide: 14.40 g; water: 900 mL) was added to the ethyl acetate solution of tolvaptan phosphate, stirred, allowed to stand, and separated. The pH of the aqueous phase was adjusted to 7.0-9.0 with a 10% sodium hydroxide aqueous solution, and lyophilized in a lyophilizer to obtain 105.82 g of tolvaptan sodium phosphate solid, with a molar yield of 92.36% and a solid purity of 99.87%.

[0072] Example 2

[0073] (1) 83.29 g (0.4 mmol, 2.0 eq) of phosphorus pentachloride and 1080 mL of methyltetrahydrofuran were added to a clean three-necked flask and stirred evenly. Then, 89.79 g (0.2 mol, 1.0 eq) of tolvaptan solid was added. After the addition was completed, the reaction was stirred until the residual raw material was less than 1.0% as detected by HPLC. The reaction was terminated to obtain a reaction solution A containing the compound of formula II.

[0074] (2) The qualified reaction solution A was cooled to 0°C, and 180 mL of water was added dropwise. After the addition was completed, a 20% aqueous sodium hydroxide solution was used to adjust the pH to 7.0-9.0, and 245.88 g (0.4 mol, 2.0 eq) of Oxone was added in batches. The residual intermediate was <0.5% by HPLC. The reaction was terminated to obtain a reaction solution containing tolvaptan sodium phosphate with a purity of 95.8%.

[0075] (3) The post-treatment and freeze-drying steps of Example 1 were repeated to obtain 106.21 g of tolvaptan sodium phosphate solid with a molar yield of 92.70% and a solid purity of 99.89%.

[0076] Example 3

[0077] (1) 83.29 g (0.4 mmol, 2.0 eq) of phosphorus pentachloride and 1080 mL of dichloromethane were added to a clean three-necked flask and stirred evenly. Then, 89.79 g (0.2 mol, 1.0 eq) of tolvaptan solid was added. After the addition was completed, the reaction was stirred until the residual raw material was less than 1.0% as detected by HPLC. The reaction was terminated to obtain a reaction solution A containing the compound of formula II.

[0078] (2) The qualified reaction solution A was cooled to 0°C, and 180 mL of water was added dropwise. After the addition was completed, a 20% aqueous sodium hydroxide solution was used to adjust the pH to 7.0-9.0, and 245.88 g (0.4 mol, 2.0 eq) of Oxone was added in batches. The residual intermediate was <0.5% by HPLC, and the reaction was terminated to obtain a reaction solution containing tolvaptan sodium phosphate with a purity of 96.3%.

[0079] (3) Post-treatment: The qualified reaction solution is allowed to stand and separated, the aqueous phase is retained, and the organic phase is discarded. 450 mL of ethyl acetate is added to the aqueous phase, stirred, allowed to stand, separated, the aqueous phase is retained, and the organic phase is discarded. 900 mL of ethyl acetate is added to the aqueous phase, concentrated hydrochloric acid is added to adjust the pH to 1-3, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discarded. 450 mL of water is added to the organic phase, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discarded to obtain an ethyl acetate solution of tolvaptan phosphoric acid.

[0080] (4) The freeze-drying step of Example 1 was repeated to obtain 107.39 g of tolvaptan sodium phosphate solid. The molar yield was 93.73% and the solid purity was 99.88%.

[0081] Example 4

[0082] (1) 54.93 g (0.4 mmol, 2.0 eq) of phosphorus trichloride and 1080 mL of dichloromethane were added to a clean three-necked flask and stirred evenly. Then, 89.79 g (0.2 mol, 1.0 eq) of tolvaptan solid was added. After the addition was completed, the reaction was stirred until the residual raw material was less than 1.0% as detected by HPLC. The reaction was terminated to obtain a reaction solution A containing the compound of formula II.

[0083] (2) The qualified reaction solution A was cooled to -30°C, and 180 mL of water was added dropwise. The temperature was controlled at -30 to -10°C during the addition. After the addition was completed, the reaction solution was warmed to room temperature, and a 20% aqueous sodium hydroxide solution was used to adjust the pH to 7.0 to 9.0. 184.41 g (0.3 mol, 1.5 eq) of Oxone was added in batches. The residual intermediate was <0.5% by HPLC, and the reaction was terminated to obtain a reaction solution containing tolvaptan sodium phosphate with a purity of 98.1%.

[0084] (3) Post-treatment: The qualified reaction solution is allowed to stand and separated, the aqueous phase is retained, and the organic phase is discarded. 450 mL of ethyl acetate is added to the aqueous phase, stirred, allowed to stand, separated, the aqueous phase is retained, and the organic phase is discarded. 900 mL of ethyl acetate is added to the aqueous phase, concentrated hydrochloric acid is added to adjust the pH to 1-3, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discarded. 450 mL of water is added to the organic phase, stirred, allowed to stand, separated, the organic phase is retained, and the aqueous phase is discarded to obtain an ethyl acetate solution of tolvaptan phosphoric acid.

[0085] (4) Repeat the freeze-drying step of Example 1 to obtain 109.32 g of tolvaptan sodium phosphate solid, with a molar yield of 95.41% and a solid purity of 99.88%. The HPLC test results are as follows: Figure 1 As shown in Table 3, the NMR test results are as follows Figure 2 ( 1 H-NMR spectrum) and Figure 3 ( 31 P-NMR spectrum).

[0086] Table 3. Figure 1 Data Sheet

[0087]

[0088] Example 5

[0089] Repeat steps (1) to (3) of Example 4 to obtain an ethyl acetate solution of tolvaptan phosphate. Concentrate under reduced pressure until the flow is cut off, add a methanolic sodium hydroxide solution, stir to dissolve, add 720 mL of methyl tert-butyl ether dropwise to the tolvaptan sodium phosphate solution, filter and dry after crystallization to obtain 99.8 g of tolvaptan sodium phosphate solid, with a molar yield of 87.10% and a solid purity of 99.89%.

[0090] Example 6

[0091] Repeat steps (1) to (3) of Example 4 to obtain an ethyl acetate solution of tolvaptan phosphate. Concentrate under reduced pressure until the flow is cut off, add a methanolic sodium hydroxide solution, stir to dissolve, slowly add the tolvaptan sodium phosphate solution dropwise to 720 mL of methyl tert-butyl ether, filter and dry after crystallization to obtain 100.6 g of tolvaptan sodium phosphate solid, with a molar yield of 87.80% and a solid purity of 99.88%.

[0092] Example 7

[0093] Repeat steps (1) to (3) of Example 4 to obtain an ethyl acetate solution of tolvaptan phosphate. Concentrate under reduced pressure until the flow is cut off, add a methanolic sodium hydroxide solution, stir to dissolve, slowly add the tolvaptan sodium phosphate solution dropwise to 720 mL of ether, filter and dry after crystallization to obtain 100.1 g of tolvaptan sodium phosphate solid, with a molar yield of 87.36% and a solid purity of 99.86%.

Claims

1. A method for preparing tolvaptan sodium phosphate, characterized in that: The steps include: (1) using tolvaptan as a raw material and conducting a phosphoesterification reaction with a phosphorus reagent to obtain a reaction solution A; the reaction solution A contains a compound represented by formula II; (2) adding an oxidant to the reaction solution A obtained in step (1) to cause an oxidation reaction to obtain tolvaptan sodium phosphate; in step (1), no alkaline substance needs to be added, and the alkaline substance includes triethylamine; the structural formula of the tolvaptan is shown in formula I; the structural formula of the tolvaptan sodium phosphate is shown in formula III; 2. The method according to claim 1, characterized in that The phosphorus reagent includes any one or more of phosphorus pentachloride, phosphorus pentafluoride, phosphorus pentabromide, phosphorus pentaiodide, phosphorus trichloride, phosphorus trifluoride, phosphorus tribromide, and phosphorus triiodide.

3. The method according to claim 1, characterized in that The molar ratio of the tolvaptan to the phosphorus reagent is 1:0.7-10.

4. The method according to claim 1, characterized in that: The oxidant includes any one or more of Oxone, hydrogen peroxide, TCCA, sodium hypochlorite, m-CPBA, calcium hypochlorite, and potassium permanganate.

5. The method according to claim 1, characterized in that The molar ratio of the tolvaptan to the oxidant is 1:0.7-20.

6. The method according to claim 1, characterized in that In step (1), the solvent is any one or more mixed solvents of methyltetrahydrofuran, dichloromethane, tetrahydrofuran, and chloroform.

7. The method according to claim 1, characterized in that The method further comprises the step (3) after the step (2): washing, extracting, salifying, freeze-drying or crystallizing the reaction liquid obtained by the oxidation reaction to obtain tolvaptan sodium phosphate.

8. The method according to claim 7, characterized in that The crystal is a crystal of tolvaptan sodium phosphate non-aqueous system, and the crystallization solvent is an organic solvent and an ether solvent; the organic solvent includes any one or more of methanol, ethanol, acetone, tetrahydrofuran, and dichloromethane; the ether solvent is any one or more of ethyl ether, isopropyl ether, methyl tert-butyl ether, and anisole.

9. The method according to claim 7, characterized in that: The crystallization comprises the following steps: concentrating the ethyl acetate solution of tolvaptan phosphate obtained by extraction under reduced pressure until the flow is cut off, adding a mixed solution of an organic solvent and sodium hydroxide to react; after stirring to dissolve clearly, adding an ether solvent to crystallize, filtering and drying to obtain tolvaptan sodium phosphate.

10. A production system for preparing tolvaptan sodium phosphate, characterized in that: The production system comprises a production unit, a temperature control unit, an extraction unit, a salt-forming unit, a freeze-drying unit or a crystallization unit; the production unit is respectively connected to the stirring unit, the temperature control unit and the extraction unit, and the extraction unit is connected to the freeze-drying unit or the crystallization unit; the tolvaptan undergoes phosphoesterification reaction and oxidation reaction in the production unit, during which the temperature is controlled by the temperature control unit; after the reaction, the tolvaptan is washed and extracted in the extraction unit, salt is formed in the salt-forming unit, and finally freeze-dried in the freeze-drying unit or crystallized in the crystallization unit to obtain tolvaptan sodium phosphate.

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