Preparation method of oxaggolil sodium and intermediate of oxaggolil sodium

Abstract

The invention discloses a preparation method of oxaggolil sodium and an intermediate thereof, relates to the field of medicinal chemistry, and aims to provide the preparation method of the oxaggolil sodium and the intermediate thereof. A bulk material Meldrum's acid is adopted as a starting material, the price is low, the material cost is reduced, the quality of the intermediate (4) is effectively controlled, and the quality of API is further improved. Hydrochloric acid is adopted during BOC protecting group removal in the fourth step, methanesulfonic acid is prevented from generating methanesulfonic acid ester-based toxic substances, and the risk of generating the methanesulfonic acid ester-based toxic substances is avoided; in the API crystallization process, a poor solvent is reversely dropwise added, so that the drying time is shortened, and commercialized production is facilitated; the method is applied to the field of drug synthesis.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of elagolid sodium and an intermediate thereof. Background Art

[0002] Elagolix tablets are oral gonadotropin-releasing hormone (GnRH) antagonists developed by AbbVie. They were first launched in the United States in 2018 under the trade name Orilissa for the treatment of moderate to severe pain associated with endometriosis. Elagolix competes with endogenous GnRH for receptors on pituitary cells, rapidly inhibits the pituitary-gonadal axis, blocks endogenous LH and FSH, and thus reduces hormone secretion to achieve the purpose of treating endometriosis. Elagolix tablets are currently only available in the United States and Canada. In addition, AbbVie also launched capsules containing Elagolix for the first time in the United States in 2020 under the trade name: Oriahnn, for the treatment of heavy menstrual bleeding caused by uterine leiomyoma (fibroids) in premenopausal women. In addition to the approved indications, Elagolix is ​​also being studied in female infertility (Phase 2) and polycystic ovary syndrome (Phase 2). According to the results of a foreign clinical trial network meta-analysis, elagolix may have advantages over well-known GnRH agonists because it does not cause a "flare up" effect and its side effects are dose-dependent. Therefore, clinicians can adjust the elagolix dose suitable for their patients to achieve the maximum therapeutic effect with the lowest side effects, which has application potential.

[0003]

[0004] The existing preparation method of elagolid sodium has the problem of long API drying time. Summary of the Invention

[0005] The purpose of the present invention is to solve the above technical problems and to provide a method for preparing elagolid sodium and its intermediates.

[0006] The preparation method of elagolid sodium and its intermediates of the present invention is carried out according to the following contents:

[0007] 1) Adding compound I and acid anhydride to an organic solvent to react to obtain compound II;

[0008] 2) adding compound II, compound III and acyl chloride to an organic solvent to react to obtain compound IV;

[0009] 3) adding compound IV and iodide to an organic reagent to react to obtain compound V;

[0010] 4) adding compound V and compound VI to an organic reagent and subjecting the mixture to a catalytic reaction to obtain compound VII;

[0011] 5) Compound VII and Compound VIII are added to an organic reagent, subjected to substitution reaction, and then reacted with an acid to remove the protecting group, and then reacted with an organic acid to form a salt to obtain Compound X;

[0012] 6) Compound X and a halogenated alkane are added to an organic reagent for a substitution reaction to obtain compound XI, which is then hydrolyzed with a base to obtain compound XII, i.e., elagolid sodium;

[0013] The molecular formula of compound I is C6H8O4, and the molecular formula of compound II is C8H 10 O5, the molecular formula of compound III is C9H8F4N2O, and the molecular formula of compound IV is C 13 H 10 F4N2O2, compound V has the molecular formula C 13 H9F4IN2O2, the molecular formula of compound VI is C7H8BFO3, and the molecular formula of compound VII is C 20 H 15 F5N2O3, compound VIII has the molecular formula C 14 H 21 NO5S, compound X has the molecular formula C 35 H 30 F5N3O6, compound XI has the molecular formula C 34 H 34 F5N3O5, compound Ⅻ has the molecular formula C 32 H 29 F5N3NaO5.

[0014] Furthermore, the organic solvent in step 1) is DMF, DMSO or THF; the organic solvent in step 2) is isopropanol or n-butanol; the organic reagent in step 3) is DMF; the organic reagent in step 4) is a mixed solution of dioxane and alkaline water, and the mixing ratio of dioxane to water and alkaline water is 7-8:7-8:1; the organic reagent in step 5) is DMF; the organic reagent in step 6) is a mixture of methyl tert-butyl ether and alkaline water, and the mixing ratio of methyl tert-butyl ether to water and alkaline water is 23-29:13-17:1.

[0015] Furthermore, the acid anhydride in step 1) is acetic anhydride, and the molar ratio of compound I to acetic anhydride is 1:1.1-1.6;

[0016] The feed ratio of compound I to the organic solvent is 1:5-10.

[0017] Furthermore, the acyl chloride in step 2) is acetyl chloride, the molar ratio of compound II, compound III and acyl chloride is 1:1.2-1.4:2.1-2.3, and the feed ratio of compound II to organic solvent is 1:5-8.

[0018] Furthermore, the molar ratio of compound IV to iodosuccinimide in step 3) is 1:1.1-1.5; and the feed ratio of compound IV to the organic solvent is 1:3-5.

[0019] Furthermore, the compound IV described in step 3) and the iodide are added to the organic reagent and the reaction conditions are as follows: react at 60-100° C. for 2-4 hours, cool to 10-20° C., add water dropwise, grow crystals for 2-4 hours, filter, rinse with water, collect the filter cake, and dry to obtain compound V.

[0020] Furthermore, the molar ratio of compound V to compound VI in step 4) is 1:1.2-1.7, and the feed ratio of compound V to organic solvent is 1:4-6.

[0021] Furthermore, in step 4), compound V and compound VI are added to an organic reagent and catalytically reacted to obtain compound VII. The reaction conditions are:

[0022] Compound V and compound VI are added to an organic reagent, and the ligand phenylphosphine is added. After oxygen is removed, the catalyst palladium acetate is added. The condensation reaction is carried out at 55-80°C with stirring for 2-4 hours. A mixture of glacial acetic acid and dioxane is added as a crystallization liquid. Crystallization is carried out at 75-85°C, and the mixture is filtered and rinsed with a mixture of methanol and water. The filter cake is collected and dried to obtain compound VII.

[0023] Furthermore, the compound VII and compound VIII described in step 5) are added to an organic reagent for substitution reaction to obtain compound IX, which is then reacted with an inorganic acid to remove the protecting group, and then reacted with an organic acid to form a salt to obtain compound X. The reaction conditions are:

[0024] Compound VII and compound VIII are added to an organic solvent, DMF, and an organic base, with a feed ratio of compound VII to the organic solvent of 1:0.5-1.5, and a condensation reaction is carried out at 50-65°C. After the reaction is completed, ammonia water is added at a feed ratio of 1:3.0-3.5, and an esterification reaction is carried out at 50-75°C. After the reaction is completed, isopropyl acetate is added, and an inorganic acid aqueous solution is used for extraction. Then, an inorganic acid is added at a feed ratio of 1:2.5-3.5, and a deprotection reaction is carried out at 45-65°C. Extraction is carried out with an inorganic base aqueous solution, and after rotary evaporation at 40-50°C with a vacuum degree of ≥0.095MPa, the organic phase is replaced with a methanol solution, and an organic acid is added at a feed ratio of 1:1.0-1.2 for salt formation. The temperature is lowered to 5°C-15°C for secondary crystallization, filtered, the filter cake is collected, and dried to obtain compound X; the molar ratio of compound VII to compound VIII is 1:2.0-3.0.

[0025] Furthermore, the compound X described in step 6) and a halogenated alkane are added to an organic reagent to undergo a substitution reaction to obtain a compound XI, which is then hydrolyzed with a base to obtain a compound XII. The specific process is as follows:

[0026] Compound X is added to an organic solvent consisting of a mixture of methyl tert-butyl ether and alkaline water, and the reaction is carried out at 50-70°C. Extraction is carried out, and the solvent is replaced with DMF after rotary evaporation at a feed ratio of 1:1.0-1.5. An organic base and a halogenated alkane are added at a feed ratio of 1:2.2-2.8, and the reaction is carried out at 50-70°C. A phosphoric acid aqueous solution is added, and extraction is carried out. The solvent is replaced with methyl isobutyl ketone, ethanol, and an alkaline solution by distillation at 40-50°C under a vacuum degree of ≥0.095 MPa. The feed ratio of compound XI to the base is 1:1.1-1.2, and the reaction is carried out at 30-40°C. Extraction is carried out after rotary evaporation, and the phase is transferred with a sodium chloride aqueous solution. Purification and distillation are carried out, and the solution concentration is controlled at 15-25%. n-heptane is added dropwise, and the mixture is filtered with suction. The filter cake is collected and dried to obtain compound XII.

[0027] The present invention has the following beneficial effects:

[0028] The present invention uses hydrochloric acid when removing the BOC protecting group, thereby avoiding the use of methanesulfonic acid to produce methylsulfonate-type toxic substances and avoiding the risk of producing toxic substances; at the same time, Michaelis acid, a bulk material, is used as the starting material, which is relatively cheap and reduces the material cost, and effectively controls the quality of the intermediate (4), thereby further improving the quality of the API. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the 1H-NMR spectrum of elagolid sodium prepared in an embodiment of the present invention;

[0030] Figure 2 This is the 13C-NM spectrum of elagolid sodium prepared in an embodiment of the present invention;

[0031] Figure 3 HPLC spectrum of elagolid sodium prepared in the examples of the present invention; Figure a is a partial HPLC spectrum, and Figure b is the HPLC spectrum of the remaining retention time, height, peak area, and sealing area %. DETAILED DESCRIPTION

[0032] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed in the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify the contents of the present invention based on the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0033] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0034] Example

[0035] 1: Preparation of Compound IV

[0036] To a reaction flask, add 36.5g of DMF, 14.4g of Michaelis' acid of Compound I, and 5.61g of acetic anhydride. Stir and heat to 50°C. Time the reaction for 3 hours. HPLC analysis indicates a residual of less than 0.5%, allowing the reaction to complete. Add 9.8g of potassium acetate and time the reaction at 50°C for 1 hour. Cool to 10°C and slowly add a mixture of hydrochloric acid and water dropwise. Allow to react for 1 hour until the reaction is complete. Filter to obtain Compound II. Wash the mixture with water (30g) and dry at 50°C.

[0037] Add 46 g of toluene to 18.6 g of compound II, 23.6 g of 1-(2-fluoro-6-(trifluoromethyl)benzyl)urea, 30 g of isopropanol, and 39 g of acetyl chloride, stir and heat to 30°C, time the reaction for 3 hours, and the residue is less than 0.5% by HPLC, until the reaction is complete. Cool to 10°C, filter to obtain compound IV, wash with 30 g of methyl tert-butyl ether, and dry at 50°C.

[0038] The compound yield was 160% and the purity was ≥99.6%.

[0039] 2: Preparation of Compound V

[0040] After anhydrous treatment, 70 g of N,N-dimethylformamide (DMF) and 25 g of EL007 were added to a 250 mL reaction vessel and stirred at room temperature. A total of 22.7 g of iodosuccinimide was added.

[0041] The reaction solution was slowly heated to an internal temperature of 60-90°C. After 5 hours, the EL007 residue was <1.0% under HPLC monitoring. The reaction solution was slowly cooled to 15°C and 25 g of water was added dropwise over a period of about 0.5 hours. After the addition was complete, the mixture was stirred at 15°C. The reaction solution was filtered, and the filter cake was rinsed with methanol each time and dried at 50°C.

[0042] The yield of the obtained compound is 130%, and the purity is ≥98.5%.

[0043] 3: Preparation of Compound VII

[0044] The nitrogen in a 500 mL reaction flask was replaced by vacuum three times, and 18.3 g of KOH, 132 g of water, 130 g of dioxane, 31 g of compound V, 20 g of compound VI, and 12.2 g of phenylphosphine were added. Nitrogen was passed below the liquid surface to remove oxygen for 1.5-2 hours, and 0.6 g of palladium acetate was added.

[0045] The reaction mixture was stirred for 10 minutes, then slowly heated to 55-80°C while continuing to flow nitrogen for 20 minutes. After 2 hours, HPLC monitoring indicated that the residual amount of Compound V was <1.0%. The reaction mixture was rapidly cooled to 15-25°C, filtered, and the reaction vessel heated to 40-50°C until ready for use.

[0046] To a 1000mL reaction flask, add 1g N-acetylcysteine, 94g dioxane, 51g glacial acetic acid, and 32g water. Stir at room temperature until completely dissolved, then heat to 75-85°C. Add the filtrate to be used dropwise to a crystallization jar, controlling the temperature at 75-85°C. Slowly cool to 15°C, maintain the temperature, and grow crystals by stirring. Filter the reaction mixture, and rinse the filter cake with a mixture of methanol and water. Dry at 50°C to obtain Compound VII with an 85% yield and a purity of ≥99.5%.

[0047] 4: Preparation of Compound X

[0048] After anhydrous treatment, add 18g of N,N-dimethylformamide (DMF), 26g of tetramethylguanidine, 27.6g of compound VII, and 49g of compound VIII to a 500mL reaction vessel. Heat to 50°C-65°C and react for 4 hours. HPLC monitoring indicates that the residual ELO10 is <1.0%. Cool to below 40°C, add 8mL of aqueous ammonia to the reaction solution, and stir for 10 minutes. Heat to 50°C-75°C and react for 3 hours. HPLC monitoring indicates that the residual compound VIII is <0.3%. After the reaction is complete, cool the reaction solution to room temperature and stop stirring.

[0049] In a 1000 mL reaction flask, add 216 g of isopropyl acetate, 53 g of phosphoric acid and 166 g of water. Stir the mixed solution for 10 minutes, let it stand for separation, take the organic phase (upper layer) and discard the aqueous layer (lower layer).

[0050] Add 53 g of phosphoric acid and 166 g of water to the organic layer and stir the mixture for 10 minutes. Let it stand for separation, take the organic phase (upper layer) and discard the aqueous layer (lower layer).

[0051] Add 8 g of water to the organic layer and slowly dropwise add 70 mL of 2 M hydrochloric acid, maintaining the temperature below 35°C. The reaction mixture was stirred and insulated for 10 minutes. The temperature was then raised to 50-60°C for 3 hours. HPLC monitoring indicated a residual compound IX of <1.5%. Upon completion of the reaction, the temperature was lowered to room temperature.

[0052] Add a mixture of 41g potassium phosphate and 255g water. Transfer 500mL of the reaction mixture to a 1000mL extraction kettle and stir for 10 minutes. Allow to stand and separate, remove the organic phase (upper layer), and discard the aqueous layer (lower layer). Add a mixture of 41g potassium phosphate and 255g water to the organic phase and stir for 10 minutes. Allow to stand and separate, remove the organic phase (upper layer), and discard the aqueous layer (lower layer).

[0053] The organic phase was concentrated to dryness under reduced pressure, and 209 g of methanol was added and evaporated to dryness. 192 g of methanol was added and dissolved completely. The reaction solution was heated to 40-50°C, and 9.5 g of salicylic acid and 22 g of water were added. The reaction solution was kept warm and reacted for 4 hours. The temperature was slowly lowered to 15°C, and 79 g of water was added dropwise over a period of about 1 hour. After the addition was complete, the mixture was kept warm and stirred for 1 hour. Filtered with suction, the filter cake was washed with a mixture of methanol and water, and dried at 50°C to obtain compound (10) with a yield of 145% and a purity of ≥97.5%.

[0054] 5. Preparation of Compound XII

[0055] To a 1000 mL reactor, add 221 g of methyl tert-butyl ether, 125 g of water, 8.5 g of NaOH, and 38.5 g of Compound X. Heat the reaction mixture to 50°C-70°C and react for 3 hours. Cool to room temperature, allow to stand, and separate. Discard the organic phase (upper layer) and the aqueous layer (lower layer).

[0056] The organic phase was concentrated to dryness under reduced pressure, and 39 g of DMF was added to dissolve the mixture completely. Then, 10.5 g of diisopropylethylamine and 27.5 g of ethyl 4-bromobutyrate were added. The reaction mixture was heated to 50°C-70°C and allowed to react for 5 hours. HPLC monitoring revealed that the residual amount of Compound X was <1.0%. After the reaction was complete, the mixture was cooled to room temperature, 209 g of methyl tert-butyl ether and 251 g of water were added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand for separation, and the organic phase (upper layer) was collected and the aqueous layer (lower layer) was discarded.

[0057] The organic phase was washed twice with 192 g of water, each time stirring for 10 minutes, allowed to stand for separation, and the organic phase (upper layer) was collected, while the aqueous layer (lower layer) was discarded. A mixed solution of 18 g of phosphoric acid and 242 g of water was added, stirred for 10 minutes, allowed to stand for separation, and the aqueous phase (lower layer) was collected, while the organic phase (upper layer) was discarded. The aqueous phase was washed twice with 209 g of methyl tert-butyl ether, each time stirring for 10 minutes, allowed to stand for separation, and the aqueous phase (lower layer) was collected, while the organic phase (upper layer) was discarded. HPLC analysis showed that the residual amount of compound (10) was <0.15%. A mixed solution of 227 g of methyl isobutyl ketone, 53 g of potassium phosphate, and 106 g of water was added to the aqueous phase, stirred for 10 minutes, allowed to stand for separation, and the organic phase (upper layer) was collected, while the aqueous layer (lower layer) was discarded.

[0058] 170 g of ethanol, 39 g of water and 7 g of NaOH solution were added to the organic phase. The reaction solution was heated to 30-40°C and reacted for 3 hours. HPLC analysis showed that the residual compound XI was <0.5%.

[0059] The reaction solution was concentrated to dryness under reduced pressure, 86 g of methyl isobutyl ketone and 169 g of water were added, stirred for 10 minutes, allowed to stand for separation, the aqueous phase (lower layer) was taken, and the organic phase (upper layer) was discarded. 167 g of methyl isobutyl ketone was added to the aqueous phase, stirred for 10 minutes, allowed to stand for separation, the aqueous phase (lower layer) was taken, and the organic phase (upper layer) was discarded.

[0060] Add 238g of methyl isobutyl ketone and 63.5g of sodium chloride to the aqueous phase. Stir for 10 minutes, let stand and separate the liquids. Take the organic phase (upper layer) and discard the aqueous layer (lower layer).

[0061] The organic phase was washed twice with 126 g of water and 25 g of sodium chloride solution each time, stirred for 10 minutes, allowed to stand and separate, and the organic phase (upper layer) was taken and the aqueous layer (lower layer) was discarded.

[0062] The reaction mixture was concentrated under reduced pressure, and 105 g of methyl isobutyl ketone (MIBK) was added, stirred, and dissolved. The mixture was evaporated to dryness, and another 105 g of MIBK was added and evaporated to dryness. The mixture was back-gassed under nitrogen, and 80 g of MIBK was added until completely dissolved. The filtrate was measured for moisture content of <0.35%. Under nitrogen protection, the reaction mixture was cooled to 10-20°C. Filtered, the filter cake was washed with 5 g of MIBK, and the external standard content (20%) was measured. The amount of n-heptane used was 0.7 times that of MIBK. The reaction mixture was added dropwise to the n-heptane, and the crystals were grown at 15°C for 1 hour. Filtered and statically dried at 60°C to obtain Compound XII with a yield of 65% and a purity of ≥99.8%.

[0063] The 1H-NMR spectrum of elagolid sodium is as follows Figure 1 As shown, 1H NMR (DMSO-D6): δ 1.43-1.45 (d, 2H), 1.78 (s, 2H), 2.08 (s, 3H), 2.19-2.27 (m, 2H), 3.88 (s, 3H), 3.95 (m, 3H), 5.33 (s, 2H), 6.59-6.62 (m, 1H), 7.1-7.25 (m, 7H), 7.56-7.66 (m, 3H).

[0064] The 13C-NMR spectrum of elagolid sodium is as follows Figure 2 shown

[0065] HPLC spectrum Figure 3 As shown by Figure 3 It can be concluded that the purity is ≥99.8%.

[0066] The molecular formula of compound IV is C 13 H 10 F4N2O2, the structural formula is Compound V has the molecular formula C 13 H9F4IN2O2, the structural formula is Compound VII has the molecular formula C 20 H 15 F5N2O3, the structural formula is Compound X has the molecular formula C 35 H 30 F5N3O6, the structural formula is The molecular formula of compound Ⅻ is C 32 H 29F5N3NaO5, the structural formula is

Claims

1. A method for preparing elagolid sodium and its intermediates, characterized in that It is carried out as follows: 1) Adding compound I and acid anhydride into an organic solvent to react to obtain compound II; 2) adding compound II, compound III and acyl chloride into an organic solvent to react to obtain compound IV; 3) adding compound IV and iodide to an organic reagent to react to obtain compound V; 4) adding compound V and compound VI to an organic reagent, and subjecting the mixture to a catalytic reaction to obtain compound VII; 5) Compound VII and Compound VIII are added to an organic reagent for substitution reaction, then reacted with an acid to remove the protecting group, and then reacted with an organic acid to form a salt to obtain Compound X; 6) Compound X and halogenated alkane are added to an organic reagent for substitution reaction to obtain compound XI, which is then hydrolyzed with a base to obtain compound XII, i.e., elagolid sodium; The molecular formula of compound I is C6H8O4, and the molecular formula of compound II is C8H 10 O5, the molecular formula of compound III is C9H8F4N2O, and the molecular formula of compound IV is C 13 H 10 F4N2O2, compound V has the molecular formula C 13 H9F4IN2O2, the molecular formula of compound VI is C7H8BFO3, and the molecular formula of compound VII is C 20 H 15 F5N2O3, compound VIII has the molecular formula C 14 H 21 NO5S, compound X has the molecular formula C 35 H 30 F5N3O6, compound XI has the molecular formula C 34 H 34 F5N3O5, compound Ⅻ has the molecular formula C 32 H 29 F5N3NaO5.

2. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The organic solvent described in step 1) is DMF, DMSO or THF; the organic solvent in step 2) is isopropanol or n-butanol; the organic reagent described in step 3) is DMF; the organic reagent in step 4) is a mixed solution of dioxane and alkaline water, and the mixing ratio of dioxane to water and alkali is 7-8:7-8:1; the organic reagent in step 5) is DMF; the organic reagent in step 6) is a mixed solution of methyl tert-butyl ether and alkaline water, and the mixing ratio of methyl tert-butyl ether to water and alkaline water is 23-29:13-17:

1.

3. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that Step 1) The acid anhydride described in the method is acetic anhydride, and the molar ratio of compound I to acetic anhydride is 1:1.1-1.6; the feed ratio of compound I to organic solvent is 1:5-10.

4. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The acyl chloride in step 2) is acetyl chloride, the molar ratio of compound II, compound III and acyl chloride is 1:1.2-1.4:2.1-2.3, and the feed ratio of compound II to organic solvent is 1:5-8.

5. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The molar ratio of compound IV to iodosuccinimide in step 3) is 1:1.1-1.5; the feed ratio of compound IV to organic solvent is 1:3-5.

6. The method for preparing elagolid sodium and its intermediates according to claim 1 or 5, characterized in that The compound IV and the iodide described in step 3) are added to the organic reagent under the following reaction conditions: react at 60-100°C for 2-4 hours, cool to 10-20°C, add water dropwise, grow crystals for 2-4 hours, filter with suction, rinse with water, collect the filter cake, and dry to obtain compound V.

7. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The molar ratio of compound V to compound VI in step 4) is 1:1.2-1.7, and the feed ratio of compound V to organic solvent is 1:4-6.

8. The method for preparing elagolid sodium and its intermediates according to claim 1 or 7, characterized in that In step 4), compound V and compound VI are added to an organic reagent and subjected to a catalytic reaction to obtain compound VII. The reaction conditions are: Compound V and compound VI are added to an organic reagent, and a ligand phenylphosphine is added. After oxygen is removed, a catalyst palladium acetate is added. After a condensation reaction is carried out at 55-80° C. with stirring for 2-4 hours, a mixture of glacial acetic acid and dioxane is added as a crystallization liquid, and crystallization is carried out at 75-85° C. The mixture is filtered, rinsed with a mixture of methanol and water, the filter cake is collected, and dried to obtain compound VII.

9. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The compound VII and compound VIII described in step 5) are added to an organic reagent for substitution reaction to obtain compound IX, which is then reacted with an inorganic acid to remove the protecting group, and then reacted with an organic acid to form a salt to obtain compound X. The reaction conditions are: Compound VII and compound VIII are added to an organic solvent DMF, the feed ratio of compound VII to the organic solvent is 1:0.5-1.5, a condensation reaction is carried out at 50-65°C, after the reaction is completed, ammonia water is added at a feed ratio of 1:3.0-3.5, esterification reaction is carried out at 50-75°C, isopropyl acetate is added after the reaction is completed, an inorganic acid aqueous solution is extracted, and then an inorganic acid is added at a feed ratio of 1:2.5-3.5, 45-65°C for deprotection reaction, and an inorganic base aqueous solution is extracted, 40-50°C, vacuum degree ≥0.095MPa, after rotary evaporation, the organic phase is replaced with a methanol solution, an organic acid is added at a feed ratio of 1:1.0-1.2 for salt formation, the temperature is lowered to 5°C-15°C for secondary crystallization, suction filtration is performed, the filter cake is collected, and drying is performed to obtain compound X; the molar ratio of compound VII to compound VIII is 1:2.0-3.

0.

10. The method for preparing elagolid sodium and its intermediates according to claim 1, characterized in that The compound X described in step 6) and the halogenated alkane are added to an organic reagent, and a substitution reaction is performed to obtain a compound XI, which is then hydrolyzed with a base to obtain a compound XII. The specific process is as follows: Compound X is added to an organic solvent composed of a mixture of methyl tert-butyl ether and alkaline water, reacted at 50-70°C, extracted, and replaced the solvent with DMF after rotary evaporation at a feed ratio of 1:1.0-1.5, and an organic base and a halogenated alkane are added at a feed ratio of 1:2.2-2.8, reacted at 50-70°C, phosphoric acid aqueous solution were added, extracted, and distilled at 40-50°C with a vacuum degree of ≥0.095MPa, and the solvent was replaced with methyl isobutyl ketone and ethanol, and an alkaline solution: the feed ratio of compound XI to the base was 1:1.1-1.2, reacted at 30-40°C, extracted after rotary evaporation, phase-transferred with sodium chloride aqueous solution, purified, distilled, the solution concentration was controlled at 15-25%, n-heptane was added dropwise, filtered, the filter cake was collected, and dried to obtain compound XII.

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