Preparation method and intermediate of rerugolix

Abstract

The invention relates to a preparation method and an intermediate of rerugolix. The method comprises the following steps: 1) carrying out bromination, amination, reduction, urea formation and hydrolysis reaction on a compound I to obtain a compound VI; (2) carrying out condensation reaction on the compound VI and 3-amino-6-methoxypyridazine hydrochloride to obtain a compound VII; 3) hydrolyzing the compound VII to obtain a compound VIII; 4) carrying out reductive amination reaction on the compound VIII and 2, 6-difluorobenzaldehyde to obtain a compound IX; and (5) carrying out ring closing reaction on the compound IX and carbonyl diimidazole to obtain the relugolix. The preparation method is convenient to operate, high in purity and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of relugolix and an intermediate thereof. Background Art

[0002] Relugolix, with CAS number 737789-87-6, is a new drug jointly developed by Myovant and Takeda. It is a small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist and is used for indications such as uterine fibroids, endometriosis, and prostate cancer. The reported synthetic route methods for this compound are as follows:

[0003] Patent CN104703992B discloses a synthetic route. Using ethyl 2-[(2,6-difluorobenzyl)ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate as the starting material, relugolix is obtained through seven steps of reactions including bromination, alkylation with dimethylamine, hydrolysis, condensation, ring closure, hydrogenation reduction, and urea formation. The synthetic route is as follows:

[0004]

[0005] In this method, the reduction step requires a hydrogenation reaction, with harsh reaction conditions and high requirements for equipment. Moreover, in the last step of urea formation, the generated biuret impurities are difficult to remove by purification, which affects the product quality.

[0006] Patents CN110194776A and CN111423452B disclose a preparation method of relugolix. After multiple steps of reactions, intermediate 6 is obtained. Then, intermediate 6 undergoes bromination, alkylation with dimethylamine, hydrogenation reduction, and urea formation to obtain relugolix. The generation of biuret impurities cannot be avoided in the last step of this method. The preparation method is as follows:

[0007]

[0008] Patent CN111333633A discloses a method for preparing relugolix. The structure of urea is introduced in the earlier steps, and relugolix is obtained through subsequent multiple steps of reactions. Biuret impurities are not detected in the product, but column chromatography technology is used in the purification of the key intermediate G, which brings certain difficulties to industrial production. The last step of ring closure is carried out under high-temperature conditions with methanol and sodium methoxide reagents, and the conditions are relatively harsh. The preparation method is as follows:

[0009]

[0010] Patent CN109983017B discloses another method for preparing relugolix. In the process of preparing intermediate III, quaternary ammonium salt impurities are inevitably generated, and these impurities are difficult to remove. The preparation route is as follows:

[0011] SUMMARY OF THE INVENTION

[0012] The object of the present invention is to develop a new preparation method of relugolix and its intermediates. This method has mild reaction conditions, low equipment requirements, convenient operation, easy purification of the product, high purity, and is conducive to industrial production.

[0013] The present invention provides a preparation method of relugolix, which is characterized in that it is prepared by condensation reaction of compound of formula IX with N,N-carbonyldiimidazole in an organic solvent under the action of a base. The steps are as follows:

[0014]

[0015] The organic solvent is selected from acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, and preferably acetonitrile;

[0016] The base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, sodium methoxide, diisopropylethylamine, and preferably sodium methoxide or sodium hydroxide;

[0017] The temperature of the condensation reaction is 20-80°C, preferably 30-50°C;

[0018] Specifically, dissolve compound IX in the organic solvent, add N,N-carbonyldiimidazole and the base, stir the mixture, and react at 30-50°C for 5-8 hours; it may further include a post-treatment step: add water to the reaction solution, stir for crystallization, filter the mixture, dissolve the filter cake in dimethyl sulfoxide, add ethanol to the above solution for crystallization, filter the mixture, and dry.

[0019] The preparation method as described above is characterized in that the compound of formula IX is prepared by reductive amination reaction of compound VIII with 2,6-difluorobenzaldehyde in an organic solvent under the action of a reducing agent and a catalyst. The steps are as follows:

[0020]

[0021] The organic solvent is selected from methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and preferably methanol or ethanol;

[0022] The catalyst is selected from sulfuric acid, hydrogen chloride, phosphoric acid, formic acid, acetic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, citric acid, malic acid, oxalic acid, and preferably acetic acid, p-toluenesulfonic acid;

[0023] The reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride, sodium cyanoborohydride;

[0024] The reaction temperature of the reductive amination reaction is 0 - 80 °C, preferably 30 - 40 °C;

[0025] Specifically, dissolve compound VIII in an organic solvent, add 2,6-difluorobenzaldehyde and a catalyst, stir the mixture, then add the reducing agent, and react for 3 - 5 hours; A post-treatment step may further be included: add an acid to the reaction solution to adjust the pH for crystallization, filter to obtain a solid, dissolve the solid in an organic solvent by heating, cool down for crystallization, filter, and dry; The acid is preferably 2M hydrochloric acid; The pH is preferably 6 - 7; The organic solvent is preferably ethanol.

[0026] The preparation method as described above is characterized in that compound VIII is prepared by reacting compound VII with an acid in an organic solvent, and the steps are as follows:

[0027]

[0028] Wherein R1 in formula VII is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; The preferred R1 is tert-butoxycarbonyl;

[0029] The organic solvent is selected from methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, preferably dichloromethane or ethanol;

[0030] The acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, preferably hydrochloric acid or trifluoroacetic acid;

[0031] The reaction temperature of the reaction is 0 - 80 °C, preferably 10 - 30 °C;

[0032] Specifically, dissolve compound VII in an organic solvent, stir the mixture, then add the acid, and react for 1 - 2 hours; A post-treatment step may further be included: filter the reaction mixture to obtain a light yellow solid, disperse the solid by stirring with a solvent, adjust the pH to 8 - 9 with a base, filter, crystallize the filtrate with an organic solvent, filter, and dry; The solid dispersion solvent is preferably ethanol; The base is preferably one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, more preferably sodium bicarbonate; The crystallization solvent is preferably n-heptane or methyl tert-butyl ether.

[0033] The preparation method as described above is characterized in that compound VII is prepared by a condensation reaction of compound VI with 3-amino-6-methoxypyridazine hydrochloride in an organic solvent under the action of a condensing agent and an organic base, and the steps are as follows;

[0034]

[0035] Among them, R1 in Formula VII and Formula VI is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl; preferably, R1 is tert-butoxycarbonyl;

[0036] The condensing agent is selected from dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, propylphosphoric anhydride, preferably O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or propylphosphoric anhydride;

[0037] The organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide;

[0038] The organic base is selected from diisopropylethylamine, triethylamine, pyridine, piperidine, N-methylmorpholine, piperazine, preferably diisopropylethylamine;

[0039] The reaction temperature is 20 - 80 °C, preferably 25 - 35 °C;

[0040] Specifically, dissolve Compound VI in an organic solvent, stir the mixture to dissolve it, add 3-amino-6-methoxypyridazine hydrochloride, a condensing agent, and a base, stir the mixture, and react at 25 - 35 °C for 3 - 5 hours; it may further include a post-treatment step: add an aqueous solution of an inorganic base to the reaction solution for crystallization, filter and dry the mixture; the inorganic base is preferably sodium hydroxide.

[0041] The preparation method as described above is characterized in that Compound VI of the formula is prepared by the following steps:

[0042] (1) Compound I undergoes a bromination reaction with a bromine reagent in an organic solvent in the presence of an initiator to form Compound II;

[0043] (2) Compound II undergoes a condensation reaction with dimethylamine in an organic solvent under the action of a base to form Compound III;

[0044] (3) Compound III undergoes a reduction reaction in an organic solvent under the action of iron powder / ammonium chloride to form Compound IV;

[0045] (4) Compound IV undergoes a condensation reaction with N,N-carbonyldiimidazole and methoxylamine hydrochloride in an organic solvent in the presence of a base to form Compound V;

[0046] (5) Compound V undergoes a hydrolysis reaction in an organic solvent under basic conditions to form Compound VI;

[0047]

[0048] Wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably, R1 is tert-butoxycarbonyl;

[0049] In the step (1), the organic solvent is selected from dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, chlorobenzene, preferably dichloromethane or chloroform; the bromine reagent is selected from N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, preferably N-bromosuccinimide; the initiator is selected from azobisisobutyronitrile, benzoyl peroxide, preferably azobisisobutyronitrile; the reaction temperature of the bromination reaction is 10-80 °C, preferably 20-30 °C;

[0050] The step (1) includes: dissolving Compound I in an organic solvent, stirring the mixture to dissolve, adding an initiator and a bromination reagent, stirring the mixture, and reacting at 20-30 °C for 5-8 hours; it may further include a post-treatment step: adding a sodium thiosulfate solution to the reaction solution, separating the layers, and concentrating the organic phase under reduced pressure;

[0051] In the step (2), the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide; the base is selected from organic bases, preferably triethylamine, diisopropylethylamine, pyridine, piperidine, N,N-dimethylaminopyridine, morpholine, N-methylmorpholine, more preferably triethylamine or diisopropylethylamine; the reaction temperature of the condensation reaction is 25-40 °C, preferably 25-35 °C;

[0052] The step (2) includes: dissolving Compound II in an organic solvent, stirring the mixture to dissolve, adding dimethylamine hydrochloride and a base, stirring the mixture, and reacting at 25-35 °C for 3-5 hours; it may further include a post-treatment step: adding water and ethyl acetate to the reaction solution, separating the layers, and concentrating the organic phase under reduced pressure;

[0053] In the step (3), the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, preferably methanol or ethanol; the reaction temperature of the reduction reaction is 20-60 °C, preferably 30-40 °C;

[0054] The step (3) includes: dissolving Compound III in an organic solvent, stirring the mixture to dissolve, adding iron powder and an ammonium chloride solution, stirring the mixture, and reacting at 30-40 °C for 2-5 hours; it may further include a post-treatment step: filtering the reaction mixture and concentrating the filtrate;

[0055] In step (4), the organic solvent is selected from acetonitrile, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetonitrile or N,N-dimethylformamide; the base is selected from potassium carbonate, sodium carbonate, diisopropylethylamine, triethylamine, N-methylmorpholine, preferably diisopropylethylamine; the reaction temperature of the condensation reaction is 25-85°C, preferably 65-75°C;

[0056] Step (4) includes: dissolving compound IV in an organic solvent, stirring the mixture to dissolve, adding N,N-carbonyldiimidazole, a base, and methoxyamine hydrochloride, stirring the mixture, and heating to 65-75°C for reaction for 2-5 hours; it may further include a post-treatment step: adding water and ethyl acetate to the reaction mixture with stirring, standing for liquid separation, separating the liquid, and concentrating the organic phase;

[0057] In step (5), the organic solvent is selected from methanol, ethanol, tetrahydrofuran, acetonitrile, preferably methanol or ethanol; the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium hydroxide, lithium hydroxide; the reaction temperature of the hydrolysis reaction is 20-80°C, preferably 60-80°C;

[0058] Step (5) includes: dissolving compound V in an organic solvent, adding a base, and heating to 60-80°C for reaction for 1-3 hours; it may further include a post-treatment step: concentrating the reaction mixture, dissolving in water, extracting with an extraction solvent, adjusting the pH of the aqueous phase with an acid, stirring for crystallization, filtering, washing, and drying; the extraction solvent is dichloromethane; the acid is sodium hydrogen phosphate-citric acid buffer solution; the pH value is 6.0-6.5.

[0059] The present invention provides a preparation method of relugolix, which is characterized by comprising the following steps:

[0060]

[0061] Wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

[0062] The present invention also provides the following compounds of formula VI, VII, VIII or their salts:

[0063]

[0064]

[0065] Wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

[0066] The present invention also provides the use of compounds of formula VI, VII, and VIII for the preparation of relugolix and its salts, derivatives, or analogs.

[0067] Advantageous technical effects of the present invention:

[0068] (1) The present invention provides a new method for preparing relugolix and intermediates.

[0069] (2) The present invention provides completely new relugolix intermediate compounds of formula VI, VII, and VIII, which can be used to prepare relugolix and its salts or analogs. The preparation method of the completely new intermediates is simple, convenient to operate, and has high purity, being suitable for industrial production.

[0070] (3) In the relugolix preparation method provided by the present invention, the structure of urea is introduced into compound V. After multiple subsequent steps, the biuret impurities are removed relatively thoroughly, and no biuret impurities are detected in relugolix. The yields of each step are relatively high, and the total yield is relatively high. Description of the Drawings

[0071] Figure 1 : HPLC detection and analysis chromatogram of the purity of relugolix in Example 9;

[0072] Figure 2 : HPLC liquid phase localization chromatogram of biuret impurity SN in Example 9. Detailed Embodiments

[0073] The following is a further detailed description of the above content of the present invention through specific embodiments, but this should not be construed as any limitation to the protection subject matter of the present invention. All technical solutions implemented based on the above content of the present invention fall within the scope of the present invention. The present invention generally and / or specifically describes the materials and test methods used in the experiments. Those skilled in the art are aware that, hereinafter, if not otherwise specified, the operations carried out in the present invention are carried out under the conventional room temperature conditions in the art, and the term "room temperature" has the technical meaning known in the art, generally referring to 10 - 30 °C, preferably 15 - 25 °C, and more preferably 20 - 25 °C.

[0074] Example 1: Preparation of Compound of Formula II

[0075]

[0076] 121.8 g of the compound of formula I, 605 ml of dichloromethane, 53.4 g of N-bromosuccinimide, and 4.9 g of azobisisobutyronitrile were successively added to a reaction flask, and the mixture was stirred and reacted at 20 - 30 °C for 5 hours. Then, 60 ml of saturated sodium thiosulfate solution was added for washing, and the layers were separated. The organic phase was concentrated under reduced pressure to obtain an oily substance, which was directly used in the next step of the reaction.

[0077] Example 2: Preparation of Compound of Formula III

[0078]

[0079] To the reaction flask were successively added the compound II concentrate of Example 1, 610 ml of N,N-dimethylformamide, 24.5 g of dimethylamine hydrochloride, and the mixture was stirred at 30 °C for 10 minutes. Then 32.8 g of triethylamine was added, and the reaction system was stirred at 30 °C for 3 h. Then 610 ml of water and 610 ml of ethyl acetate were added, and stirring was continued for 30 minutes. The layers were separated, and the organic phase was washed once with 610 ml of water. The organic phase was concentrated to obtain an oily substance, which was directly used for the next reaction.

[0080] Example 3: Preparation of Compound of Formula IV

[0081]

[0082] To the reaction flask were successively added the compound III concentrate of Example 2, 610 ml of ethanol, and stirring was started. Then 62.1 g of iron powder was added, and the temperature was raised to 35 °C and stirred for 10 minutes. A 100 g (20%) aqueous ammonium chloride solution was added dropwise. After the addition was complete, the mixture was stirred at 35 °C for 3 h, filtered, and the organic phase was concentrated under reduced pressure to obtain an oily substance, which was directly used for the next reaction.

[0083] Example 4: Preparation of Compound of Formula V

[0084]

[0085] To the reaction flask were successively added 610 ml of acetonitrile, 19.2 g of methoxyamine hydrochloride, 34.2 g of carbonyldiimidazole, and 19.4 g of triethylamine. The mixture was stirred at 20 °C for 1 h, and then the compound IV concentrate of Example 3 was added in portions. The temperature was raised to 70 °C and stirred at 70 °C for 4 h. The temperature was then lowered to room temperature, 300 ml of purified water and 610 ml of ethyl acetate were added, and stirring was continued for 30 minutes. The layers were separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance, which was directly used for the next reaction.

[0086] Example 5: Preparation of Compound of Formula VI

[0087]

[0088] To the reaction flask were successively added the compound IV concentrate of Example 4, 610 ml of ethanol, and the mixture was stirred until dissolved. A 62 g 30% aqueous sodium hydroxide solution was added dropwise. After the addition was complete, the temperature was raised to 70 °C and stirred at 70 °C for 2 h. The temperature was then lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution was diluted with 300 ml of water, extracted with dichloromethane, and the layers were separated. The aqueous phase was adjusted to a pH value of 6.0 - 6.5 with a disodium hydrogen phosphate-citric acid buffer solution, stirred for 30 minutes, filtered, and the filter cake was washed with 150 ml of water. The filter cake was dried to obtain 101.9 g of a white solid, and the total yield of the five steps was 79.1%.

[0089] 1 H-NMR (DMSO-d6, 600 MHz) δ: 1.486 (s, 9H), 2.577 (s, 6H), 3.635 (s, 3H), 4.002 (s, 2H), 7.261 - 7.276 (dd, 2H), 7.710 - 7.724 (dd, 2H), 9.084 (s, 1H), 9.622 (s, 1H), 12.389 (s, 1H), 15.061 (brs, 1H).

[0090] Example 6: Preparation of Compound VII

[0091]

[0092] 60 g of Compound VI, 25.0 g of 3-amino-6-methoxypyridazine hydrochloride, and 300 ml of N,N-dimethylformamide were successively added to a reaction flask, stirred and dissolved. 41.6 g of diisopropylethylamine was added, and the temperature was raised to 30 °C. 1-Propylphosphonic anhydride was added dropwise. After completion of the dropwise addition, the reaction was kept at a constant temperature for 4 h. Then the reaction solution was added dropwise to 300 ml of 3N aqueous sodium hydroxide solution. After completion of the dropwise addition, it was stirred for 30 minutes, filtered, and the filter cake was washed with 300 ml of water. The filter cake was dried to obtain 65.9 g of a white solid, with a yield of 98.4%.

[0093] 1 H-NMR (DMSO-d6, 600 MHz) δ: 1.497 (s, 9H), 2.221 (s, 6H), 3.563 (s, 2H), 3.643 (s, 3H), 4.011 (s, 3H), 7.254 - 7.270 (d, 1H), 7.288 - 7.303 (dd, 2H), 7.709 - 7.724 (dd, 2H), 8.386 - 8.407 (m, 1H), 9.075 (s, 1H), 9.626 (s, 1H), 11.194 (s, 1H), 14.987 (s, 1H).

[0094] Example 7: Preparation of Compound VIII

[0095]

[0096] 480 ml of ethanol and 60.0 g of Compound VII were successively added to a reaction flask, stirred and dissolved. 20 ml of concentrated hydrochloric acid was added dropwise. After stirring and reacting for 2 h, the reaction system was filtered. The filter cake was dispersed with 300 ml of ethanol, and the pH was adjusted to 8 - 9 with sodium bicarbonate. Then it was filtered, and the filtrate was crystallized with 300 ml of methyl tert-butyl ether. After filtration, the filter cake was dried to obtain 48 g of a white solid, with a yield of 97.0%.

[0097] 11H-NMR (DMSO-d6, 600 MHz) δ: 2.213 (s, 6H), 3.442 (s, 2H), 3.636 (s, 3H), 3.974 (s, 3H), 7.198 - 7.214 (d, 1H), 7.226 - 7.241 (dd, 2H), 7.654 - 7.668 (dd, 4H), 8.362 - 8.378 (d, 1H), 9.023 (s, 1H), 9.590 (s, 1H), 14.122 (s, 1H).

[0098] Example 8: Preparation of Compound IX

[0099]

[0100] Add 400 ml of methanol, 20.6 g of Compound VIII, and 6.8 g of 2,6-difluorobenzaldehyde to the reaction flask in sequence. While stirring, add 5.0 g of acetic acid dropwise. Heat up to 35 °C and stir at 35 °C for 1 h. Then add 18.5 g of sodium triacetoxyborohydride and stir at the same temperature for 4 h. Adjust the pH to 6 - 7 with 2 N hydrochloric acid, filter, and concentrate the filtrate to obtain a light yellow solid. Add 100 ml of ethanol to the light yellow solid, stir and heat up to 80 °C to dissolve, then cool down to 5 °C for crystallization. Filter, wash the filter cake with 20 ml of cold ethanol, and dry the filter cake to obtain 22.9 g of a white solid with a yield of 87.8%.

[0101] 1 1H-NMR (DMSO-d6, 600 MHz) δ: 2.208 (s, 6H), 3.457 (s, 2H), 3.642 (s, 3H), 3.974 (s, 3H), 4.524 - 4.534 (d, 2H), 7.140 - 7.196 (m, 3H), 7.236 - 7.250 (d, 2H), 7.427 - 7.477 (m, 1H), 7.674 - 7.688 (d, 2H), 7.326 - 7.342 (d, 1H), 8.974 - 8.995 (m, 1H), 9.044 (s, 1H), 9.603 (s, 1H), 14.270 (s, 1H).

[0102] Example 9: Preparation of Relugolix

[0103]

[0104] Add 150 ml of acetonitrile, 15.2 g of the compound of formula IX, 4.9 g of carbonyldiimidazole, and 4.9 g of diisopropylethylamine to the reaction flask. Stir and heat up, and keep the reaction at 50 °C for 6 hours. Cool the reaction solution to room temperature, add 100 ml of purified water to the reaction system for crystallization for 1 hour, filter, dissolve the filter cake in 10 ml of dimethyl sulfoxide, and add 50 ml of ethanol for crystallization. Filter, and dry the filter cake to obtain 14.3 g of relugolix product, with a yield of 90.2%, a purity of 99.60%, a maximum single impurity of 0.09%, and no biuret impurity SN (the impurity at 23.566 min) detected.

[0105] HPLC detection and analysis of Example 9:

[0106] The HPLC detection and analysis chromatogram of the relugolix purity in Example 9 is shown in Figure 1 , and the HPLC liquid phase localization chromatogram of the biuret impurity SN in Example 9 is shown in Figure 2 , and the analysis method is as follows:

[0107] Chromatographic column: Octadecylsilyl silica gel as the filler (YMC-Pack ODS AQ, 4.6 mm × 150 mm, 3 μm or a chromatographic column with equivalent efficiency)

[0108] Mobile phase A: Aqueous solution of 0.05% trifluoroacetic acid

[0109] Mobile phase B: Acetonitrile solution of 0.02% trifluoroacetic acid

[0110]

[0111] Detection wavelength: 250 nm

[0112] Flow rate: 1.0 ml / min

[0113] Column temperature: 30 °C

[0114] Injector temperature: 15 °C

[0115] Injection volume: 10 μl.

Claims

1. A preparation method of relugolix, characterized in that, it is prepared by carrying out a condensation reaction of compound of formula IX with N,N-carbonyldiimidazole in an organic solvent under the action of a base, and the steps are as follows:

2. The preparation method according to claim 1, wherein the organic solvent is selected from acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, preferably acetonitrile; the base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, sodium methoxide, diisopropylethylamine, preferably sodium methoxide or sodium hydroxide; the temperature of the condensation reaction is 20-80 °C, preferably 30-50 °C.

3. The preparation method according to claim 1, characterized in that, the compound of formula IX is prepared by carrying out a reductive amination reaction of compound VIII with 2,6-difluorobenzaldehyde in an organic solvent under the action of a reducing agent and a catalyst, and the steps are as follows:

4. The preparation method according to claim 3, wherein the organic solvent is selected from methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, preferably methanol or ethanol; the catalyst is selected from sulfuric acid, hydrogen chloride, phosphoric acid, formic acid, acetic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, citric acid, malic acid, oxalic acid, preferably acetic acid, p-toluenesulfonic acid; the reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride, sodium cyanoborohydride; the reaction temperature of the reductive amination reaction is 0-80 °C, preferably 30-40 °C.

5. The preparation method according to claim 3, characterized in that, the compound VIII is prepared by reacting compound VII with an acid in an organic solvent, and the steps are as follows: wherein R1 in formula VII is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

6. The preparation method according to claim 5, wherein the organic solvent is selected from methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, preferably dichloromethane or ethanol; the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, preferably hydrochloric acid or trifluoroacetic acid; the reaction temperature of the reaction is 0-80 °C, preferably 10-30 °C.

7. The preparation method according to claim 5, characterized in that, the compound of formula VII is prepared by carrying out a condensation reaction of compound VI with 3-amino-6-methoxypyridazine hydrochloride in an organic solvent under the action of a condensing agent and an organic base, and the steps are as follows; wherein R1 in formula VII and formula VI is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

8. The preparation method according to claim 7, wherein the condensing agent is selected from dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate, propylphosphonic anhydride, preferably O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or propylphosphonic anhydride; the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide; the organic base is selected from diisopropylethylamine, triethylamine, pyridine, piperidine, N-methylmorpholine, piperazine, preferably diisopropylethylamine; the reaction temperature is 20 - 80 °C, preferably 25 - 35 °C.

9. The preparation method according to claim 7, characterized in that, the compound of formula VI is prepared by the following steps: (1) Compound I undergoes a bromination reaction with a bromine reagent in an organic solvent in the presence of an initiator to form Compound II; (2) Compound II undergoes a condensation reaction with dimethylamine in an organic solvent under the action of a base to form Compound III; (3) Compound III undergoes a reduction reaction in an organic solvent under the action of iron powder / ammonium chloride to form Compound IV; (4) Compound IV undergoes a condensation reaction with N,N-carbonyldiimidazole and methoxylamine hydrochloride in an organic solvent in the presence of a base to form Compound V; (5) Compound V undergoes a hydrolysis reaction in an organic solvent under basic conditions to form Compound VI; wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

10. The preparation method according to claim 9, wherein in step (1), the organic solvent is selected from dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, chlorobenzene, preferably dichloromethane or chloroform; the bromine reagent is selected from N-bromosuccinimide, dibromo hydantoin, preferably N-bromosuccinimide; the initiator is selected from azobisisobutyronitrile, benzoyl peroxide, preferably azobisisobutyronitrile; the reaction temperature of the bromination reaction is 10 - 80 °C, preferably 20 - 30 °C; in step (2), the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide; the base is selected from organic bases, preferably triethylamine, diisopropylethylamine, pyridine, piperidine, N,N-dimethylaminopyridine, morpholine, N-methylmorpholine, more preferably triethylamine or diisopropylethylamine; the reaction temperature of the condensation reaction is 25 - 40 °C, preferably 25 - 35 °C; in step (3), the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, preferably methanol or ethanol; the reaction temperature of the reduction reaction is 20 - 60 °C, preferably 30 - 40 °C; The organic solvent in step (4) is selected from acetonitrile, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetonitrile or N,N-dimethylformamide; the base is selected from potassium carbonate, sodium carbonate, diisopropylethylamine, triethylamine, N-methylmorpholine, preferably diisopropylethylamine; the reaction temperature of the condensation reaction is 25-85 °C, preferably 65-75 °C; The organic solvent in step (5) is selected from methanol, ethanol, tetrahydrofuran, acetonitrile, preferably methanol or ethanol; the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium hydroxide, lithium hydroxide; the reaction temperature of the hydrolysis reaction is 20-80 °C, preferably 60-80 °C.

11. A preparation method of relugolix, characterized in that, it comprises the following steps: wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

12. Compound of formula VI, VII, VIII or its salt: wherein R1 is an amino protecting group selected from methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl; preferably R1 is tert-butoxycarbonyl.

13. Use of the compound of formula VI, VII, VIII for the preparation of relugolix and its salts, derivatives or analogs.

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