Relagoride key intermediate compound G and preparation method thereof

Abstract

The invention provides a key intermediate compound G of relagoride and a preparation method thereof, and belongs to the technical field of medicine synthesis. The intermediate is a compound as shown in a chemical formula (G), and the preparation method comprises the following steps: (1) under the condition that an initiator azodiisobutyronitrile participates in, a compound D reacts with N-bromosuccinimide to obtain a compound E; (2) reacting the compound E with dimethylamine hydrochloride to obtain a compound F; and (3) carrying out hydrolysis reaction on the compound F under the action of alkali to obtain the relugolix intermediate compound G. The method is mild in reaction condition, high in reaction yield, easy in product purification, low in production cost, green, environment-friendly and suitable for commercial scale.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a key intermediate compound G of relugolix and a preparation method thereof. Background Art

[0002] Relugoli is a non-peptide small molecule gonadotropin-releasing hormone GnRH receptor antagonist. As the first oral GnRH antagonist, it can reduce the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by binding to and blocking the GnRH receptor in the anterior pituitary gland, thereby reducing the production of estrogen and progesterone in the female ovaries. This product will also reduce the production of testosterone in men, so it has a good therapeutic effect on hormone-dependent diseases.

[0003] Relugolix, CAS No.: 737789-87-6, chemical name is N-[4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl)-N'-methoxyurea. Relugolix is ​​an oral small molecule gonadotropin-releasing hormone receptor (GnRH) antagonist developed by Takeda Pharmaceutical Co Ltd and ASKS for the treatment of various sex hormone-related diseases. On January 8, 2019, it was approved for marketing in Japan by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) under the trade name Relumina. The marketing indications are the following indications caused by uterine leiomyoma: menorrhagia, lower abdominal pain, low back pain, and anemia. On December 18, 2020, Relugolix was approved by the U.S. Food and Drug Administration (FDA) and sold by Myovant Sciences GmbH under the trade name Orgovyx for the treatment of advanced prostate cancer in adults.

[0004] Patent CN104703992 B discloses a method for preparing Relugolix, and its synthetic route is as follows. In this method, compound 2 (CAS: 174072-89-0) is first cyclized and then coupled to obtain intermediate products 3-9 in sequence, and then intermediate product 9 is used as a raw material to obtain intermediate products 10 and 11 in sequence, and finally obtain the product Relugolix. However, this method uses the highly toxic substance ethyl chloroformate, and the lightning is low, the reaction conditions are harsh, and the nitro reduction reaction needs to be reacted under heating and pressurization conditions, which has high requirements for equipment.

[0005]

[0006] Another synthetic route of Religolix disclosed in patent CN 110194776 B is as follows: This route cleverly uses intramolecular cyclization to construct intermediate 13, thereby avoiding the protection of the amino group and the use of the highly toxic substance ethyl chloroformate. However, this route also requires the nitro reduction reaction to be carried out under heating and pressurization conditions, which places high requirements on equipment.

[0007]

[0008] Takeda Pharmaceuticals, J. Med. Chem. 2011, vol. 54, pp. 4998–5012. Another original research route reported: 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylic acid ethyl ester (11) is used as the starting material, the amino group is protected by ethyl chloroformate, and then the intermediate 2 is obtained by nucleophilic substitution with 2,6-difluorobenzyl chloride under the action of a base; AIBN (azobisisobutyronitrile) is used as a free radical initiator, and the thienylmethyl monobromination reaction is carried out with NBS to produce intermediate 3; 3 is reacted with N-(2-methoxyethyl)methylamine under alkaline conditions to produce intermediate 34; catalytic hydrogenation and coupling are then carried out to complete the construction of alkoxy urea, and then the ester is hydrolyzed, 3-amino-6-methoxypyridazine is amidated, and an intramolecular cyclization reaction is carried out, and finally the amino protecting group replacement reaction is completed to obtain relugolix, but the yield of this step is only 22%. The route is too long and the overall yield is low. The step-by-step synthesis of the N,N-dimethyl fragment is the main reason for these problems.

[0009]

[0010] Therefore, developing a method for preparing relugolix with low cost, high yield, mild reaction conditions, low equipment requirements and high product purity has great application value. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a relugoli intermediate completely different from the prior art, a preparation method thereof and a preparation method of relugoli in order to overcome the defects of the prior art preparation method of relugoli such as harsh reaction conditions, low yield, low purity of the obtained product, high equipment requirements, and unsuitability for industrial production. The preparation method of the present invention is simple and safe to operate, has simple post-processing steps, is environmentally friendly, has a high total yield, and the relugoli product obtained from the intermediate of the present invention has high purity, meets the standard of raw materials, has low production cost, and is suitable for industrial production.

[0012] The present invention provides a method for preparing a relugolix intermediate compound G, wherein the synthesis route of the method is:

[0013]

[0014] The following steps are involved:

[0015] (1) Compound D reacts with N-bromosuccinimide in the presence of an initiator, azobisisobutyronitrile, to obtain compound E;

[0016] (2) Compound E reacts with dimethylamine hydrochloride in the presence of a base to obtain compound F;

[0017] (3) Compound F is hydrolyzed under the action of a base to obtain compound G.

[0018] The present invention provides compound D, compound E, compound F, and compound G, whose structures are shown below:

[0019]

[0020] Step (1) The present invention provides a method for preparing compound E, comprising the following steps: Compound D undergoes a halogenation reaction with a halogenation reagent in an organic solvent to obtain compound E, wherein the reaction equation is as follows:

[0021]

[0022] In step (1), the molar ratio of compound D, N-bromosuccinimide and azobisisobutyronitrile is 1:(1-1.5):(0.01-0.2), preferably 1:(1.2-1.3):(0.05-0.12);

[0023] In step (1), the organic solvent is ethyl acetate, carbon tetrachloride, acetonitrile, or dichloroethane, preferably ethyl acetate;

[0024] In step (1), the reaction temperature is 45 to 80°C, preferably 65 to 75°C;

[0025] In step (1), the reaction time is 0.5-5h, preferably 0.5-2h;

[0026] In step (1), a post-treatment step is further included. More preferably, the post-treatment includes but is not limited to steps such as reduced pressure distillation, extraction, washing, filtering, and drying;

[0027] In step (1), the steps are: dissolving compound D in an organic solvent, adding N-bromosuccinimide and azobisisobutyronitrile, heating to 65-75° C., and reacting for 0.5-2 h; further post-treatment may be performed: adding an aqueous solution, stirring, separating the aqueous phase for extraction, combining the organic phases, washing, drying the organic phases, filtering, and concentrating the organic phases.

[0028] Step (2) The present invention provides a method for preparing compound F, comprising the following steps: Compound E undergoes a nucleophilic substitution reaction with dimethylamine hydrochloride and a base in an organic solvent to obtain compound F, wherein the reaction equation is as follows:

[0029]

[0030] In step (2), the molar ratio of compound E, dimethylamine hydrochloride and base is 1:(1-3):(1-5), preferably 1:(1.2-2):(2-3);

[0031] In step (2), the base is one or more of triethylamine and N,N-diisopropylethylamine;

[0032] In step (2), the organic solvent is one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, preferably N,N-dimethylformamide;

[0033] In step (2), the reaction temperature is 0 to 50°C, preferably 10 to 25°C;

[0034] In step (2), the reaction time is 0.5 to 5 h, preferably 1 to 2 h;

[0035] Step (2) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, filtering, washing, drying and the like;

[0036] In step (2), the steps are as follows: adding dimethylamine hydrochloride and alkali to an organic solvent, adding compound E under stirring, reacting at a temperature of 10 to 25° C., and reacting for 1 to 2 hours; further post-treatment is performed: adding ethanol, heating to 40 to 50° C. and stirring, adding water and stirring for 1 hour, then cooling to 10 to 25° C., filtering, washing, and drying.

[0037] Step (3) The present invention provides a method for preparing compound G, comprising the following steps: Compound F undergoes an ester hydrolysis reaction with a base in an organic solvent to obtain compound G, wherein the reaction equation is as follows:

[0038]

[0039] In step (3), the molar ratio of compound F to base is 1:(1-4), preferably 1:(1-2);

[0040] In step (3), the base is used for hydrolysis, and the base is one or more of potassium hydroxide, sodium hydroxide, and lithium hydroxide, preferably potassium hydroxide;

[0041] In step (3), the organic solvent is one or more water-miscible organic solvents selected from methanol, ethanol, isopropanol, and tetrahydrofuran, preferably ethanol;

[0042] In step (3), the reaction temperature is 25 to 80°C, preferably 55 to 65°C;

[0043] In step (3), the reaction time is 1 to 12 hours, preferably 1 to 4 hours;

[0044] Step (3) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, adjusting pH, concentrating, extracting, washing, filtering and the like;

[0045] In step (3), the steps are as follows: dissolving compound F in an organic solvent, adding an aqueous solution of alkali, heating to 55-65° C., reacting for 1-4 hours, concentrating under reduced pressure to remove ethanol, extracting, drying, filtering, and concentrating.

[0046] The present invention also discloses a compound E, which is prepared according to step (1) of the above-mentioned method for preparing the key intermediate of relugolix. The chemical formula of compound E is:

[0047]

[0048] The present invention also discloses a compound F, which is prepared according to step (1) and step (2) of the above-mentioned method for preparing the key intermediate of relugolix. The chemical formula of compound F is:

[0049]

[0050] The present invention also discloses a compound G, which is prepared according to steps (1) to (3) of the above-mentioned method for preparing the key intermediate of relugolix. The chemical formula of compound G is:

[0051]

[0052] Beneficial technical effects:

[0053] The novel intermediates of relugolix of the present invention (including formula E, formula F, and formula G) can be used to prepare relugolix. The preparation methods of these intermediates are simple, and they are all solids with good properties and stable properties; they have high purity, simple post-treatment, and low purification cost; and the use of dangerous and highly toxic reagents is avoided in the reaction; therefore, they have good commercial prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and should not be regarded as limiting the scope.

[0055] Figure 1 The H NMR spectrum of the relugolix intermediate compound G provided in Example 1 of the present invention;

[0056] Figure 2 This is the NMR carbon spectrum of the relugolix intermediate compound G provided in Example 1 of the present invention.

[0057] Figure 3 This is a high-resolution mass spectrum of the relugolix intermediate compound G provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0058] The above contents of the present invention are further described in detail below through examples, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0059] Example 1. Preparation of the relugolix intermediate of the present invention

[0060] Step 1, Synthesis of ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-5-(4-bromophenyl)thiophene-3-carboxylate (Compound E):

[0061]

[0062] At room temperature, add 100g of compound D and 1000mL of ethyl acetate into a 2000mL four-necked bottle and stir mechanically; add 39.28g of N-bromosuccinimide and 2.9g of azobisisobutyronitrile into the reaction system in sequence, heat to 75°C, react for 1 hour, and the system turns red and clear. Cool the reaction mixture to 25°C, add 100mL of water to wash twice, concentrate the organic phase under reduced pressure, add 300mL of ethanol, stir at 45°C for about 1 hour, concentrate the organic phase under reduced pressure, add 500mL of n-heptane to the system, cool to 0-10°C, stir for 1 hour, filter, wash with ethanol / n-heptane = 1 / 3, and dry under reduced pressure at 45°C; obtain 101.79g of light yellow solid, i.e., yield 89.68%, purity 96.87%.

[0063] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 6.85 (t, J = 8.0 Hz, 2H), 4.97 (s, 2H), 4.70 (s, 2H), 4.30 (q, J = 8.0 Hz, 2H), 3.88 (d, J = 4.0 Hz, 2H), 1.82 (m, 1H), 1.36 (t, J = 8.0 Hz, 3H), 0.79 (d, J = 4.0 Hz, 6H).

[0064] HRMS m / z:643.9858[M+H]+

[0065] Step 2, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (Compound F):

[0066]

[0067] In an ice-water bath, 43.19 g of dimethylamine hydrochloride, 790 mL of DMF and 92.89 g of triethylamine were added to a clean reaction bottle and mechanical stirring was started; the mixture was stirred at 5°C for 0.5 hour; a DMF solution of 227 g of compound E was added dropwise, the temperature was controlled below 10°C, and the container used for the compound was washed with 50 mL of DMF, then the temperature was raised to 25°C for 1 hour and the sample was sent to monitor whether the raw material was basically reacted completely; 800 mL of ethanol was added for post-treatment, the mixture was heated to 45°C with stirring, 800 mL of water was added dropwise at 45°C, the mixture was stirred for 1 hour, the temperature was lowered below 10°C, the mixture was stirred for 1 hour for crystallization, filtered, washed with ethanol / water = 3 / 1, and dried under reduced pressure at 45°C to obtain 177.12 g of a yellow solid, i.e., a yield of 82.30% and a purity of 98.57%.

[0068] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.52 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 3H), 7.28 (s, 1H), 5.02 (s, 2H), 4.24 (q, J = 8.0 Hz, 2H), 3.91 (d, J = 4.0 Hz, 2H), 3.49 (s, 2H), 2.04 (s, 6H), 1.86 (m, 1H), 1.33 (t, J = 8.0 Hz, 3H), 0.82 (d, J = 8.0 Hz, 6H)

[0069] HRMS m / z:609.1225[M+H]+

[0070] Step 3, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)thiophene-3-carboxylic acid (Compound G):

[0071]

[0072] At room temperature, add 20.0g of compound F and 100mL of ethanol to a clean reaction bottle and start stirring, raise the temperature to 60℃; stir at 60℃ for 0.5 hours; drop 9.21g of 40% KOH, and the raw material reaction is complete after TLC spot plate detection for about 1h; post-treatment: cool the reaction mixture to below 20℃, adjust the pH value to 6-7 with 6N hydrochloric acid; at 50℃, reduce pressure and concentrate the mixture system, then add 20mL of ethyl acetate and 20mL of ethanol at 50℃, then add 200mL of water at the same temperature, and stir at the same temperature for 1 hour; cool the system to 0-10℃, stir at the same temperature for 1 hour, filter, wash with ethanol / water = 1 / 5, and dry under reduced pressure at 45℃ to obtain 17.63g of yellow solid, i.e., the yield is 92.41% and the purity is 97.62%. And the attached Figure 1-3 H NMR spectrum, C NMR spectrum, and high-resolution mass spectrum.

[0073] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.55 (d, J = 8.0 Hz, 2H), 7.22 (td, J1 = 8.0, J2 = 4.0, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 8.0 Hz, 2H), 5.09 (s, 2H), 3.91 (d, J = 4.0 Hz, 2H), 3.75 (s, 2H), 2.39 (s, 6H), 1.84 (m, 1H), 0.79 (d, J = 8.0 Hz, 6H).

[0074] HRMS m / z:581.0910[M+H]+

[0075] Example 2: Preparation of the relugolix intermediate of the present invention

[0076] Step 1, Synthesis of ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-5-(4-bromophenyl)thiophene-3-carboxylate (Compound E):

[0077] At room temperature, add 100g of compound D and 1000mL of acetonitrile into a 2000mL four-necked bottle and stir mechanically; add 39.28g of N-bromosuccinimide and 2.9g of azobisisobutyronitrile to the reaction system in sequence, heat to 70°C, react for 2 hours, and the system turns red and clear. Concentrate the system under reduced pressure, cool the reaction mixture to 25°C, add 200mL of ethyl acetate and water to wash, extract and separate, combine the organic phases, concentrate the organic phase under reduced pressure, add 300mL of ethanol, stir at 45°C for about 1 hour, concentrate the organic phase under reduced pressure, add 500mL of n-heptane to the system, cool to 0-10°C, stir for 1 hour, filter, wash with ethanol / n-heptane = 1 / 3, and dry under reduced pressure at 45°C; 98.35g of light yellow solid is obtained, i.e., the yield is 86.44% and the purity is 95.69%.

[0078] Step 2, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (Compound F):

[0079] In an ice-water bath, 43.19 g of dimethylamine hydrochloride, 790 mL of DMF, and 118.1 g of N,N-diisopropylethylamine were added to a clean reaction bottle and mechanical stirring was started; the mixture was stirred at 5°C for 0.5 hour; a DMF solution of 227 g of compound E was added dropwise, the temperature was controlled below 10°C, and the container used for the compound was washed with 50 mL of DMF, and then the temperature was raised to 30°C for 2 hours and samples were sent to monitor whether the raw materials were basically reacted completely; 800 mL of ethanol was added for post-treatment, the mixture was heated to 45°C with stirring, 800 mL of water was added dropwise at 45°C, the mixture was stirred for 1 hour, the temperature was lowered below 10°C, the mixture was stirred for 1 hour for crystallization, suction filtered, washed with ethanol / water = 3 / 1, and dried under reduced pressure at 45°C to obtain 196.32 g of a yellow solid, i.e., a yield of 91.22% and a purity of 96.38%.

[0080] Step 3, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)thiophene-3-carboxylic acid (Compound G):

[0081] At room temperature, 20.0 g of compound F and 100 mL of ethanol were added to a clean reaction bottle and stirred, and the temperature was raised to 60°C; at 60°C, stirred for 0.5 hours; 21.18 g of 20% NaOH was added dropwise, and the raw material reaction was completed after TLC spot plate detection for about 3 hours; post-treatment: the reaction mixture was cooled to below 20°C, and the pH value was adjusted to 6-7 with 6N hydrochloric acid; at 50°C, the mixture system was concentrated under reduced pressure, and then 20 mL of ethyl acetate and 20 mL of ethanol were added at 50°C, and then 200 mL of water was added at the same temperature, and stirred for 1 hour at the same temperature; the system was cooled to 0-10°C, stirred for 1 hour at the same temperature, filtered, washed with ethanol / water = 1 / 5, and dried under reduced pressure at 45°C to obtain 16.39 g of yellow solid, i.e., the yield was 85.75% and the purity was 96.39%.

[0082] Example 3: Preparation of the relugolix intermediate of the present invention

[0083] Step 1, Synthesis of ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-5-(4-bromophenyl)thiophene-3-carboxylate (Compound E):

[0084] At room temperature, add 100g of compound D and 1000mL of ethyl acetate into a 2000mL four-necked bottle and stir mechanically; add 47.16g of N-bromosuccinimide and 1.45g of azobisisobutyronitrile into the reaction system in sequence, heat to 75°C, react for 1.5 hours, and the system turns red and clear. Cool the reaction mixture to 25°C, add 100mL of water to wash twice, concentrate the organic phase under reduced pressure, add 300mL of ethanol, stir at 45°C for about 1 hour, concentrate the organic phase under reduced pressure, add 500mL of n-heptane to the system, cool to 0-10°C, stir for 1 hour, filter, wash with ethanol / n-heptane = 1 / 3, and dry under reduced pressure at 45°C; obtain 102.61g of light yellow solid, i.e., yield 90.37%, purity 93.58%.

[0085] Step 2, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (Compound F):

[0086] In an ice-water bath, 43.19 g of dimethylamine hydrochloride, 790 mL of DMAc, and 92.89 g of triethylamine were added to a clean reaction bottle and mechanical stirring was started; the mixture was stirred at 5°C for 0.5 hour; a DMAc solution of 227 g of compound E was added dropwise, the temperature was controlled below 10°C, and the container used for the compound was washed with 50 mL of DMAc, then the temperature was raised to 35°C for 0.5 hour, and a sample was sent to monitor whether the reaction of the raw material was basically complete; 800 mL of ethanol was added for post-treatment, the mixture was heated to 45°C with stirring, 800 mL of water was added dropwise at 45°C, the mixture was stirred for 1 hour, the temperature was lowered below 10°C, the mixture was stirred for 1 hour for crystallization, suction filtered, washed with ethanol / water = 3 / 1, and dried under reduced pressure at 45°C to obtain 177.12 g of a yellow solid, i.e., a yield of 82.30% and a purity of 98.57%.

[0087] Step 3, Synthesis of 2-[(2,6-difluorobenzyl)isobutoxycarbonylamino]-4-dimethylaminomethyl-5-(4-bromophenyl)thiophene-3-carboxylic acid (Compound G):

[0088] At room temperature, 20.0 g of compound F and 100 mL of methanol were added to a clean reaction bottle, and stirring was started, and the temperature was raised to 60°C; at 60°C, the mixture was stirred for 0.5 hours; 18.42 g of 20% KOH was added dropwise, and the reaction of the raw materials was completed after TLC spot plate detection for about 2 hours; post-treatment: the reaction mixture was cooled to below 20°C, and the pH value was adjusted to 6-7 with 6N hydrochloric acid; at 50°C, the mixture system was concentrated under reduced pressure, and then 20 mL of ethyl acetate and 20 mL of methanol were added at 50°C, and then 200 mL of water was added at the same temperature, and stirred at the same temperature for 1 hour; the system was cooled to 0-10°C, stirred at the same temperature for 1 hour, filtered, washed with methanol / water = 1 / 5, and dried under reduced pressure at 45°C to obtain 17.08 g of yellow solid, i.e., the yield was 89.52% and the purity was 97.62%.

[0089] In summary, the present invention provides a new method for preparing a relugolix intermediate, which has simpler operation, fewer side reactions, mild reaction conditions, high yield and purity, easy product purification, low production cost, and is more suitable for commercial-scale production.

Claims

1. A method for preparing a key intermediate compound G of relugolix, characterized in that: Its synthetic route is: The steps include: (1) Compound D reacts with N-bromosuccinimide in the presence of an initiator, azobisisobutyronitrile, to obtain compound E; (2) Compound E reacts with dimethylamine hydrochloride in the presence of a base to obtain compound F; (3) Compound F is hydrolyzed under the action of a base to obtain compound G.

2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of compound D, N-bromosuccinimide and azobisisobutyronitrile is 1:(1-1.5):(0.01-0.2); the reaction temperature is 45-80°C; and the reaction time is 0.5-5h.

3. The preparation method according to claim 1, characterized in that: In step (1), the organic solvent is selected from one or more of ethyl acetate, carbon tetrachloride, acetonitrile and dichloroethane.

4. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of compound E, dimethylamine hydrochloride and base is 1:(1-3):(1-5); the reaction temperature is 0-50°C, and the reaction time is 0.5-5h.

5. The preparation method according to claim 1, characterized in that: In step (2), the base is one of triethylamine and N,N-diisopropylethylamine; the reaction solvent is one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, tetrahydrofuran, and acetonitrile.

6. The preparation method according to claim 1, characterized in that: In step (2), the reaction solvent is one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, tetrahydrofuran, and acetonitrile.

7. The preparation method according to claim 1, characterized in that: In step (3), the molar ratio of compound F to base is 1: (1~4); the reaction temperature is 25~80℃; the reaction time is 1~12h.

8. The preparation method according to claim 1, characterized in that: The base in step (3) is selected from one of potassium hydroxide, sodium hydroxide and lithium hydroxide; the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol and tetrahydrofuran.

9. The preparation method according to claim 1, characterized in that: In step (3), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol and tetrahydrofuran.

10. A key intermediate compound G of relugolix, characterized in that: It is prepared according to the preparation method of the key intermediate compound G of relugolix as described in claim 1.

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