Rerugolix and three-step synthesis method thereof

Abstract

The invention provides rerugolix and a three-step synthesis method thereof, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: (1) reacting a compound G with 3-amino-6-methoxypyridazine under the action of a condensing agent and alkali to obtain a compound H; (2) carrying out cyclization reaction on the compound H under the action of alkali to obtain a compound I; (3) reacting the compound I with N-methoxyurea under the action of metal palladium or copper, a ligand and alkali to obtain rerugolix; the method is mild in reaction condition, high in reaction yield, few in side reaction, 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 relugolix and a three-step synthesis 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 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 relugoli preparation method in order to overcome the defects of the prior art such as harsh reaction conditions, low yield, low purity of the obtained product, excessive heavy metal elements, 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, low heavy metal element content, meets the standards of raw materials, has low production costs, and is suitable for industrial production.

[0012] The present invention provides a method for preparing relugolix, the method comprising the following steps:

[0013] (1) Compound G reacts with 3-amino-6-methoxypyridazine in the presence of a condensing agent and a base to produce compound H through an amide condensation reaction;

[0014] (2) Compound H undergoes a cyclization reaction under the action of a base to obtain Compound I;

[0015] The present invention provides compound G, compound H, and compound I, whose structures are shown in the formula:

[0016]

[0017] Step (1) The present invention provides a method for preparing compound H, comprising the following steps: Compound G undergoes an amide condensation reaction with 3-amino-6-methoxypyridazine in an organic solvent under the action of a condensing agent and a base to obtain compound H, wherein the reaction equation is as follows:

[0018]

[0019] In step (1), the molar ratio of compound G, 3-amino-6-methoxypyridazine, base and condensing agent is 1:(1-3):(1-4):(1-3), preferably 1:(1-1.5):(1.5-3):(1-1.5);

[0020] In step (1), the base is one or more of N,N-diisopropylethylamine and triethylamine;

[0021] In step (1), the condensing agent is one or more of 1-propylphosphonic anhydride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, and HBTU, preferably 1-propylphosphonic anhydride;

[0022] In step (1), the organic solvent is one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, and ethyl acetate, preferably N,N-dimethylacetamide;

[0023] In step (1), the reaction temperature is 25 to 80°C, preferably 50 to 60°C;

[0024] In step (1), the reaction time is 1 to 12 hours, preferably 1 to 4 hours;

[0025] In step (1), a post-treatment step is further included. More preferably, the post-treatment includes but is not limited to cooling, adjusting pH, filtering, washing, drying and the like;

[0026] In step (1), the specific steps are: dissolving compound G in an organic solvent, adding 3-amino-6-methoxypyridazine, and then adding 1-propylphosphonic anhydride, heating to 50-60°C, keeping warm, and reacting for 1-4 hours; post-treatment step: cooling the reaction solution to room temperature, adding alkali to adjust the pH value to 7-8, filtering, washing, and drying.

[0027] Step (2) The present invention provides a method for preparing compound I, comprising the following steps: Compound H undergoes a cyclization reaction in an organic solvent under the action of a base to obtain compound I, wherein the reaction equation is as follows:

[0028]

[0029] In step (2), the molar ratio of compound H to base is 1:(0.01-4), preferably 1:(0.02-0.5)

[0030] In step (2), the cyclization reaction can be carried out in the presence of a base, and the base is sodium methoxide or sodium ethoxide;

[0031] In step (2), the organic solvent is one of methanol, ethanol, tetrahydrofuran, acetonitrile or a mixed solvent thereof;

[0032] In step (2), the reaction temperature is 25 to 80°C, preferably 40 to 60°C;

[0033] In step (2), the reaction time is 0.5 to 12 h, preferably 1 to 4 h;

[0034] Step (2) further comprises a post-treatment step, and more preferably, the post-treatment includes but is not limited to steps such as cooling, adjusting pH, filtering, washing, and drying;

[0035] In step (2), the steps are: dissolving compound H in an organic solvent, adding a base, heating to 40-60°C, keeping warm, and reacting for 1-4 hours; post-treatment step: cooling the reaction solution to room temperature, adjusting the pH value to 5-7 with acid, adding an alcohol solvent, cooling to 0-5°C, crystallizing, filtering, and drying.

[0036] Step (3) is the last step in the preparation of relugolix and there are two synthetic processes.

[0037] One of the processes in step (3) comprises the following steps: Compound I undergoes a Buchwald-Hartwing CN coupling reaction with N-methoxyurea in an organic solvent under the action of metal palladium, a ligand, and a base to obtain relugoli, and the reaction equation is as follows:

[0038]

[0039] In step (3), the molar ratio of compound I, N-methoxyurea, metal palladium, ligand and base is 1: (1-2): (0.001-0.2): (0.001-0.2): (1-3), preferably 1: (1.1-1.8): (0.001-0.1): (0.001-0.1): (1.1-2.5);

[0040] In step (3), the metal palladium catalyst is one or more of Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(PPh3)2Cl2;

[0041] In step (3), the ligand is one or more of SPhos, XPhos, Josiphos, RuPhos, BrettPhos, and RockPhos;

[0042] In step (3), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide;

[0043] In step (3), the organic solvent is one of dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran or a mixed solvent thereof;

[0044] In step (3), the reaction temperature is 50 to 120° C., preferably 80 to 100° C.;

[0045] In step (3), the reaction time is 1 to 24 hours, preferably 4 to 10 hours;

[0046] Step (3) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, extraction, filtration, washing, drying and the like;

[0047] In step (3), the steps are: adding compound I, N-methoxyurea, metal palladium, ligand, and base to an organic solvent, heating to 80-100° C., keeping warm, and reacting for 4-10 hours; post-treatment step: cooling the reaction solution to room temperature, extracting and concentrating the solvent, adding an alcohol solvent, filtering, and drying.

[0048] Step (3) Another three-step synthesis process of relugolix comprises the following steps: Compound I undergoes Ullmann's CN coupling reaction with N-methoxyurea in an organic solvent under the action of metallic copper, a ligand, and a base to obtain relugolix, and the reaction equation is as follows:

[0049]

[0050] In step (3), the molar ratio of compound I, N-methoxyurea, metallic copper, ligand and base is 1: (1-2): (0.01-0.2): (0.01-0.2): (1-3), preferably 1: (1.1-1.8): (0.01-0.1): (0.01-0.1): (1.1-2.5);

[0051] In step (3), the metallic copper catalyst is one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide;

[0052] In step (3), the ligand is one of N,N-dimethylethylenediamine, N,N-diethylsalicylamide, N,N-di-(thiophene-2-methyl)-oxalic acid diamide, N-1-(2-methylnaphthyl)-N-benzyl oxalic acid diamide, N-1-(2-methylnaphthyl)-N-furan-2-methyl-oxalic acid diamide, (1S,2S)-(+)-1,2-cyclohexanediamine, and o-phenanthroline;

[0053] In step (3), the base is one of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide;

[0054] In step (3), the organic solvent is dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran or a mixed solvent thereof;

[0055] In step (3), the reaction temperature is 50 to 150° C., preferably 100 to 130° C.;

[0056] In step (3), the reaction time is 1 to 24 hours, preferably 12 to 24 hours;

[0057] Step (3) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, extraction, filtration, washing, drying and the like;

[0058] In step (3), the steps are: adding compound I, N-methoxyurea, metallic copper, ligand, and base to an organic solvent, heating to 80-100° C., keeping warm, and reacting for 12-24 hours; post-treatment step: cooling the reaction solution to room temperature, extracting and concentrating the solvent, adding an alcohol solvent, filtering, and drying.

[0059] The present invention also provides a three-step synthesis method of relugolix, and the reaction equation is as follows:

[0060]

[0061] Preferably, each step G, H, I or relugoli in the reaction equation is as described above.

[0062] The present invention also discloses a compound H, which is prepared according to step (1) of the above-mentioned method for preparing the key intermediate of relugolix. The chemical formula of compound H is:

[0063]

[0064] The present invention also discloses a compound I, 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 I is:

[0065]

[0066] The present invention also discloses a compound, relugolix, 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 the compound relugolix is:

[0067]

[0068] Beneficial technical effects:

[0069] The novel intermediates of relugolix of the present invention (including compounds of formula G, formula H and formula I) can be used to prepare relugolix; the preparation methods of these intermediates are simple, and they are all solids with good properties, stable properties, high purity and low purification cost.

[0070] The present invention adopts the one-step method of compound formula I to prepare relugolix, shortens the operation steps, avoids the generation of urea by-products, and greatly reduces the cost of crude product purification.

[0071] The preparation method of relugolix of the present invention uses compound G as a starting material, first introduces a pyridazine fragment, and has high yield and purity, and subsequently can stably obtain API crystals with a light yellow property; on the other hand, compared with the method disclosed in the prior art, no foamy solid appears during the reaction process of the ring-closing step of the present invention, stirring is smooth, and the amount of solvent used is relatively small, so the production process of the present invention is conducive to large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] 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.

[0073] Figure 1 The H NMR spectrum of relugolix provided in Example 1 of the present invention;

[0074] Figure 2 This is the carbon NMR spectrum of relugolix provided in Example 1 of the present invention.

[0075] Figure 3 This is a high-resolution mass spectrum of relugolix provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0076] 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.

[0077] The raw materials and reagents used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0078] Example 1. Preparation of relugolix of the present invention

[0079] Step 1, synthesis of isobutyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0080]

[0081] Under the protection of nitrogen, 18.00g of compound G, 4.65g of 3-amino-6-methoxypyridazine and 80mL of N,N-dimethylacetamide were added to a clean 250mL reaction bottle and mechanically stirred; 10.01g of N,N-diisopropylethylamine was added dropwise at 30°C and stirred for 30min; 23.64g of 50% propylphosphoric anhydride in ethyl acetate was added dropwise at 55-60°C, and the solvent used was washed with 10mL of N,N-dimethylacetamide and stirred at 55°C for 2 hours; then 135mL of water was added dropwise at 0-10°C and stirred for 1 hour; pH was adjusted to 7-8 with 40% KOH at 0-10°C and stirred for 1 hour; suction filtered, washed with 40mL of ice methanol, and dried under reduced pressure at 45°C to obtain 20.17g of light yellow solid, i.e., yield 94.66% and purity 97.52%.

[0082] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d): δ (13.98s, 1H), 8.56 (d, J = 12 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.16-7.08 (m, 3H), 6.98 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 8.0 Hz, 2H), 5.02 (s, 2H), 4.10 (s, 2H), 3.92 (d, J = 8.0 Hz, 2H), 3.48 (s, 2H), 2.20 (s, 6H), 1.82 (m, 1H), 0.77 (d, J = 8.0 Hz, 6H).

[0083] HRMS m / z:688.1404[M+H]+

[0084] Step 2, Synthesis of 1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-6-(4-bromophenyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Compound I):

[0085]

[0086] Into a clean reaction bottle, add 75 g of compound H, a methanol solution containing 3.92 g of 30% sodium methoxide, and 750 mL of methanol, and start mechanical stirring; heat to 55-65 ° C, stir for 2 hours, add concentrated hydrochloric acid at 20 ° C, adjust the pH to 6-7, and stir for 1 hour; add 750 mL of isopropanol, and stir for 0.5 h under this system, then cool to 0-5 ° C and stir for 1 hour, filter, wash with icy isopropanol, and dry under reduced pressure at 45 ° C to obtain 61.21 g of light yellow solid, i.e., the yield is 91.47% and the purity is 98.53%.

[0087] The nuclear magnetic resonance data are as follows: 1H NMR (400MHz, Chloroform-d): δ7.55 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.30 (m, J = 8.4, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 2H), 5.34 (s, 2H), 4.17 (s, 3H), 3.65 (s, 2H), 2.15 (s, 6H).

[0088] HRMS m / z:614.0659[M+H]+

[0089] Step 3, Synthesis of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]-phenyl}-3-methoxyurea (Relugoli):

[0090]

[0091] Based on the different selection of metal palladium or metal copper, there are two reaction routes:

[0092] Step 3 Process 1:

[0093] At room temperature, 30.7g of compound I, 6.75g of N-methoxyurea and 245.6mL of toluene were stirred and dissolved, and then 112mg of Pd(OAc)2, 476.7mg of Xphos, 24.5g of cesium carbonate were added, nitrogen was replaced three times, the temperature was raised to 80-85°C, the reaction was stirred for 10h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 245.6mL of ammonium chloride solution was added to quench the reaction, the extraction was separated, the aqueous phase was extracted twice with 245.6mL of toluene, the toluene layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, 307mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 26.52g of white solid, i.e., a yield of 85% and a purity of 98.16%.

[0094] Step 3 Process 2:

[0095] At room temperature, 3.07g of compound I, 675.1mg of N-methoxyurea and 24mL of dimethyl sulfoxide were stirred and dissolved, and then 94.92mg of cuprous iodide, 151.56mg of N-1-(2-methylnaphthyl)-N-benzyl oxalic acid diamide, 841mg of potassium tert-butoxide were added, nitrogen was replaced three times, the temperature was raised to 110-120°C, the reaction was stirred for 24h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 24mL of ammonium chloride solution was added to quench the reaction, 24mL of ethyl acetate was added to extract three times, the aqueous phase was extracted twice with 24mL of ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. 31mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 2.87g of yellow solid, i.e., a yield of 76.46% and a purity of 96.35%. The final finished product was tested and the attached Figure 1-3 H NMR spectrum, C NMR spectrum, and high-resolution mass spectrum.

[0096] The nuclear magnetic resonance data are as follows: 1H NMR (400MHz, Chloroform-d): δ8.06 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 12 Hz, 2H), 7.32 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 2H), 5.30 (s, 2H), 4.18 (s, 3H), 3.77 (s, 3H), 3.59 (s, 2H), 2.13 (s, 6H).

[0097] HRMS m / z:624.1822[M+H]+

[0098] Example 2. Preparation of relugolix of the present invention

[0099] Step 1, synthesis of isobutyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0100] Under the protection of nitrogen, 18.00 g of compound G, 5.03 g of 3-amino-6-methoxypyridazine and 80 mL of tetrahydrofuran were added to a clean 250 mL reaction bottle and mechanically stirred; 10.01 g of DIPEA (N,N-diisopropylethylamine) was added dropwise at 30°C and stirred for 30 min. 14.64 g of HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) was added at 55-60°C, and the solvent used was washed with 10 mL of tetrahydrofuran and stirred at 55°C for 2 hours; then 135 mL of water was added dropwise at 0-10°C and stirred for 1 hour; 40% Adjust the pH to 7-8 with KOH, stir for 1 hour, filter with suction, wash with 40 mL of ice methanol, and dry under reduced pressure at 45°C to obtain 19.82 g of light yellow solid, with a yield of 89.11% and a purity of 93.57%.

[0101] Step 2, Synthesis of 1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-6-(4-bromophenyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Compound I):

[0102] Into a clean reaction bottle, 75 g of compound H, 1.96 g of 30% sodium methoxide methanol solution, 750 mL of tetrahydrofuran were added and mechanical stirring was started; the temperature was raised to 55-65°C, stirred for 2 hours, concentrated hydrochloric acid was added at 20°C, the pH value was adjusted to 6-7, and stirred for 1 hour; the tetrahydrofuran was concentrated under reduced pressure and cooled to room temperature, 750 mL of isopropanol was added thereto, and stirred for 0.5 h under this system, then the temperature was lowered to 0-10°C and stirred for 1 hour, filtered, washed with icy isopropanol, and dried under reduced pressure at 45°C to obtain 60.35 g of light yellow solid, i.e., the yield was 90.37% and the purity was 97.51%.

[0103] Step 3, Synthesis of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]-phenyl}-3-methoxyurea (Relugoli):

[0104] Based on the different selection of metal palladium or metal copper, there are two reaction routes:

[0105] Step 3 Process 1:

[0106] At room temperature, 30.7g of compound I, 6.75g of N-methoxyurea and 245.6mL of dioxane were stirred and dissolved, and then 457mg of Pd2(dba)3, 233.32mg of RuXphos, 24.5g of cesium carbonate were added, nitrogen was replaced three times, the temperature was raised to 80-85°C, the reaction was stirred for 10h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 245.6mL of ammonium chloride solution was added to quench the reaction, 245.6mL of dichloromethane was extracted twice, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, 307mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 28.36g of white solid, i.e., a yield of 90.46% and a purity of 96.25%.

[0107] Step 3 Process 2:

[0108] At room temperature, 3.07g of compound I, 675.1mg of N-methoxyurea and 24mL of DMF were stirred and dissolved, and then 99mg of cuprous chloride, 303.12mg of N-1-(2-methylnaphthyl)-N-benzyl oxalic acid diamide, 841mg of potassium tert-butoxide were added, nitrogen was replaced three times, the temperature was raised to 110-120°C, the reaction was stirred for 24h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 24mL of ammonium chloride solution was added to quench the reaction, 24mL of ethyl acetate was added to extract three times, the aqueous phase was extracted twice with 24mL of ethyl acetate, the organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, 31mL of n-heptane was added to pulp, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 2.76g of yellow solid, i.e., a yield of 88.03% and a purity of 92.28%.

[0109] Example 3. Preparation of relugolix of the present invention

[0110] Step 1, synthesis of isobutyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0111] Under the protection of nitrogen, 18.00g of compound G, 4.65g of 3-amino-6-methoxypyridazine and 80mL of ethyl acetate were added to a clean 250mL reaction bottle and mechanically stirred; 10.01g of DIPEA was added dropwise at 30°C and stirred for 30min; 23.64g of 50% propylphosphoric anhydride in ethyl acetate was added dropwise at 55-60°C, and the solvent used was washed with 10mL of ethyl acetate, and stirred at 55°C for 2 hours; then 135mL of water was added dropwise at 0-10°C and stirred for 1 hour; pH was adjusted to 7-8 with 40% KOH at 0-10°C and stirred for 1 hour; suction filtered, washed with 40mL of ice methanol, and dried under reduced pressure at 45°C to obtain 19.58g of light yellow solid, i.e., yield 88.04% and purity 96.32%.

[0112] Step 2, Synthesis of 1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-6-(4-bromophenyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Compound I):

[0113] Into a clean reaction bottle, 75 g of compound H, 4.94 g of 30% sodium ethanol ethanol solution, and 750 mL of ethanol were added and mechanical stirring was started; the temperature was raised to 55-65 ° C, stirred for 2 hours, concentrated hydrochloric acid was added at 20 ° C, the pH value was adjusted to 6-7, and stirred for 1 hour; 750 mL of isopropanol was added thereto, and stirred for 0.5 h under this system, then the temperature was lowered to 0-10 ° C, stirred for 1 hour, filtered, washed with icy isopropanol, and dried under reduced pressure at 45 ° C to obtain 61.21 g of light yellow solid, i.e., the yield was 95.15% and the purity was 98.53%.

[0114] Step 3, Synthesis of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazine-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]-phenyl}-3-methoxyurea (Relugoli):

[0115] Based on the different selection of metal palladium or metal copper, there are two reaction processes:

[0116] Step 3 Process 1:

[0117] At room temperature, 30.7g of compound I, 8.1g of N-methoxyurea and 245.6mL of dimethyl sulfoxide were stirred and dissolved, and then 112mg of Pd(OAc)2, 476.7mg of Xphos, 10.35g of potassium carbonate were added, nitrogen was replaced three times, the temperature was raised to 80-85°C, the reaction was stirred for 10h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 245.6mL of ammonium chloride solution was added to quench the reaction, 245.6mL of dichloromethane was extracted twice, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, 307mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 25.38g of white solid, i.e., a yield of 80.95% and a purity of 97.61%.

[0118] Step 3 Process 2:

[0119] At room temperature, 3.07g of compound I, 810mg of N-methoxyurea and 24mL of dimethyl sulfoxide were stirred and dissolved, and then 94.92mg of cuprous iodide, 140.18mg of N, N-di-(thiophene-2-methyl)-oxalic acid diamide, 841mg of potassium tert-butoxide were added, nitrogen was replaced three times, the temperature was raised to 110-120°C, the reaction was stirred for 24h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 24mL of ammonium chloride solution was added to quench the reaction, 24mL of ethyl acetate was added to extract three times, the aqueous phase was extracted twice with 24mL of ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, 31mL of n-heptane was added to pulp, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 2.36g of yellow solid, i.e., a yield of 74.59% and a purity of 93.99%.

[0120] In summary, the present invention provides a method for preparing relugolix. The method of the present invention adopts a route of first ring closure and then coupling, which is simpler to operate, has fewer side reactions, mild reaction conditions, high yield and purity, and the product is easy to purify. The production cost is low and it is more suitable for commercial-scale production.

Claims

1. A three-step synthesis method of relugolix, characterized in that: Its synthetic route includes: The steps include: (1) Compound G reacts with 3-amino-6-methoxypyridazine to obtain compound H; (2) Compound H undergoes a cyclization reaction under the action of a base to obtain Compound I; (3) Compound I is reacted with N-methoxyurea in the presence of metal palladium or metal copper, a ligand and a base to obtain relugolix.

2. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (1), compound G reacts with 3-amino-6-methoxypyridazine in an organic solvent under the action of a condensing agent and a base; the molar ratio of compound G, 3-amino-6-methoxypyridazine, base and condensing agent is 1:(1-3):(1-4):(1-3); the reaction temperature is 25-80°C; and the reaction time is 1-12h.

3. The three-step synthesis method of relugolix according to claim 2, characterized in that: In step (1), the base is selected from one of N,N-diisopropylethylamine and triethylamine; the condensing agent is selected from one of 1-propylphosphoric anhydride, dicyclohexylcarbodiimide, diisopropylcarbodiimide and HBTU; the organic solvent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile and ethyl acetate.

4. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (2), the molar ratio of compound H to base is 1:(0.01-4); the reaction temperature is 25-80°C; and the reaction time is 0.5-12h.

5. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (2), the base is selected from sodium methoxide and sodium ethoxide; and the organic solvent is one or more of methanol, ethanol, tetrahydrofuran and acetonitrile.

6. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (3), when metallic palladium is used as a catalyst, the molar ratio of the compound I, N-methoxyurea, metallic palladium, ligand, and base is 1:(1-2):(0.001-0.2):(0.001-0.2):(1-3); the metallic palladium is selected from one of Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, and Pd(PPh3)2Cl2; and the ligand is selected from one of SPhos, XPhos, Josiphos, RuPhos, BrettPhos, and RockPhos.

7. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (3), when metal palladium is used as a catalyst, the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide; the organic solvent is one or more of dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran; the reaction temperature is 50-120° C.; and the reaction time is 1-24 h.

8. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (3), when metallic copper is used as a catalyst, the molar ratio of the compound I, N-methoxyurea, metallic copper, ligand, and base is 1: (1~2):(0.01~0.2):(0.01~0.2):(1~3); the metallic copper is one of cuprous iodide, cuprous bromide, cuprous chloride and cuprous oxide; the ligand is one of N,N-dimethylethylenediamine, N,N-diethylsalicylamide, N,N-di-(thiophene-2-methyl)-oxalic acid diamide, N-1-(2-methylnaphthyl)-N-benzyl oxalic acid diamide, N-1-(2-methylnaphthyl)-N-furan-2-methyl-oxalic acid diamide, (1S,2S)-(+)-1,2-cyclohexanediamine and o-phenanthroline.

9. The three-step synthesis method of relugolix according to claim 1, characterized in that: In step (3), when metallic copper is used as a catalyst, the base is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, and sodium tert-butoxide; the organic solvent is selected from one or more of dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, tert-butanol, and ethylene glycol; the reaction temperature is 50-150° C., and the reaction time is 1-24 h.

10. Ruilugol, characterized by: It is prepared by the three-step synthesis method of relugolix as described in claim 1.

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