Rerugolix and four-step synthesis method thereof

Abstract

The invention provides a four-step synthesis method of rerugolix, and belongs to the technical field of medicine synthesis. The four-step synthesis 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) obtaining a compound J from the compound I and carbamic acid ester under the action of metal palladium or copper, a ligand and alkali; and (4) carrying out amine ester exchange reaction on the compound J and methoxyamine hydrochloride under the action of alkali to obtain the rerugolix. The method has the advantages of mild reaction conditions, simplicity and convenience in operation, high reaction yield, safer process, easiness in product purification, low production cost, greenness, environmental friendliness and suitability for commercial scale.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and specifically, to relugolix and its four-step synthesis method. Background Art

[0002] Relugolix is a non-peptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist. As the first orally administered GnRH antagonist, it can bind to the GnRH receptor in the anterior pituitary gland and block this receptor, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby reducing the production of estrogen and progesterone in the ovaries of women. This product also reduces the production of testosterone in men, and thus 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 orally administered 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. It was approved for marketing in Japan by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 8, 2019, under the trade name Relumina, and the approved indications for marketing are the following indications caused by uterine leiomyoma: menorrhagia, lower abdominal pain, low back pain, anemia. On December 18, 2020, Relugolix was approved by the US Food and Drug Administration (FDA) and is 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 subjected to cyclization first and then coupling to obtain intermediate products 3-9 in sequence. Then, using intermediate product 9 as the raw material, intermediate products 10 and 11 are prepared in sequence, and finally the product Relugolix is obtained. However, this method uses highly toxic ethyl chloroformate, and it has a low flash point and harsh reaction conditions. The nitro reduction reaction needs to be carried out under heating and pressurization conditions, which requires high equipment requirements.

[0005]

[0006] Another synthetic route of Relugolix disclosed in Patent CN 110194776 B is as follows: This route ingeniously uses intramolecular cyclization to construct Intermediate 13, thus avoiding the protection of amino groups and the use of highly toxic ethyl chloroformate. However, this route also requires the nitro reduction reaction to be carried out under heating and pressurized conditions, which has relatively high requirements for equipment.

[0007]

[0008] Another original research route reported by Takeda Pharmaceutical in J. Med. Chem. 2011, vol. 54, pages 4998–5012: Starting from ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate (11), the amino group was protected with ethyl chloroformate, and then nucleophilic substitution occurred with 2,6-difluorobenzyl chloride under the action of a base to obtain Intermediate 2; Using AIBN (azobisisobutyronitrile) as a radical initiator, a thiophene methyl monobromination reaction occurred with NBS to generate Intermediate 3; 3 reacted with N-(2-methoxyethyl)methylamine under basic conditions to form Intermediate 34; Then, catalytic hydrogenation and coupling were carried out to complete the construction of alkoxyurea, and then ester hydrolysis and amidation with 3-amino-6-methoxypyridazine, intramolecular cyclization reaction, and finally the replacement reaction of the ammonia protecting group were completed to obtain Relugolix, but the yield of this step was only 22%. This route has too many steps and a relatively low overall yield. The stepwise 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 an intermediate of Relugolix, a preparation method thereof, and a preparation method of Relugolix that are completely different from the prior art in order to overcome the defects of the prior art in the preparation method of Relugolix, such as harsh reaction conditions, low yield, low purity of the prepared 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-treatment steps, is environmentally friendly, has a high overall yield, the Relugolix product prepared from the intermediate of the present invention has high purity, low heavy metal element content, meets the raw material drug standard, has low production cost, and is suitable for industrial production.

[0012] The present invention provides a method for preparing Relugolix intermediate compound J, and the method includes the following steps:

[0013] (1) Compound G reacts with 3-amino-6-methoxypyridazine under the action of a condensing agent and a base to obtain compound H;

[0014] (2) Compound H undergoes a cyclization reaction with a base to obtain compound I;

[0015] (3) Compound I reacts with a carbamate to obtain compound J;

[0016] The present invention provides compounds H, I, and J, whose structures are as follows:

[0017]

[0018] Among them, R is methyl, ethyl, or tert-butyl.

[0019] Step (1) The present invention provides a preparation method of compound H, which comprises the following steps: Compound G in an organic solvent reacts with 3-amino-6-methoxypyridazine under the action of a condensing agent and a base to undergo an amide condensation reaction to obtain compound H, and its reaction equation is as follows:

[0020]

[0021] 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);

[0022] In step (1), the base is one or more of N,N-diisopropylethylamine and triethylamine;

[0023] In step (1), the condensing agent is one or more of 1-propylphosphonic anhydride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, and HBTU, preferably 1-propylphosphonic anhydride;

[0024] 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;

[0025] In step (1), the reaction temperature is 25-80°C, preferably 50-60°C;

[0026] In step (1), the reaction time is 1-12 h, preferably 1-4 h;

[0027] In step (1), a post-treatment step is also included. More preferably, the post-treatment includes, but is not limited to, steps such as cooling, adjusting the pH value, filtering, washing, and drying;

[0028] In step (1), the steps are as follows: Dissolve compound G in an organic solvent, add 3-amino-6-methoxypyridazine, then add 1-propylphosphonic anhydride, heat up to 50-60 °C, keep warm, and react for 1-4 h; Post-treatment steps: Cool the reaction solution to room temperature, add a base to adjust the pH value to 7-8, filter, wash, and dry.

[0029] Step (2) The present invention provides a method for preparing compound I, which comprises the following steps: Compound H undergoes a cyclization reaction in an organic solvent under the action of a base to obtain compound I, and its reaction equation is as follows:

[0030]

[0031] In step (2), the molar ratio of compound H to the base is 1:(0.01-4), preferably 1:(0.02-0.5)

[0032] 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;

[0033] In step (2), the organic solvent is one or a mixture of methanol, ethanol, tetrahydrofuran, and acetonitrile;

[0034] In step (2), the reaction temperature is 25-80 °C, preferably 40-60 °C;

[0035] In step (2), the reaction time is 0.5-12 h, preferably 1-4 h;

[0036] In step (2), it also includes post-treatment steps. More preferably, the post-treatment includes, but is not limited to, steps such as cooling, adjusting the pH value, filtering, washing, and drying;

[0037] In step (2), the steps are as follows: Dissolve compound H in an organic solvent, add a base, heat up to 40-60 °C, keep warm, and react for 1-4 h; Post-treatment steps: Cool the reaction solution to room temperature, adjust the pH value to 5-7 with an acid, add an alcohol solvent, cool to 0-5 °C, crystallize, filter, and dry.

[0038] Step (3) is a method for preparing compound J, and there are two preparation processes.

[0039] One of the processes includes the following steps: Compound I undergoes a Buchwald-Hartwing C-N coupling reaction with a carbamate in an organic solvent under the action of palladium metal, a ligand, and a base to obtain compound J, and its reaction equation is as follows:

[0040]

[0041] In step (3), the molar ratio of compound I, carbamate, palladium metal, 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);

[0042] In step (3), R1 of the carbamate is methyl, ethyl, propyl, tert-butyl, preferably methyl;

[0043] In step (3), the palladium metal catalyst is Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(PPh3)2Cl2;

[0044] In step (3), the ligand is one or more of SPhos, XPhos, Josiphos, RuPhos, BrettPhos, RockPhos;

[0045] In step (3), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide;

[0046] In step (3), the organic solvent is a mixed solvent of one or more of dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran;

[0047] In step (3), the reaction temperature is 50 - 120°C, preferably 80 - 100°C;

[0048] In step (3), the reaction time is 1 - 24 h, preferably 4 - 10 h;

[0049] In step (3), a post-treatment step is further included. More preferably, the post-treatment includes, but is not limited to, steps such as cooling, extraction, filtration, washing, drying, etc.;

[0050] In step (3), the steps are as follows: Add compound I, methyl carbamate, palladium metal, ligand, and base to an organic solvent, heat to 80 - 100°C, keep warm, and react for 4 - 10 h; Post-treatment steps: Cool the reaction solution to room temperature, extract and concentrate the solvent, add an alcohol solvent, filter, and dry.

[0051] Another process for preparing compound J in step (3) includes the following steps: Compound I in an organic solvent undergoes Ullmann's C-N coupling reaction with carbamate under the action of copper metal, ligand, and base to obtain compound J. The reaction equation is as follows:

[0052]

[0053] In step (3), the molar ratio of compound I, carbamate, copper metal, 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);

[0054] In step (3), R1 of the carbamate is methyl, ethyl, propyl, tert-butyl, preferably methyl;

[0055] In step (3), the copper metal catalyst is one or more of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide;

[0056] In step (3), the ligand is one or more of N,N-dimethylethylenediamine, N,N-diethylsalicylamide, N,N-bis(thiophen-2-ylmethyl)oxamide, N-1-(2-methylnaphthyl)-N-benzyl oxamide, N-1-(2-methylnaphthyl)-N-furan-2-ylmethyl oxamide, (1S,2S)-(+)-1,2-cyclohexanediamine, and o-phenanthroline;

[0057] In step (3), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide;

[0058] In step (3), the organic solvent is a mixed solvent of one or more of dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran;

[0059] In step (3), the reaction temperature is 50 - 150°C, preferably 100 - 130°C;

[0060] In step (3), the reaction time is 1 - 24 h, preferably 12 - 24 h;

[0061] In step (3), a post-treatment step is also included. More preferably, the post-treatment includes, but is not limited to, steps such as cooling, extraction, filtration, washing, and drying;

[0062] In step (3), the steps are as follows: Add compound I, methyl carbamate, copper metal, ligand, and base to an organic solvent, heat to 80 - 100°C, keep warm, and react for 12 - 24 h; Post-treatment steps: Cool the reaction solution to room temperature, extract and concentrate the solvent, add an alcohol solvent, filter, and dry.

[0063] On the basis of the first three-step reaction, the present invention provides a four-step synthesis method of relugolix. On the basis of the first three-step reaction, the following steps are further included: Compound J reacts with methoxylamine hydrochloride in an organic solvent under the action of a base to synthesize relugolix, and the reaction equation is as follows:

[0064]

[0065] Among them, R1 is methyl, ethyl, isopropyl, or tert-butyl;

[0066] The molar ratio of compound J to methoxyamine hydrochloride is 1:(1 - 2);

[0067] Preferably, the organic solvent is one or more of toluene, acetonitrile, dimethyl sulfoxide, and tetrahydrofuran;

[0068] The base is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide;

[0069] The reaction temperature is 20 - 100 °C, preferably 50 - 80 °C;

[0070] The reaction time is 1 - 24 h, preferably 4 - 12 h;

[0071] It also includes post-treatment steps: cooling, filtration, washing, drying, slurrying, etc.;

[0072] The steps are as follows: Dissolve methoxyamine hydrochloride in an organic solvent (such as toluene, acetonitrile), add the base and stir, then add compound J, heat up to 50 - 80 °C for reaction for 4 - 12 h; The post-treatment includes cooling to 0 - 10 °C, filtering, washing the filter cake with an organic solvent, drying to obtain a white solid, adding an organic solvent for slurrying, filtering, and drying.

[0073] The present invention also provides a four-step synthesis method of relugolix, and its reaction equation is as follows:

[0074]

[0075] Wherein R1 is as described above.

[0076] Preferably, H, I, J or relugolix in each step of the reaction equation is as described above.

[0077] The present invention also discloses a compound H, which is prepared according to step (1) of the preparation method of the key intermediate of relugolix described above. The chemical formula of compound H is:

[0078]

[0079] The present invention also discloses a compound I, which is prepared according to steps (1) and (2) of the preparation method of the key intermediate of relugolix described above. The chemical formula of compound I is:

[0080]

[0081] The present invention also discloses a compound J, which is prepared according to steps (1)-(3) of the preparation method of the above-mentioned relugolix key intermediate. The chemical formula of compound J is:

[0082]

[0083] The present invention also discloses a compound relugolix, which is prepared according to steps (1)-(3) of the preparation method of the above-mentioned relugolix key intermediate. The chemical formula of compound relugolix is:

[0084]

[0085] Beneficial technical effects:

[0086] The novel intermediates of relugolix of the present invention (including formula H, formula I, formula J) 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.

[0087] The present invention uses compound of formula J to prepare relugolix, avoiding the generation of biuret by-products, and can greatly reduce the cost of crude product purification.

[0088] The preparation method of relugolix of the present invention uses compound G as the starting material, and first introduces a pyridazine fragment, and its yield and purity are both high. Subsequently, API crystals with a light yellow color can be stably obtained; on the other hand, compared with the methods disclosed in the prior art, during the ring-closing step reaction process of the present invention, no foamy solid appears, the stirring is smooth, and the relative solvent usage is small. Therefore, the production process of the present invention is conducive to large-scale production. Description of the Drawings

[0089] 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 some embodiments of the present invention and should not be regarded as limiting the scope.

[0090] Figure 1 1H NMR spectrum of relugolix provided in Example 1 of the present invention;

[0091] Figure 2 13C NMR spectrum of relugolix provided in Example 1 of the present invention.

[0092] Figure 3 High-resolution mass spectrum of relugolix provided in Example 1 of the present invention. Detailed Description of the Invention

[0093] The above contents of the present invention will be further described in detail by way of examples below. However, 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 implemented based on the above contents of the present invention fall within the scope of the present invention.

[0094] The raw materials and reagents used in the present invention are all known products and are obtained by purchasing commercially available products.

[0095] Example 1. Preparation of relugolix of the present invention

[0096] Step 1. Synthesis of isobutyl (2,6-difluorobenzyl)-[4-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0097]

[0098] Under the protection of nitrogen, 18.00 g of Compound G, 4.65 g of 3-amino-6-methoxypyridazine, and 80 mL of N,N-dimethylacetamide were added to a clean 250 mL reaction flask, and mechanically stirred. At 30 °C, 10.01 g of N,N-diisopropylethylamine was added dropwise, and the mixture was stirred for 30 min. At 55 - 60 °C, a solution of 23.64 g of 50% propylphosphonic anhydride in ethyl acetate was added dropwise, and the container used was washed with 10 mL of N,N-dimethylacetamide. The mixture was stirred at 55 °C for 2 hours. Then, at room temperature, 135 mL of water was added dropwise and stirred for 1 hour. At room temperature, the pH was adjusted to 7 - 8 with 40% KOH and stirred for 1 hour. The mixture was filtered by suction, washed with 40 mL of ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 20.17 g of a light yellow solid, with a yield of 94.66% and a purity of 97.52%.

[0099] The NMR data are as follows: 1 H NMR(400MHz,Chloroform-d):δ13.98(s,1H),8.56(d,J=12Hz,1H),7.55(d,J=8.0Hz,2H),7.16 - 7.08(m,3H),6.98(d,J=8.0Hz,1H),6.74(t,J=8.0Hz,2H),5.02(s,2H),4.10(s,2H),3.92(d,J=8.0Hz,2H),3.48(s,2H),2.20(s,6H),1.82(m,1H),0.77(d,J=8.0Hz,6H).

[0100] HRMS m / z:688.1404[M+H] +

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

[0102]

[0103] Put 75 g of Compound H, 3.92 g of 30% sodium methoxide in methanol solution, and 750 mL of methanol into a clean reaction flask and start mechanical stirring; heat up to 55 - 65 °C and stir for 2 hours. At 20 °C, add concentrated hydrochloric acid to adjust the pH value to 6 - 7 and stir for 1 hour; add 750 mL of isopropanol thereto and stir in this system for 0.5 min, then cool down to 0 - 5 °C and stir for 1 hour, filter, wash with ice-cold isopropanol, and dry under reduced pressure at 45 °C to obtain 61.21 g of a light yellow solid, with a yield of 91.47% and a purity of 98.53%.

[0104] The NMR data are as follows: 1 H NMR(400MHz,Chloroform-d):δ7.55(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,1H),7.30(m,J=8.4,1H),7.11(d,J=8.0Hz,1H),6.91(t,J=8.0Hz,2H),5.34(s,2H),4.17(s,3H),3.65(s,2H),2.15(s,6H).

[0105] HRMS m / z:614.0659[M+H] +

[0106] Step 3. Synthesis of methyl {4-(1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl}carbamate (Compound J):

[0107]

[0108] Step 3 is divided into two process routes according to different choices of reaction reagents.

[0109] Process Route 1 of Step 3:

[0110] At room temperature, 30.7 g of Compound I, 11.7 g of methyl carbamate and 245.6 mL of toluene were stirred and dissolved, then 112 mg of Pd(OAc)₂ and 476.7 mg of Xphos were added. 24.5 g of cesium carbonate was added, and the mixture was purged with nitrogen three times. The temperature was raised to 80 - 85 °C, and the mixture was stirred and reacted for 10 h, with sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and 245.6 mL of ammonium chloride solution was added to quench the reaction. Liquid - liquid extraction was carried out. The aqueous phase was extracted with 245.6 mL of toluene twice. The toluene layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. 307 mL of n - heptane was added for slurrying, filtration was carried out, and the product was washed with ice - cold ethanol and dried under reduced pressure at 45 °C to obtain 24.73 g of a yellow solid, with a yield of 80.55% and a purity of 95.16%.

[0111] Step 3, Process 2:

[0112] At room temperature, 3.07 g of Compound I, 1.17 g of methyl carbamate and 24 mL of dimethyl sulfoxide were stirred and dissolved, then 94.92 mg of copper(I) iodide and 151.56 mg of N - 1 - (2 - methylnaphthalenyl) - N - benzyloxamide were added. 841 mg of potassium tert - butoxide was added, and the mixture was purged with nitrogen three times. The temperature was raised to 110 - 120 °C, and the mixture was stirred and reacted for 24 h, with sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, 24 mL of ammonium chloride solution was added to quench the reaction, and 24 mL of ethyl acetate was added for extraction three times. The aqueous phase was extracted with 24 mL of ethyl acetate twice. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. 31 mL of n - heptane was added for slurrying, filtration was carried out, and the product was washed with ice - cold ethanol and dried under reduced pressure at 45 °C to obtain 2.36 g of a yellow solid, with a yield of 78.60% and a purity of 96.35%.

[0113] The NMR data are as follows: 1 H NMR(400MHz,Chloroform - d):δ7.47(s,4H),7.34–7.27(m,1H),7.12(d,J=8.0Hz,1H),6.91(t,J=8.0Hz,2H),6.88(s,1H),5.38(s,2H),4.17(s,3H),3.78(s,3H),3.55(s,2H),2.13(s,6H).

[0114] HRMS m / z:609.1723[M + H] +

[0115] Step 4. Synthesis of 1 - {4 - [1 - (2,6 - difluorobenzyl)-5 - dimethylaminomethyl - 3 - (6 - methoxypyridazin - 3 - yl)-2,4 - dioxo - 1,2,3,4 - tetrahydrothieno[2,3 - d]pyrimidin - 6 - yl]-phenyl}-3 - methoxyurea (relugolix):

[0116]

[0117] Under an ice-water bath, 1.58 g of methoxyamine hydrochloride and 1.92 g of potassium tert-butoxide were added to 31 mL of dimethyl sulfoxide, and the mixture was stirred at the same temperature. After about 30 minutes or longer, 6.08 g of Compound J was added to the system. The reaction system was heated to 70 - 80 °C and reacted for 4 hours, and a sample was taken to detect the completion of the reaction. The temperature was lowered to 0 - 10 °C, 31 mL of ethanol was added, and crystallization was carried out by stirring for 1 hour. Filtration was carried out, and it was washed with ice-cold ethanol and dried under reduced pressure at 45 °C to obtain 4.83 g of a white solid, with a yield of 78% and a purity of 96.23%. The obtained product was detected to obtain the Figures 1-3 attached 1H NMR spectrum, 13C NMR spectrum, and high-resolution mass spectrum.

[0118] The NMR data is as follows: 1 H NMR(400MHz,Chloroform-d):δ8.06(s,1H),7.88(s,1H),7.55(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,1H),7.42(d,J=12Hz,2H),7.32(m,1H),7.14(d,J=8.0Hz,1H),6.91(t,J=8.0Hz,2H),5.30(s,2H),4.18(s,3H),3.77(s,3H),3.59(s,2H),2.13(s,6H).HRMS m / z:624.1822[M+H] +

[0119] Example 2. Preparation of Relugolix of the present invention

[0120] Step 1. Synthesis of isobutyl (2,6-difluorobenzyl)-[4-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0121] 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 flask, and mechanically stirred; at 25 °C, 10.01 g of DIPEA was added dropwise, and stirred for 30 min. At 55-60 °C, 14.64 g of HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) was added, and the solvent used in 10 mL of tetrahydrofuran was used, and stirred at 55 °C for 2 hours; then at 0-10 °C, 135 mL of water was added dropwise and stirred for 1 hour; at room temperature, the pH was adjusted to 7-8 with 40% KOH and stirred for 1 hour; filtered by suction, washed with 40 mL of ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 19.82 g of a light yellow solid, with a yield of 89.11% and a purity of 93.57%.

[0122] Step 2: Synthesis of 1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-bromophenyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Compound I):

[0123] 75 g of compound H, 1.96 g of 30% sodium methoxide methanol solution and 750 mL of tetrahydrofuran were added to a clean reaction flask and mechanical stirring was started; the temperature was raised to 55-65 °C and stirred for 4 hours. At 20 °C, concentrated hydrochloric acid was added to adjust the pH value to 6-7 and stirred for 1 hour; the tetrahydrofuran was concentrated under reduced pressure, cooled to room temperature, 750 mL of isopropanol was added thereto, and stirred in this system for 0.5 min, then cooled to 0-5 °C and stirred for 1 hour, filtered, washed with ice-cold isopropanol, and dried under reduced pressure at 45 °C to obtain 60.35 g of a light yellow solid, with a yield of 90.37% and a purity of 97.51%.

[0124] Step 3: Synthesis of methyl {4-(1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl}carbamate (Compound J):

[0125] Step 3 is divided into two process routes according to the different choices of reaction reagents.

[0126] Process Route 1 of Step 3:

[0127] At room temperature, 30.7 g of Compound I, 11.7 g of methyl carbamate and 245.6 mL of dioxane were stirred and dissolved, then 457 mg of Pd2(dba)3 and 233.32 mg of Ruphos were added. 24.5 g of cesium carbonate was added, and the mixture was purged with nitrogen three times. The temperature was raised to 80 - 85 °C and the mixture was stirred and reacted for 8 h, with sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched by adding 245.6 mL of ammonium chloride solution. The mixture was extracted twice with 245.6 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 307 mL of n-heptane was added for slurrying, and the mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 25.82 g of a yellow solid, with a yield of 84.91% and a purity of 96.14%.

[0128] Process 2 of Step 3:

[0129] At room temperature, 3.07 g of Compound I, 1.17 g of methyl carbamate and 24 mL of DMF were stirred and dissolved, then 99 mg of copper(I) chloride and 303.12 mg of N-1-(2-methylnaphthalen-1-yl)-N-benzyloxamide were added. 841 mg of potassium tert-butoxide was added, and the mixture was purged with nitrogen three times. The temperature was raised to 110 - 120 °C and the mixture was stirred and reacted for 24 h, with sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched by adding 24 mL of ammonium chloride solution. The mixture was extracted three times with 24 mL of ethyl acetate, and the aqueous phase was extracted twice with 24 mL of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 31 mL of n-heptane was added for slurrying, and the mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 2.51 g of a yellow solid, with a yield of 82.56% and a purity of 97.21%.

[0130] Step 4. Synthesis of 1-{4-[1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (relugolix):

[0131] Under an ice-water bath, 1.58 g of methoxyamine hydrochloride and 1.08 g of sodium methoxide were added to 31 mL of acetonitrile, and the mixture was stirred at the same temperature. After about 30 minutes or longer, 6.08 g of Compound J was added to the system. The reaction system was heated to 70 - 80 °C and reacted for 4 h, with sampling for detecting complete reaction. The temperature was lowered to 0 - 10 °C, 31 mL of ethanol was added, and the mixture was stirred for crystallization for 1 h. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 4.68 g of a white solid, with a yield of 75% and a purity of 98.93%.

[0132] Example 3. Preparation of relugolix of the present invention

[0133] Step 1. Synthesis of Isobutyl (2,6-difluorobenzyl)-[4-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-bromophenyl)thiophen-2-yl]carbamate (Compound H):

[0134] Under the protection of nitrogen, 18.00 g of Compound G, 4.65 g of 3-amino-6-methoxypyridazine, and 80 mL of ethyl acetate were added to a clean 250 mL reaction flask, and mechanically stirred. At 30 °C, 10.01 g of DIPEA was added dropwise, and the mixture was stirred for 30 min. At 55 - 60 °C, a solution of 25.21 g of 50% propylphosphonic anhydride in ethyl acetate was added dropwise, and the container used was washed with 10 mL of ethyl acetate. The mixture was stirred at 55 °C for 2 h. Then, at 0 - 10 °C, 135 mL of water was added dropwise, and the mixture was stirred for 1 h. At room temperature, the pH was adjusted to 7 - 8 with 40% KOH, and the mixture was stirred for 1 h. It was filtered by suction, washed with 40 mL of ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 19.58 g of a light yellow solid, with a yield of 88.04% and a purity of 96.32%.

[0135] Step 2. Synthesis of 1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-6-(4-bromophenyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Compound I):

[0136] 75 g of Compound H, 4.94 g of a 30% sodium ethoxide ethanol solution, and 750 mL of ethanol were added to a clean reaction flask, and mechanical stirring was started. The temperature was raised to 55 - 65 °C and stirred for 2 h. At 20 °C, concentrated hydrochloric acid was added to adjust the pH to 6 - 7, and the mixture was stirred for 1 h. 750 mL of isopropanol was added thereto, and the mixture was stirred in this system for 0.5 min, then cooled to 0 - 5 °C and stirred for 1 h, filtered, washed with ice-cold isopropanol, and dried under reduced pressure at 45 °C to obtain 63.58 g of a light yellow solid, with a yield of 95.15% and a purity of 98.53%.

[0137] Step 3. Synthesis of Methyl {4-(1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl}carbamate (Compound J):

[0138] Step 3 is divided into two process routes according to different selections of reaction reagents.

[0139] Process Route 1 of Step 3:

[0140] At room temperature, 30.7 g of Compound I, 11.7 g of methyl carbamate and 245.6 mL of dimethyl sulfoxide were stirred and dissolved, then 112 mg of Pd(OAc)₂ and 476.7 mg of Xphos were added, followed by 10.35 g of potassium carbonate. After purging with nitrogen three times, the temperature was raised to 95 °C and the mixture was stirred and reacted for 12 h while sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched by adding 245.6 mL of ammonium chloride solution. The mixture was extracted twice with 245.6 mL of dichloromethane, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase was slurried with 307 mL of n-heptane, filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 24.73 g of a yellow solid, with a yield of 80.55% and a purity of 95.16%.

[0141] Process 2 of Step 3:

[0142] At room temperature, 3.07 g of Compound I, 2.34 g of methyl carbamate and 24 mL of DMSO were stirred and dissolved, then 99 mg of cuprous chloride and 140.18 mg of N,N-bis(thiophen-2-ylmethyl)oxamide were added, followed by 841 mg of potassium tert-butoxide. After purging with nitrogen three times, the temperature was raised to 110 - 120 °C and the mixture was stirred and reacted for 24 h while sampling for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched by adding 24 mL of ammonium chloride solution. The mixture was extracted three times with 24 mL of ethyl acetate, and the aqueous phase was extracted twice with 24 mL of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase was slurried with 31 mL of n-heptane, filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 2.69 g of a yellow solid, with a yield of 88.48% and a purity of 96.37%.

[0143] Step 4. Synthesis of 1-{4-[1-(2,6-difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (relugolix):

[0144] Under an ice-water bath, 1.58 g of methoxylamine hydrochloride and 2.58 g of sodium tert-butoxide were added to 31 mL of dimethyl sulfoxide, and the mixture was stirred at the same temperature. After about 30 minutes or longer, 6.08 g of Compound J was added to the system. The reaction system was heated to 70 - 80 °C and reacted for 4 h while sampling for detecting complete reaction. The temperature was lowered to 0 - 10 °C, 31 mL of ethanol was added, and the mixture was stirred for crystallization for 1 h. The product was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 4.96 g of a white solid, with a yield of 79% and a purity of 93.57%.

[0145] In summary, the present invention provides a method for preparing relugolix. The method of the present invention adopts a route of first closing the ring and then coupling, which has simpler operation, fewer side reactions, mild reaction conditions, high yield and purity, easy purification of the product, and low production cost, and is more suitable for commercial scale production.

Claims

1. A four-step synthesis method of relugolix, characterized in that: Its synthetic route includes: It includes the following steps: (1) Compound G reacts with 3-amino-6-methoxypyridazine under the action of a condensing agent and a base to obtain compound H; (2) Compound H undergoes a cyclization reaction under the action of a base to obtain compound I; (3) Compound I reacts with a carbamate under the action of palladium metal or copper metal, a ligand, and a base to obtain compound J; (4) Compound J undergoes a transesterification reaction with methoxylamine hydrochloride under the action of a base to obtain relugolix.

2. The four-step synthesis method of relugolix according to claim 1, wherein: 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); the reaction temperature is 25-80 °C; the reaction time is 1-12 h.

3. The four-step synthesis method of relugolix according to claim 1, wherein: In step (2), the molar ratio of compound H and base is 1:(0.01-4); the reaction temperature is 25-80 °C; the reaction time is 0.5-12 h; the base is selected from one of sodium methoxide and sodium ethoxide; the organic solvent is one or more of methanol, ethanol, tetrahydrofuran, and acetonitrile.

4. Compound J: Among them, R is methyl, ethyl, or tert-butyl.

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

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

7. The four-step synthesis method of relugolix according to claim 1, characterized in that: In step (3), when copper metal is used as a catalyst, the molar ratio of compound I, carbamate, copper metal, ligand, and base is 1:(1-2): (0.01-0.2):(0.01-0.2):(1-3); the copper metal catalyst is one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide; the ligand is selected from one of N,N-dimethylethylenediamine, N,N-diethylsalicylamide, N,N-bis-(thiophen-2-ylmethyl)-oxamide, N-1-(2-methylnaphthyl)-N-benzyl-oxamide, N-1-(2-methylnaphthyl)-N-furan-2-ylmethyl-oxamide, (1S,2S)-(+)-1,2-cyclohexanediamine, and o-phenanthroline.

8. The four-step synthesis method of relugolix according to claim 1, wherein: In step (3), when metallic copper is used as the 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.

9. The four-step synthesis method of relugolix according to claim 1, characterized in that: In step (4), the molar ratio of compound J to methoxylamine hydrochloride is 1:(1-2); the organic solvent is selected from one or more of toluene, acetonitrile, dimethyl sulfoxide, and tetrahydrofuran; the base is selected from one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide; the reaction temperature is 20-100 °C; the reaction time is 1-24 h.

10. Relugolix, characterized in that: It is prepared by the four-step synthesis method of relugolix according to claim 1.

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