Rilugolimod and three-step synthetic process thereof

Abstract

The application provides a three-step synthesis method of relugolix, and belongs to the technical field of drug synthesis. The preparation method comprises the following steps: (1) compound G is reacted with 3-amino-6-methoxypyridazine in the presence of a condensing agent and an alkali to obtain compound H; (2) compound H is subjected to a cyclization reaction in the presence of an alkali to obtain compound I; and (3) compound I is reacted with N-methoxyurea in the presence of metal palladium or copper, a ligand and an alkali to obtain relugolix. The application has the advantages of mild reaction condition, high reaction yield, few side reactions, good product purification, low production cost, green environmental protection and commercial scale.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, specifically to a relugoli and its three-step synthesis method. Background Technology

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

[0003] Relugolix, CAS No.: 737789-87-6, chemical name: 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 disorders. It was approved for marketing in Japan on January 8, 2019, under the brand name Relumina, for the following indications caused by uterine leiomyomas: menorrhagia, lower abdominal pain, back pain, and anemia. On December 18, 2020, Relugolix received FDA approval and will be marketed by Myovant Sciences GmbH under the brand name Orgovyx for the treatment of advanced prostate cancer in adults.

[0004] Patent CN104703992 discloses a method for preparing Relugolix, with the following synthetic route. This method involves cyclizing compound 2 (CAS: 174072-89-0) first, then coupling it to obtain intermediates 3-9 sequentially. Intermediate 9 is then used as a starting material to sequentially prepare intermediates 10 and 11, ultimately yielding the product Relugolix. However, this method uses the highly toxic substance ethyl chloroformate, has low flash point, and requires harsh reaction conditions. The nitro reduction reaction needs to be carried out under heating and pressure, placing high demands on the equipment.

[0005]

[0006] The following is another synthetic route for Religolix disclosed in patent CN 110194776 B: 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 ethyl chloroformate. However, this route also requires the nitro reduction reaction to be carried out under heating and pressure conditions, which places high demands on the equipment.

[0007]

[0008] Takeda Pharmaceuticals J.Med.Chem. 2011, vol.54, pp.4998–5012. Another original research route reported: using ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate (11) as the starting material, the amino group was protected by ethyl chloroformate, and then nucleophilic substitution was carried out with 2,6-difluorobenzyl chloride under alkaline conditions to obtain intermediate 2; using AIBN (azobisisobutyronitrile) as a free radical initiator, thiophene methyl monobromination reaction was carried out with NBS to generate intermediate 3; 3 reacted with N-(2-methoxyethyl)methylamine under alkaline conditions to generate intermediate 34; then catalytic hydrogenation and coupling were carried out to complete the construction of alkoxyurea, and then ester hydrolysis, amidation of 3-amino-6-methoxypyridazine, intramolecular cyclization reaction, and finally the amino protecting group substitution reaction was completed to obtain relugoli, but the yield of this step was only 22%. The route is too lengthy, resulting in a low overall yield. The stepwise synthesis of the N,N-dimethyl fragment is the main cause of these problems.

[0009]

[0010] Therefore, developing a method for preparing rilugoline that is low-cost, high-yield, has mild reaction conditions, low equipment requirements, and high product purity has great application value. Summary of the Invention

[0011] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for preparing regrangolide, such as harsh reaction conditions, low yield, low product purity, excessive heavy metal content, high equipment requirements, and unsuitability for industrial production. This invention provides a regrangolide intermediate, its preparation method, and a method for preparing regrangolide that are completely different from existing technologies. The preparation method of this invention is simple and safe to operate, has simple post-processing steps, is environmentally friendly, has a high overall yield, and the regrangolide product obtained using the intermediate of this invention has high purity, low heavy metal content, meets the standards for active pharmaceutical ingredients, has low production costs, and is suitable for industrial production.

[0012] This invention provides a method for preparing relugoli, the method comprising the following steps:

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

[0014] (2) Compound H undergoes a cyclization reaction under alkaline conditions to give compound I;

[0015] This invention provides compounds G, H, and I, the structures of which 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 reacts with 3-amino-6-methoxypyridazine in an organic solvent under the action of a condensing agent and a base to obtain compound H, the reaction equation of which 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 25–80°C, preferably 50–60°C;

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

[0025] Step (1) also includes a post-processing step. More preferably, the post-processing includes, but is not limited to, cooling, pH adjustment, filtration, washing, and drying steps.

[0026] In step (1), the specific steps are as follows: dissolve compound G in an organic solvent, add 3-amino-6-methoxypyridazine, then add 1-propylphosphonic anhydride, heat to 50-60℃, keep warm, and react for 1-4 hours; post-treatment steps: cool the reaction solution to room temperature, add alkali to adjust the pH value to 7-8, filter, wash, and dry.

[0027] Step (2) The present invention provides a method for preparing compound I, comprising the following steps: compound H undergoes a cyclization reaction with a base in an organic solvent to obtain compound I, and 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, wherein the base is sodium methoxide or sodium ethoxide;

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

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

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

[0034] Step (2) also includes a post-processing step. More preferably, the post-processing includes, but is not limited to, cooling, pH adjustment, filtration, washing, and drying steps.

[0035] In step (2), the steps are as follows: dissolve compound H in an organic solvent, add alkali, heat to 40-60℃, keep warm, and react for 1-4 hours; post-treatment steps: cool the reaction solution to room temperature, adjust the pH value to 5-7 with acid, add alcohol solvent, cool to 0-5℃, crystallize, filter, and dry.

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

[0037] Step (3) One of the processes includes the following steps: Compound I reacts with N-methoxyurea in an organic solvent in the presence of palladium, a ligand, and a base via a Buchwald-Hartwing CN coupling reaction to obtain relugoli. The reaction equation is as follows:

[0038]

[0039] In step (3), the molar ratio of compound I, N-methoxyurea, 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 palladium catalyst is one or more of Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, and 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 alkali 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 mixture thereof;

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

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

[0046] Step (3) also includes a post-processing step, and more preferably, the post-processing includes, but is not limited to, cooling, extraction, filtration, washing, drying and other steps.

[0047] In step (3), the steps are as follows: add compound I, N-methoxyurea, palladium metal, ligand, and base to an organic solvent, heat to 80-100℃, keep warm, and react for 4-10 hours; post-processing steps: cool the reaction solution to room temperature, extract and concentrate the solvent, add an alcohol solvent, filter, and dry.

[0048] Step (3) Another three-step synthetic method for regrugoli includes the following steps: Compound I reacts with N-methoxyurea in an organic solvent in the presence of copper, a ligand, and a base via a Ullmann CN coupling reaction to obtain regrugoli. 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 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-diethylsalicylic acid amide, N,N-di-(thiophene-2-methyl)-oxalic acid diamide, N-1-(2-methylnaphthyl)-N-benzyloxalic 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 alkali 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 mixture thereof;

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

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

[0057] Step (3) also includes a post-processing step, and more preferably, the post-processing includes, but is not limited to, cooling, extraction, filtration, washing, drying and other steps.

[0058] In step (3), the steps are as follows: add compound I, N-methoxyurea, metallic copper, ligand, and base to an organic solvent, heat to 80-100℃, keep warm, and react for 12-24 hours; post-processing steps: cool the reaction solution to room temperature, extract and concentrate the solvent, add an alcohol solvent, filter, and dry.

[0059] This invention also provides a three-step synthesis method for relugoli, the reaction equation of which is as follows:

[0060]

[0061] Preferably, the steps G, H, I, or relugoli in the reaction equation are as described above.

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

[0063]

[0064] This invention also discloses a compound I, which is prepared according to steps (1) and (2) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of compound I is:

[0065]

[0066] This invention also discloses a compound called relugoli, which is prepared according to steps (1)-(3) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of the compound relugoli is:

[0067]

[0068] Beneficial technical effects:

[0069] The present invention provides novel intermediates of retargide (including compounds of formula G, H, and I) that can be used to prepare retargide. These intermediates are simple to prepare, are all solids with good properties, stable properties, high purity, and low purification cost.

[0070] This invention employs a one-step method based on compound formula I to prepare rilugoline, shortening the operation steps and avoiding the generation of urea byproducts, thus significantly reducing the cost of crude product purification.

[0071] The method for preparing regrugoli of the present invention uses compound G as the starting material and first introduces a pyridazine fragment, which has high yield and purity. Subsequently, it can stably obtain API crystals with light yellow properties. On the other hand, compared with the methods disclosed in the prior art, no foamy solids appear during the cyclization step of the present invention, the stirring is smooth, and the amount of solvent used is relatively small. Therefore, the production process of the present invention is conducive to large-scale production. Attached Figure Description

[0072] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope.

[0073] Figure 1 The hydrogen NMR spectrum of rilugoli provided in Example 1 of this invention;

[0074] Figure 2 The carbon NMR spectrum of rilugoli provided in Example 1 of this invention.

[0075] Figure 3 This is a high-resolution mass spectrum of rilugoli provided in Embodiment 1 of the present invention. Detailed Implementation

[0076] The following embodiments further illustrate the above-described content of the present invention in detail, but should not be construed as limiting the scope of the subject matter of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

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

[0078] Example 1: Preparation of Relugoline of the Present Invention

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

[0080]

[0081] Under nitrogen protection, 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, 23.64 g of a 50% propylphosphonic anhydride ethyl acetate solution was added dropwise, and the container was washed with 10 mL of N,N-dimethylacetamide. The mixture was stirred at 55 °C for 2 hours. Then, at 0–10 °C, 135 mL of water was added dropwise, and the mixture was stirred for 1 hour. At 0–10 °C, the pH was adjusted to 7–8 with 40% KOH, and the mixture was stirred for 1 hour. The mixture was filtered, washed with 40 mL of ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 20.17 g of a pale yellow solid, with a yield of 94.66% and a purity of 97.52%.

[0082] The NMR data are as follows: ¹H NMR (400MHz, Chloroform-d): δ (13.98s, 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).

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

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

[0085]

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

[0087] The NMR data are as follows: 1H NMR (400MHz, Chloroform-d): δ 7.55 (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).

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

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

[0090]

[0091] Based on the choice between palladium or copper, the reaction routes are as follows:

[0092] Step 3, Process 1:

[0093] At room temperature, 30.7 g of compound I, 6.75 g of N-methoxyurea, and 245.6 mL of toluene were dissolved by stirring. Then, 112 mg of Pd(OAc)₂, 476.7 mg of Xphos, and 24.5 g of cesium carbonate were added. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 10 h, with samples taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched by adding 245.6 mL of ammonium chloride solution. The mixture was extracted and separated. The aqueous phase was extracted twice with 245.6 mL of toluene. The combined toluene layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The mixture was then stirred with 307 mL of n-heptane, filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 26.52 g of white solid, i.e., yield 85% and purity 98.16%.

[0094] Step 3, Process 2:

[0095] At room temperature, 3.07 g of compound I, 675.1 mg of N-methoxyurea, and 24 mL of dimethyl sulfoxide were dissolved by stirring. Then, 94.92 mg of cuprous iodide and 151.56 mg of N-1-(2-methylnaphthyl)-N-benzyloxalic acid diamide were added, followed by 841 mg of potassium tert-butoxide. The mixture was purged with nitrogen three times, heated to 110-120 °C, and stirred for 24 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 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, concentrated under reduced pressure, and slurried with 31 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 2.87 g of a yellow solid, with a yield of 76.46% and a purity of 96.35%. The final product was tested, and the following results were obtained: Figure 1-3 The hydrogen NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrum.

[0096] The NMR data are as follows: 1H NMR (400MHz, Chloroform-d): δ 8.06 (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).

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

[0098] Example 2: Preparation of Relugoline of the Present Invention

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

[0100] Under nitrogen protection, 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 30 °C, 10.01 g of DIPEA (N,N-diisopropylethylamine) was added dropwise, and the mixture was stirred for 30 min. At 55–60 °C, 14.64 g of HBTU (benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate) was added, and the container was washed with 10 mL of tetrahydrofuran. The mixture was stirred at 55 °C for 2 hours. Then, at 0–10 °C, 135 mL of water was added dropwise, and the mixture was stirred for 1 hour. Finally, at 0–10 °C, 40%... Adjust the pH to 7-8 with KOH and stir for 1 hour; filter, wash with 40 mL of ice-cold methanol, and dry under reduced pressure at 45 °C to obtain 19.82 g of light yellow solid, i.e., yield 89.11% and purity 93.57%.

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

[0102] Add 75g of compound H, 1.96g of 30% sodium methoxide methanol solution, and 750mL of tetrahydrofuran to a clean reaction flask and start mechanical stirring; heat to 55-65℃ and stir for 2 hours; add concentrated hydrochloric acid at 20℃ to adjust the pH to 6-7 and stir for 1 hour; concentrate the tetrahydrofuran under reduced pressure, cool to room temperature, add 750mL of isopropanol, and stir the system for 0.5 hours; then cool to 0-10℃ and stir for 1 hour; filter, wash with ice-cold isopropanol, and dry under reduced pressure at 45℃ to obtain 60.35g of light yellow solid, i.e., yield 90.37% and purity 97.51%.

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

[0104] Based on the choice between palladium or copper, the reaction routes are as follows:

[0105] Step 3, Process 1:

[0106] At room temperature, 30.7 g of compound I, 6.75 g of N-methoxyurea, and 245.6 mL of dioxane were dissolved by stirring. Then, 457 mg of Pd2(dba)3, 233.32 mg of RuXphos, and 24.5 g of cesium carbonate were added. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 10 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with 307 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 28.36 g of white solid, i.e., yield 90.46% and purity 96.25%.

[0107] Step 3, Process 2:

[0108] At room temperature, 3.07 g of compound I, 675.1 mg of N-methoxyurea, and 24 mL of DMF were dissolved by stirring. Then, 99 mg of cuprous chloride, 303.12 mg of N-1-(2-methylnaphthyl)-N-benzyloxalic acid diamide, and 841 mg of potassium tert-butoxide were added. The mixture was purged with nitrogen three times, heated to 110-120 °C, and stirred for 24 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 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, concentrated under reduced pressure, and slurried with 31 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 2.76 g of a yellow solid, with a yield of 88.03% and a purity of 92.28%.

[0109] Example 3: Preparation of Relugoline of the Present Invention

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

[0111] Under nitrogen protection, 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, 23.64 g of a 50% propylphosphonic anhydride ethyl acetate solution was added dropwise, and the container was washed with 10 mL of ethyl acetate. The mixture was stirred at 55 °C for 2 hours. Then, at 0–10 °C, 135 mL of water was added dropwise, and the mixture was stirred for 1 hour. At 0–10 °C, the pH was adjusted to 7–8 with 40% KOH, and the mixture was stirred for 1 hour. The mixture was filtered, washed with 40 mL of ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 19.58 g of a pale yellow solid, with a yield of 88.04% and a purity of 96.32%.

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

[0113] Add 75g of compound H, 4.94g of 30% sodium ethoxide ethanol solution, and 750mL of ethanol to a clean reaction flask and start mechanical stirring; heat to 55-65℃ and stir for 2 hours; add concentrated hydrochloric acid at 20℃ to adjust the pH to 6-7 and stir for 1 hour; add 750mL of isopropanol and stir for 0.5 hours; then cool to 0-10℃ and stir for 1 hour; filter, wash with ice-cold isopropanol, and dry under reduced pressure at 45℃ to obtain 61.21g of light yellow solid, i.e., yield 95.15% and purity 98.53%.

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

[0115] Based on the choice of either palladium or copper, the reaction process can be divided into the following two types:

[0116] Step 3, Process 1:

[0117] At room temperature, 30.7 g of compound I, 8.1 g of N-methoxyurea, and 245.6 mL of dimethyl sulfoxide were dissolved by stirring. Then, 112 mg of Pd(OAc)₂ and 476.7 mg of Xphos were added, followed by 10.35 g of potassium carbonate. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 10 h, with samples taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 245.6 mL of ammonium chloride solution. The mixture was extracted twice with 245.6 mL of dichloromethane, and the organic layers were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with 307 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 25.38 g of white solid, with a yield of 80.95% and a purity of 97.61%.

[0118] Step 3, Process 2:

[0119] At room temperature, 3.07 g of compound I, 810 mg of N-methoxyurea, and 24 mL of dimethyl sulfoxide were dissolved by stirring. Then, 94.92 mg of cuprous iodide and 140.18 mg of N,N-di-(thiophene-2-methyl)-oxalic acid diamide were added, followed by 841 mg of potassium tert-butoxide. The mixture was purged with nitrogen three times, heated to 110-120 °C, and stirred for 24 h, with samples taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 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, concentrated under reduced pressure, and slurried with 31 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 2.36 g of a yellow solid, with a yield of 74.59% and a purity of 93.99%.

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

Claims

1. A three-step synthesis method for regrugoli, characterized in that: Its synthetic route includes: Includes the following steps: (1) Compound G reacts with 3-amino-6-methoxypyridazine to give compound H; (2) Compound H undergoes a cyclization reaction under the action of a base to give compound I; (3) Compound I reacts with N-methoxyurea in the presence of palladium or copper, ligands, and base to yield retlugoline; When palladium is used in step (3), the palladium 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. When copper is used in step (3), the copper is one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide; the ligand is selected from one of N,N-dimethylethylenediamine, N,N-diethylsalicylic acid amide, N,N-di-(thiophene-2-methyl)-oxalic acid diamide, N-1-(2-methylnaphthyl)-N-benzyloxalic acid diamide, N-1-(2-methylnaphthyl)-N-furan-2-methyl-oxalic acid diamide, (1S,2S)-(+)-1,2-cyclohexanediamine, and o-phenanthroline.

2. The three-step synthesis method for relugoli 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℃; and the reaction time is 1~12h.

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

4. The three-step synthesis method for relugoli 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℃; and the reaction time is 0.5~12h.

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

6. The three-step synthesis method of relugoli according to claim 1, characterized in that: In step (3), when palladium is used as a catalyst, the molar ratio of compound I, N-methoxyurea, palladium, ligand, and base is 1:(1-2):(0.001-0.2):(0.001-0.2):(1-3).

7. The three-step synthesis method of relugoli according to claim 1, characterized in that: In step (3), when palladium 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; and the reaction time is 1–24 h.

8. The three-step synthesis method of relugoli according to claim 1, characterized in that: In step (3), when using metallic copper as a catalyst, 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).

9. The three-step synthesis method of relugoli according to claim 1, characterized in that: In step (3), when using metallic copper 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℃, and the reaction time is 1–24h.

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