A relugoli intermediate and its preparation method

Abstract

This invention provides a regrugoline intermediate and its preparation method, belonging to the field of pharmaceutical synthesis technology. The preparation method of the regrugoline intermediate specifically includes the following steps: (1) reacting p-bromophenylacetic acid with a catalyst and acetic anhydride and acetic acid to generate compound A; (2) reacting compound A with ethyl cyanoacetate and elemental sulfur under the action of a base to generate compound B; (3) reacting compound B with isobutyl chloroformate to generate compound C; (4) reacting compound C with 2,6-difluorobenzyl chloride under the action of a base to generate compound D; (5) reacting compound D with N-methoxyurea under the action of palladium, a ligand, and a base to generate compound E. This invention features mild reaction conditions, high reaction yield, strong operability, low production cost, and is environmentally friendly, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and more specifically, to a relugoli intermediate and its preparation 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 B 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 long and has a 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 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 reglucogli, 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 reglucogli intermediate and its preparation method 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 produces reglucogli products with high purity, low heavy metal content, meeting active pharmaceutical ingredient standards, low production costs, and suitability for industrial production.

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

[0013] (1) The reaction of p-bromophenylacetic acid with acetic acid and acetic anhydride yields compound A;

[0014] (2) Compound A reacts with ethyl cyanoacetate and elemental sulfur to give compound B;

[0015] (3) Compound B reacts with isobutyl chloroformate to give compound C.

[0016] (4) Compound C reacts with 2,6-difluorobenzyl chloride to give compound D;

[0017] (5) Compound D reacts with N-methoxyurea in the presence of palladium, ligand, and base to form compound E.

[0018] This invention provides compounds A, B, C, D, and E, whose structures are shown in the formula:

[0019]

[0020] Step (1) The present invention provides a method for preparing compound A, comprising the following steps: reacting p-bromophenylacetic acid with acetic anhydride, acetic acid, and a catalyst to obtain compound A, the reaction equation of which is as follows:

[0021]

[0022] In step (1), the molar ratio of p-bromophenylacetic acid to acetic anhydride, acetic acid, and catalyst is 1:(1~5):(1~2):(0.05-1); the catalyst is N-methylimidazole, and the reaction temperature in step (1) is 25℃~35℃.

[0023] Step (2) The present invention provides a method for preparing compound B, comprising the following steps: Compound A undergoes a cyclization reaction with ethyl cyanoacetate and elemental sulfur in an organic solvent under the action of a catalyst to obtain compound B, and the reaction equation is as follows:

[0024]

[0025] In step (2), the molar ratio of compound A, ethyl cyanoacetate, and elemental sulfur (sulfur powder) is 1:(0.8-1.5):(0.8-1.5), preferably 1:(1-1.2):(1-1.2);

[0026] In step (2), the base is triethylamine, N,N-diisopropylethylamine, or n-butylamine, preferably n-butylamine;

[0027] In step (2), the organic solvent is selected from methanol, ethanol, isopropanol, tert-butanol, preferably methanol and / or ethanol;

[0028] In step (2), the temperature of the cyclization reaction is 20–80°C, preferably 40–60°C;

[0029] In step (2), the cyclization reaction takes 1 to 10 hours, preferably 2 to 4 hours;

[0030] Step (2) also includes a post-processing step, and more preferably, the post-processing includes, but is not limited to, cooling, filtering, washing, pulping, drying and other steps;

[0031] In step (2), the steps are as follows: dissolve compound A, ethyl cyanoacetate, and elemental sulfur (sulfur powder) in an organic solvent, heat to 20-60°C, add alkali, and react for 2-4 hours; further, the reaction solution is cooled to room temperature, filtered, washed, pulped, and dried.

[0032] Step (3) The present invention provides a method for preparing compound C, comprising the following steps: Compound B reacts with isobutyl chloroformate in an organic solvent in a nucleophilic substitution reaction to obtain compound C, and the reaction equation is as follows:

[0033]

[0034] In step (3), the molar ratio of compound B to isobutyl chloroformate is 1:(1-2), preferably 1:(1.5-2);

[0035] In step (3), the organic solvent is dioxane, toluene, acetonitrile, or tetrahydrofuran, preferably toluene;

[0036] In step (3), the reaction temperature is 60–110°C, preferably 80–110°C;

[0037] In step (3), the reaction time is 1 to 10 hours, preferably 2 to 4 hours;

[0038] Step (3) also includes a post-processing step, and more preferably, the post-processing includes, but is not limited to, cooling, filtering, washing, pulping, drying and other steps;

[0039] In step (3), the steps are as follows: dissolve compound B in an organic solvent, heat to 80-110°C, add isobutyl chloroformate, and react for 2-4 hours; it may also include post-treatment steps: cooling, adding ethanol, filtering, washing, pulping, and drying.

[0040] Step (4) The present invention provides a method for preparing compound D, comprising the following steps: Compound C reacts with 2,6-difluorobenzyl chloride in an organic solvent under the action of a base to obtain compound D, and the reaction equation is as follows:

[0041]

[0042] In step (4), the molar ratio of compound C, 2,6-difluorobenzyl chloride, and the base is 1:(1-2):(1-2), preferably 1:(1-1.3):(1-1.3);

[0043] In step (4), the organic solvent is N,N-dimethylacetamide, N,N-dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, preferably N,N-dimethylacetamide or N,N-dimethylformamide;

[0044] In step (4), the alkali is potassium carbonate, sodium carbonate, cesium carbonate, or N,N-diisopropylethylamine, preferably potassium carbonate;

[0045] In step (4), the reaction temperature is 50–90°C, preferably 70–80°C;

[0046] In step (4), the reaction time is 1 to 10 hours, preferably 2 to 4 hours;

[0047] Step (4) also includes a post-processing step. More preferably, the post-processing includes, but is not limited to, vacuum distillation, extraction, cooling, filtration, washing, pulping, drying and other steps.

[0048] In step (4), the steps are to add compound C and potassium carbonate to an organic solvent, heat to 70-80°C, react for 2-4 hours, and further process the solvent by vacuum distillation, extract with ethyl acetate and water, concentrate the organic phase, add n-heptane, cool, filter, wash and dry.

[0049] Step (5) The present invention provides a method for preparing compound E, comprising the following steps: Compound D reacts with N-methoxyurea in an organic solvent under the action of palladium, a ligand, and a base via a Buchwald-Hartwing CN coupling reaction to obtain compound E, the reaction equation of which is as follows:

[0050]

[0051] In step (5), the molar ratio of compound D, 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);

[0052] In step (5), the palladium catalyst is Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, or Pd(PPh3)2Cl2;

[0053] In step (5), the ligands are SPhos, XPhos, Josiphos, RuPhos, BrettPhos, and RockPhos;

[0054] In step (5), the alkali is potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide;

[0055] In step (5), the organic solvent is one or more of the following: dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran.

[0056] In step (5), the reaction temperature is 50–120°C, preferably 80–100°C;

[0057] In step (5), the reaction time is 1 to 24 hours, preferably 10 to 24 hours;

[0058] Step (5) 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.

[0059] In step (5), the steps are as follows: add compound D, N-methoxyurea, palladium metal, ligand, and base to an organic solvent, heat to 80-100℃, keep warm, and react for 10-24 hours; post-processing steps: cool the reaction solution to room temperature, extract and concentrate the solvent, add an alcohol solvent, filter, and dry.

[0060] This invention also discloses a compound A, which is prepared according to step (1) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of compound A is:

[0061]

[0062] This invention also discloses a compound B, 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 B is:

[0063]

[0064] This invention also discloses a compound C, which is prepared according to steps (1)-(3) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of compound C is:

[0065]

[0066] This invention also discloses a compound D, which is prepared according to steps (1)-(4) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of compound D is:

[0067]

[0068] This invention also discloses a compound E, which is prepared according to steps (1)-(4) of the above-described method for preparing the key intermediate of relugoli. The chemical formula of compound E is:

[0069]

[0070] Beneficial technical effects of the present invention:

[0071] 1) In preparing compound C, the present invention uses isobutyl chloroformate as a raw material, thereby avoiding the use of highly toxic, low flash point, and highly flammable substances such as ethyl chloroformate and methyl chloroformate.

[0072] 2) The novel intermediates of regoragoline of the present invention (including compounds of formula C, D and E) can be used to prepare regoragoline. These intermediates are simple to prepare, are all solids with good properties and stable properties, have high purity, are simple to process and have low purification cost.

[0073] 3) The present invention uses a palladium-catalyzed CN coupling reaction to construct the N-methoxyurea fragment of rilugoline in one step, thereby shortening the operation steps and avoiding the generation of urea byproducts. Therefore, it has great practical value and social and economic benefits. Attached Figure Description

[0074] 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.

[0075] Figure 1 The 1H NMR spectrum of the retinoic acid intermediate compound E provided in Example 1 of this invention;

[0076] Figure 2 The carbon NMR spectrum of the rilugoli intermediate compound E provided in Example 1 of this invention. Detailed Implementation

[0077] 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.

[0078] The raw materials and reagents used in this invention are all known products, obtained by purchasing commercially available products.

[0079] Example 1: Preparation of the regoragoline intermediate of the present invention

[0080] Step 1: Synthesis of 1-(4-bromophenyl)propane-2-one (compound A):

[0081]

[0082] At room temperature, 300.00 g of p-bromophenylacetic acid, 711.95 g of acetic anhydride, and 125.57 g of acetic acid were added sequentially to a four-necked flask and mechanically stirred to dissolve. The temperature was then raised to 50 °C. 57.26 g of 1-methylimidazole was added dropwise, and the reaction was carried out at 25–35 °C for approximately 48 hours. Post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled below 20 °C. The pH was adjusted to neutral with 40% KOH under an ice-water bath, and the mixture was extracted twice with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, and distilled under reduced pressure to obtain 261.36 g of a light yellow oily substance, namely compound A, with a yield of 88.12% and a purity of 95.58%.

[0083] The NMR data are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.46 (d, J = 8.0Hz, 2H), 7.08 (d, J = 8.0Hz, 2H), 3.67 (s, 2H), 2.17 (s, 3H).

[0084] Step 2: Synthesis of ethyl 2-amino-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound B):

[0085]

[0086] At room temperature, 100.00 g of compound A and 500 mL of anhydrous ethanol were added to a 1 L four-necked flask, mechanically stirred, and heated to 40 °C. 58.40 g of ethyl cyanoacetate was added dropwise to the system. After 1 hour, 16.55 g of elemental sulfur was added to the system, the temperature was raised to 50 °C, and the mixture was stirred for 2 hours. 17.16 g of n-butylamine was then added dropwise. The solution changed from a yellow turbidity to a reddish-brown color. After 2 hours of reaction, the reactants were essentially completely reacted. Heating was stopped, and the mixture was allowed to cool naturally to crystallize. The mixture was then cooled to room temperature and placed in an ice-water bath for 1 hour. The solution was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 145.81 g of a yellow solid, which is compound B, with a yield of 91.35% and a purity of 97.13%.

[0087] The NMR data are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.48 (d, J = 8.0Hz, 2H), 7.20 (d, J = 8.0Hz, 2H), 6.16 (s, 2H), 4.31 (q, J = 8.0Hz, 2H), 2.30 (s, 3H), 1.37 (t, J = 8.0Hz, 3H).

[0088] HRMS m / z:340.0009[M+H]+

[0089] Step 3: Synthesis of ethyl 2-isobutoxycarbonyl-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound C):

[0090]

[0091] At room temperature, 65.00 g of compound B and 195 mL of toluene were added to a four-necked flask. The mixture was mechanically stirred and heated to 110 °C. Under reflux, 52.18 g of isobutyl chloroformate was added dropwise to the system. The reaction was carried out under reflux for 2 h. The reaction was then sent to a control room, and the starting materials were found to be basically completely reacted. 585 mL of anhydrous ethanol was added to the system in a water bath at 55 °C. The mixture was allowed to cool naturally and stirred in an ice-water bath for 1 h. The mixture was then charged to form crystals. The crystals were filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 77.41 g of a yellow solid, which was compound C with a yield of 92% and a purity of 99.84%.

[0092] The NMR data are as follows: 1H NMR (400MHz, Chloroform-d) δ 10.64 (s, 1H), 7.52 (d, J = 8.0Hz, 2H), 7.25 (d, J = 8.0Hz, 2H), 4.37 (q, J = 8.0Hz, 2H), 4.01 (d, J = 4.0Hz, 2H), 2.34 (s, 3H), 2.00 (m, 1H), 1.40 (t, J = 8.0Hz, 3H), 0.97 (d, J = 4.0Hz, 6H).

[0093] HRMS m / z: 440.534 [M+H]+

[0094] Step 4: Synthesis of ethyl 2-[(2,6-difluorobenzyl)-isobutoxycarbonylamino]-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound D):

[0095]

[0096] At room temperature, 250 g of compound C, 156.98 g of K₂CO₃, and 1000 mL of DMF were added to a 2000 mL four-necked flask and mechanically stirred for 30 min. 119.92 g of 2,6-difluorobenzyl chloride was added to the system, and the temperature was raised to 95 °C. The solution turned yellow-green, and the reaction proceeded for 4 h. For post-treatment, 3V (3000 mL) of water and 1V (1000 mL) of EA were added to the reaction system for extraction. The aqueous phase was separated and back-extracted with EA (1250 mL). The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil. 1250 mL of n-heptane was added to the residue, and the mixture was stirred at 50 °C for 1 h, then cooled to 0–10 °C and stirred for 1 h. The mixture was filtered, washed with n-heptane / ethyl acetate (5 / 1), and dried under reduced pressure at 45 °C to obtain 291.05 g of a yellow solid, representing a yield of 90.5% and a purity of 98.45%.

[0097] The NMR data are as follows: ¹H NMR (400MHz, Chloroform-d) δ 7.53 (d, J = 8.0 Hz, 2H), 7.26 (m, ¹H), 7.21 (d, J = 8.0, 2H), 6.86 (m, 2H), 4.99 (s, 2H), 4.27 (q, J = 8.0 Hz, 2H), 3.96 (d, J = 4.0 Hz, 2H), 2.35 (s, 3H), 2.13–1.75 (m, ¹H), 1.35 (t, J = 8.0 Hz, 3H), 0.82 (d, J = 4.0 H, 6H).

[0098] HRMS m / z: 566.0815 [M+H]+

[0099] Step 5: Synthesis of ethyl 2-((2,6-difluorobenzyl)(isobutyryloxycarbonyl)amino)-5-(4-(3-methoxyureo)phenyl)-4-methylthiophene-3-carboxylate (compound E):

[0100]

[0101] At room temperature, 50.0 g of compound D, 11.93 g of N-methoxyurea, and 150 mL of toluene were dissolved by stirring. Then, 198.17 mg of Pd(OAc)₂, 420.79 mg of Xphos, and 43.14 g of cesium carbonate were added. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 8 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and 150 mL of ammonium chloride solution was added to quench the reaction. The mixture was extracted and separated. The aqueous phase was extracted twice with 150 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. 150 mL of n-heptane was added and the mixture was stirred. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 43.38 g of a yellow solid, with a yield of 85.39% and a purity of 92.16%. The obtained product was analyzed and showed the presence of... Figure 1 and 2 The hydrogen NMR spectrum and carbon NMR spectrum.

[0102] The NMR data are as follows: ¹H NMR (400MHz, Chloroform-d) δ 7.97 (s, ¹H), 7.71 (s, ¹H), 7.53 (d, J = 8.0Hz, 2H), 7.33–7.13 (m, 3H), 6.84 (t, J = 8.0Hz, 2H), 4.99 (s, 2H), 4.26 (q, J = 8.0Hz, 2H), 3.88 (d, J = 6.5Hz, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 1.85 (m, ¹H), 1.33 (t, J = 8.0Hz, 3H), 0.89 (t, J = 8.0Hz, 6H); ¹³C NMR (101MHz, CDCl3) δ162.76,157.16,155.29,137.17,135.59,132.54,130.35,128.89,119.59 ,111.34,77.44,77.12,76.80,72.43,64.62,60.60,42.37,27.86,26.90,18.86,15.01,14.15.

[0103] Example 2: Preparation of the regoragoline intermediate of the present invention

[0104] Step 1: Synthesis of 1-(4-bromophenyl)propane-2-one (compound A):

[0105] At room temperature, 300.00 g of p-bromophenylacetic acid, 427.17 g of acetic anhydride, and 75.34 g of acetic acid were added sequentially to a four-necked flask and mechanically stirred to dissolve. The temperature was then raised to 40°C. 57.26 g of 1-methylimidazole was added dropwise, and the reaction was carried out at 25–35°C for approximately 72 hours. Post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled below 20°C. The pH was adjusted to neutral with 40% KOH under an ice-water bath, and the mixture was extracted twice with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, and distilled under reduced pressure to obtain 253.7 g of a pale yellow oily substance, namely compound A, with a yield of 85.37% and a purity of 91.35%.

[0106] Step 2: Synthesis of ethyl 2-amino-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound B):

[0107] At room temperature, 100.00 g of compound A and 500 mL of methanol were added to a 1 L four-necked flask, mechanically stirred, and heated to 40 °C. 79.62 g of ethyl cyanoacetate was added dropwise to the system. After 1 hour, 22.52 g of elemental sulfur was added to the system, the temperature was raised to 50 °C, and the mixture was stirred for 2 hours. 17.16 g of n-butylamine was added dropwise, and the solution changed from a yellow turbidity to a reddish-brown solution. The reaction continued for 2 hours, and the reactants were basically completely reacted. Heating was stopped, and the mixture was allowed to cool naturally to crystallize. The mixture was then cooled to room temperature and placed in an ice-water bath for 1 hour. The solution was filtered, washed with ice-cold methanol, and dried under reduced pressure at 45 °C to obtain 140.21 g of a yellow solid, which is compound B with a yield of 87.79% and a purity of 96.39%.

[0108] Step 3: Synthesis of ethyl 2-isobutoxycarbonyl-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound C):

[0109] At room temperature, 65.00 g of compound B and 195 mL of dioxane were added to a four-necked flask. The mixture was mechanically stirred and heated to 101 °C. Under reflux, 52.18 g of isobutyl chloroformate was added dropwise to the system. The reaction was carried out under reflux for 2 h. The reaction was then sent to the control room, and the starting materials were found to be basically completely reacted. 585 mL of anhydrous ethanol was added to the system in a water bath at 55 °C. The mixture was allowed to cool naturally and stirred in an ice-water bath for 1 h. The mixture was then charged to form crystals. The crystals were filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 75.36 g of a yellow solid, which was compound C with a yield of 89.57% and a purity of 98.54%.

[0110] Step 4: Synthesis of ethyl 2-[(2,6-difluorobenzyl)-isobutoxycarbonylamino]-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound D):

[0111] At room temperature, 250 g of compound C, 87.78 g of K₂CO₃, and 1000 mL of dioxane were added to a 2000 mL four-necked flask and mechanically stirred for 30 min. 119.92 g of 2,6-difluorobenzyl chloride was added to the system, and the temperature was raised to 75–85 °C. The solution turned yellow-green, and the reaction proceeded for 4 h. For post-treatment, 3000 mL of water and 1000 mL of EA were added to the reaction system for extraction. The aqueous phase was then back-extracted with 1250 mL of EA. The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil. 1250 mL of n-heptane was added to the residue, and the mixture was stirred at 50 °C for 1 h, then cooled to 0–10 °C and stirred for another 1 h. The mixture was filtered, washed with a 5 / 1 ratio of n-heptane / ethyl acetate, and dried under reduced pressure at 45 °C to obtain 300.2 g of a yellow solid, representing a yield of 93.4% and a purity of 97.36%.

[0112] Step 5: Synthesis of ethyl 2-((2,6-difluorobenzyl)(isobutyryloxycarbonyl)amino)-5-(4-(3-methoxyureo)phenyl)-4-methylthiophene-3-carboxylate (compound E):

[0113] At room temperature, 50.0 g of compound D, 11.93 g of N-methoxyurea, and 150 mL of dimethyl sulfoxide were dissolved by stirring. Then, 198.17 mg of Pd(OAc)₂ and 420.79 mg of Xphos were added, along with 25.3 g of potassium carbonate. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 8 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 150 mL of ammonium chloride solution. The mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with 150 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 40.38 g of a yellow solid, with a yield of 79.42% and a purity of 96.87%.

[0114] Example 3: Preparation of the regoragoline intermediate of the present invention

[0115] Step 1: Synthesis of 1-(4-bromophenyl)propane-2-one (compound A):

[0116] At room temperature, 300.00 g of p-bromophenylacetic acid, 427.17 g of acetic anhydride, and 125.57 g of acetic acid were added sequentially to a four-necked flask and mechanically stirred to dissolve. The temperature was then raised to 30°C. 57.26 g of 1-methylimidazole was added dropwise, and the reaction was carried out at 25–35°C for approximately 72 hours. Post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled below 20°C. The pH was adjusted to neutral with 40% KOH under an ice-water bath, and the mixture was extracted twice with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, and distilled under reduced pressure to obtain 268 g of a pale yellow liquid, which is compound A with a yield of 90.18% and a purity of 89.35%.

[0117] Step 2: Synthesis of ethyl 2-amino-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound B):

[0118] At room temperature, 100.00 g of compound A and 500 mL of anhydrous ethanol were added to a 1 L four-necked flask, mechanically stirred, and heated to 40 °C. 58.40 g of ethyl cyanoacetate was added dropwise to the system. After 1 hour, 16.55 g of elemental sulfur was added to the system, the temperature was raised to 50 °C, and the mixture was stirred for 2 hours. 23.7 g of triethylamine was then added dropwise. The solution changed from a yellow turbidity to a reddish-brown color. After 4 hours of reaction, the reactants were essentially completely reacted. Heating was stopped, and the mixture was allowed to cool naturally to crystallize. The mixture was then cooled to room temperature and placed in an ice-water bath for 1 hour. The solution was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 137.3 g of a yellow solid, which is compound B, with a yield of 85.96% and a purity of 95.13%.

[0119] Step 3: Synthesis of ethyl 2-isobutoxycarbonyl-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound C):

[0120] At room temperature, 65.00 g of compound B and 195 mL of DMF were added to a four-necked flask, mechanically stirred, and heated to 100 °C. 39.15 g of isobutyl chloroformate was added dropwise to the system, and the reaction was allowed to proceed for 3 h. The sample was sent to the control room, and the reaction was found to be basically complete. 585 mL of anhydrous ethanol was added to the flask at 55 °C, and the mixture was allowed to cool naturally. The mixture was stirred in an ice-water bath for 1 h, and the solution was collected for analysis. The solution was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to obtain 71.96 g of a yellow solid, which is compound C with a yield of 85.3% and a purity of 98.36%.

[0121] Step 4: Synthesis of ethyl 2-[(2,6-difluorobenzyl)-isobutoxycarbonylamino]-4-methyl-5-(4-bromophenyl)thiophene-3-carboxylate (compound D):

[0122] At room temperature, 250 g of compound C, 156.98 g of K₂CO₃, and 1000 mL of tetrahydrofuran were added to a 2000 mL four-necked flask and mechanically stirred for 30 min. 119.92 g of 2,6-difluorobenzyl chloride was added to the system, and the temperature was raised to 65 °C. The solution turned yellow-green, and the reaction proceeded for 6 h. For post-treatment, 1 V (1000 mL) of water and 1000 mL of EA were added to the reaction system for extraction. After separation, the aqueous phase was back-extracted with EA (1250 mL). The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil. 1250 mL of n-heptane was added to the residue, and the mixture was stirred at 50 °C for 1 h, then cooled to 0–10 °C and stirred for another 1 h. The mixture was filtered, washed with a 5 / 1 ratio of n-heptane / ethyl acetate, and dried under reduced pressure at 45 °C to obtain 253 g of a yellow solid, representing a yield of 78.8% and a purity of 96.65%.

[0123] Step 5: Synthesis of ethyl 2-((2,6-difluorobenzyl)(isobutyryloxycarbonyl)amino)-5-(4-(3-methoxyureo)phenyl)-4-methylthiophene-3-carboxylate (compound E):

[0124] At room temperature, 50.0 g of compound D, 11.93 g of N-methoxyurea, and 150 mL of dioxane were dissolved by stirring. Then, 457 mg of Pd2(dba)3, 233.32 mg of RuXphos, and 43.14 g of cesium carbonate were added. The mixture was purged with nitrogen three times, heated to 80–85 °C, and stirred for 8 h. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with 150 mL of ammonium chloride solution. The mixture was extracted twice with 150 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 150 mL of n-heptane. The mixture was filtered, washed with ice-cold ethanol, and dried under reduced pressure at 45 °C to give 43.6 g of a yellow solid, with a yield of 85.82% and a purity of 91.38%.

[0125] In summary, this invention provides a novel method for preparing regrugoli intermediates, which is simpler to operate, has fewer side reactions, milder reaction conditions, higher yield and purity, easier product purification, and lower production costs, making it more suitable for commercial-scale production.

Claims

1. A method for preparing a relugoli intermediate, characterized in that: Its synthetic route is as follows: Specifically, the steps include the following: (1) Under the conditions of a catalyst and the presence of acetic anhydride and acetic acid, p-bromophenylacetic acid reacts to produce compound A; (2) Compound A reacts with ethyl cyanoacetate and elemental sulfur under the action of an alkali to form compound B; (3) Compound B reacts with isobutyl chloroformate to form compound C; (4) Compound C reacts with 2,6-difluorobenzyl chloride under the action of an alkali to form compound D; (5) Compound D reacts with N-methoxyurea in the presence of palladium, ligand, and base to form compound E.

2. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of compound A to ethyl cyanoacetate and elemental sulfur is 1:(0.8-1.5):(0.8-1.5); the reaction temperature is 20-80℃, and the reaction time is 1-10h.

3. The preparation method according to claim 1, characterized in that: In step (2), the base is selected from one of triethylamine, N,N-diisopropylethylamine, and n-butylamine; the solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol.

4. The preparation method according to claim 1, characterized in that: In step (3), the molar ratio of compound B to isobutyl chloroformate is 1:(1-2); the reaction temperature is 60-110℃; the reaction time is 1-10h; and the organic solvent is selected from one or more of dioxane, toluene, acetonitrile, and tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that: In step (4), the molar ratio of compound C, 2,6-difluorobenzyl chloride, and base is 1:(1-2):(1-2); the reaction temperature is 50-90℃; and the reaction time is 1-10h.

6. The preparation method according to claim 1, characterized in that: In step (4), the alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, and N,N-diisopropylethylamine; the organic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, acetonitrile, dioxane, and tetrahydrofuran or more.

7. The preparation method according to claim 1, characterized in that: In step (5), the molar ratio of compound D, N-methoxyurea, palladium, ligand, and base is 1:(1-2):(0.001-0.2):(0.001-0.2):(1-3); the palladium 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.

8. The preparation method according to claim 1, characterized in that: In step (5), the alkali 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.

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