Rerugolix intermediate and preparation method thereof

Abstract

The invention provides a Rurugolix intermediate and a preparation method thereof, and belongs to the technical field of medicine synthesis. The preparation method of the relagoride intermediate specifically comprises the following steps: (1) reacting p-bromophenylacetic acid in the presence of a catalyst, acetic anhydride and acetic acid to generate a compound A; (2) generating a compound B from the compound A, ethyl cyanoacetate and elemental sulfur under the action of alkali; (3) reacting the compound B with isobutyl chloroformate to generate a compound C; (4) generating a compound D from the compound C and 2, 6-difluorobenzyl chloride under the action of alkali; and (5) generating a compound E from the compound D and N-methoxyurea under the action of metal palladium, ligand and alkali. The method is mild in reaction condition, high in reaction yield, high in operability, low in production cost, environmentally friendly and suitable for large-scale industrial production.

Description

Technical Field

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

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

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

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

[0005]

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

[0007]

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

[0009]

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

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

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

[0013] (1) reacting p-bromophenylacetic acid with acetic acid and acetic anhydride to obtain compound A;

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

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

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

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

[0018] The present invention provides compound A, compound B, compound C, compound D, and compound 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: p-bromophenylacetic acid is reacted with acetic anhydride, acetic acid and a catalyst to obtain compound A, wherein the reaction equation 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° C. to 35° C.

[0023] Step (2) The present invention provides a method for preparing compound B, comprising the following steps: Compound A is subjected to a cyclization reaction with ethyl cyanoacetate and elemental sulfur in an organic solvent under the action of a catalyst to obtain compound B, wherein 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 to 80° C., preferably 40 to 60° C.;

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

[0030] Step (2) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, filtering, washing, beating, drying and the like;

[0031] In step (2), the steps are: dissolving compound A, ethyl cyanoacetate, and elemental sulfur (sulfur powder) in an organic solvent, heating to 20-60° C., adding alkali, and reacting for 2-4 hours; and further including a post-treatment step of cooling the reaction solution to room temperature, filtering, washing, pulping, and drying.

[0032] Step (3) The present invention provides a method for preparing compound C, comprising the following steps: Compound B is subjected to a nucleophilic substitution reaction with isobutyl chloroformate in an organic solvent to obtain compound C, wherein 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, tetrahydrofuran, preferably toluene;

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

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

[0038] Step (3) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, filtering, washing, beating, drying and the like;

[0039] In step (3), the steps are: dissolving compound B in an organic solvent, heating to 80-110° C., adding isobutyl chloroformate, and reacting for 2-4 hours; and further including 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 is subjected to a nucleophilic substitution reaction with 2,6-difluorobenzyl chloride in an organic solvent under the action of a base to obtain compound D, wherein the reaction equation is as follows:

[0041]

[0042] In step (4), the molar ratio of compound C, 2,6-difluorobenzyl chloride and 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 and N,N-dimethylformamide;

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

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

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

[0047] Step (4) further comprises a post-treatment step, and more preferably, the post-treatment includes but is not limited to the steps of reduced pressure distillation, extraction, cooling, filtration, washing, pulping, drying, etc.;

[0048] In step (4), the steps are as follows: adding compound C and potassium carbonate to an organic solvent, heating to 70-80° C., reacting for 2-4 hours, and further post-processing by distilling the solvent under reduced pressure, extracting with ethyl acetate and water, concentrating the organic phase, adding n-heptane, cooling, filtering, washing and drying.

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

[0050]

[0051] In step (5), the molar ratio of compound D, N-methoxyurea, metal palladium, ligand and base is 1: (1-2): (0.001-0.2): (0.001-0.2): (1-3), preferably 1: (1.1-1.8): (0.001-0.1): (0.001-0.1): (1.1-2.5);

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

[0053] In step (5), the ligand is SPhos, XPhos, Josiphos, RuPhos, BrettPhos, or RockPhos;

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

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

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

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

[0058] Step (5) further comprises a post-treatment step, and more preferably, the post-treatment step includes but is not limited to cooling, extraction, filtration, washing, drying and the like;

[0059] In step (5), the steps are: adding compound D, N-methoxyurea, metal palladium, ligand, and base to an organic solvent, heating to 80-100° C., keeping warm, and reacting for 10-24 hours; post-treatment step: cooling the reaction solution to room temperature, extracting and concentrating the solvent, adding an alcohol solvent, filtering, and drying.

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

[0061]

[0062] The present invention also discloses a compound B, which is prepared according to step (1) and step (2) of the above-mentioned method for preparing the key intermediate of relugolix. The chemical formula of compound B is:

[0063]

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

[0065]

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

[0067]

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

[0069]

[0070] Beneficial technical effects of the present invention:

[0071] 1) When preparing compound C in the present invention, isobutyl chloroformate is used as a raw material, thereby avoiding the use of ethyl chloroformate and methyl chloroformate, which are highly toxic, low flash point, and highly flammable substances;

[0072] 2) The novel intermediates of relugolix of the present invention (including compounds of formula C, formula D, and formula E) can be used to prepare relugolix. The preparation methods of these intermediates are simple, and they are all solids with good properties and stable properties; they have high purity, simple post-processing, and low purification cost.

[0073] 3) The present invention adopts a palladium-catalyzed CN coupling reaction to construct the N-methoxyurea fragment of relugolix in a one-step method, thereby shortening the operation steps and avoiding the generation of uret byproducts. Therefore, it has great implementation value and social and economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and should not be regarded as limiting the scope.

[0075] Figure 1 The H NMR spectrum of the relugolix intermediate compound E provided in Example 1 of the present invention;

[0076] Figure 2 This is the NMR carbon spectrum of the relugolix intermediate compound E provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0077] The above contents of the present invention are further described in detail below through examples, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

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

[0079] Example 1. Preparation of the relugolix 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 to a four-necked flask in sequence, mechanically stirred to dissolve, and the temperature was raised to 50°C; 57.26 g of 1-methylimidazole was added dropwise, and the temperature was controlled at 25-35°C for reaction for about 48 hours; post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled to below 20°C; the pH was adjusted to neutral with 40% KOH under an ice-water bath, and extracted twice with 500 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was distilled under reduced pressure to obtain 261.36 g of light yellow oil, i.e., compound A, with a yield of 88.12% and a purity of 95.58%.

[0083] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.46 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 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 1L four-necked bottle, 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, stirred for 2 hours, and 17.16 g of n-butylamine was added dropwise. The solution system changed from a yellow turbid state to a reddish brown solution. After reacting for 2 hours, the raw materials were basically reacted completely; heating was stopped, the temperature was naturally cooled and crystallized, and the temperature was reduced to room temperature and then transferred to an ice water bath, and the reaction was kept warm for 1 hour; suction was filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 145.81 g of a yellow solid, i.e., compound B with a yield of 91.35% and a purity of 97.13%.

[0087] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.48 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.16 (s, 2H), 4.31 (q, J = 8.0 Hz, 2H), 2.30 (s, 3H), 1.37 (t, J = 8.0 Hz, 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, stirred mechanically, and heated to 110°C. Under reflux, 52.18 g of isobutyl chloroformate was added dropwise into the system. The reaction was carried out for 2 h under reflux conditions. The raw materials were basically reacted after sampling and central control. 585 mL of anhydrous ethanol was added in a water bath at 55°C, the temperature was naturally lowered, and the mixture was stirred in an ice-water bath for 1 h, and crystallized thoroughly. The mixture was filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 77.41 g of a yellow solid, i.e., compound C with a yield of 92% and a purity of 99.84%.

[0092] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ 10.64 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.37 (q, J = 8.0 Hz, 2H), 4.01 (d, J = 4.0 Hz, 2H), 2.34 (s, 3H), 2.00 (m, 1H), 1.40 (t, J = 8.0 Hz, 3H), 0.97 (d, J = 4.0 Hz, 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, add 250g of compound C, 156.98g of K2CO3, and 1000mL of DMF into a 2000mL four-necked bottle, stir mechanically, and react for 30min; add 119.92g of 2,6-difluorobenzyl chloride into the system, heat to 95°C, the solution system is yellow-green, and react for 4h; post-treatment, add 3V (3000mL) of water and 1V (1000mL) of EA to the reaction system for extraction, and after separation, the aqueous phase is back-extracted with EA (1250mL); combine the organic phases, and concentrate the organic phase under reduced pressure to obtain a yellow oil. Add 1250mL of n-heptane to the residue, and stir the mixture at 50°C for 1 hour, then cool to 0-10°C and stir for 1 hour. Filter, wash with n-heptane / ethyl acetate = 5 / 1, and dry under reduced pressure at 45°C to obtain 291.05g of yellow solid, i.e., the yield is 90.5% and the purity is 98.45%.

[0097] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.53 (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)(isobutoxycarbonyl)amino)-5-(4-(3-methoxyureido)phenyl)-4-methylthiophene-3-carboxylate (Compound E):

[0100]

[0101] At room temperature, 50.0g of compound D, 11.93g of N-methoxyurea and 150mL of toluene were stirred and dissolved, and then 198.17mg of Pd(OAc)2, 420.79mg of Xphos, and 43.14g of cesium carbonate were added. The nitrogen was replaced three times, and the temperature was raised to 80-85°C. The reaction was stirred for 8h and the samples were taken for monitoring. After the reaction was completed, it was cooled to room temperature, 150mL of ammonium chloride solution was added to quench the reaction, the liquid was extracted, and the aqueous phase was extracted twice with 150mL of toluene. The toluene layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. 150mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 43.38g of yellow solid, i.e., the yield was 85.39% and the purity was 92.16%. The obtained product was tested and the attached Figure 1 and 2 H NMR spectrum and C NMR spectrum.

[0102] The NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.97 (s, 1H), 7.71 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.33–7.13 (m, 3H), 6.84 (t, J = 8.0 Hz, 2H), 4.99 (s, 2H), 4.26 (q, J = 8.0 Hz, 2H), 3.88 (d, J = 6.5 Hz, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 1.85 (m, 1H), 1.33 (t, J = 8.0 Hz, 3H), 0.89 (t, J = 8.0 Hz, 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 relugolix 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 to a four-necked flask in sequence, mechanically stirred to dissolve, and the temperature was raised to 40°C; 57.26 g of 1-methylimidazole was added dropwise, and the temperature was controlled at 25-35°C for reaction for about 72 hours; post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled to below 20°C; the pH was adjusted to neutral with 40% KOH under an ice-water bath, and extracted twice with 500 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was distilled under reduced pressure to obtain 253.7 g of a light yellow oil, i.e., 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 1L 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, stirred for 2 hours, and 17.16 g of n-butylamine was added dropwise. The solution system changed from a yellow turbid state to a reddish brown solution. After reacting for 2 hours, the raw materials were basically reacted completely; heating was stopped, the temperature was naturally cooled and crystallized, and the temperature was cooled to room temperature and transferred to an ice water bath, and the reaction was kept warm for 1 hour; suction was filtered, washed with ice methanol, and dried under reduced pressure at 45°C to obtain 140.21 g of a yellow solid, i.e., 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, stirred mechanically, and heated to 101°C. Under reflux, 52.18 g of isobutyl chloroformate was added dropwise to the system, and the reaction was carried out for 2 h under reflux conditions. The raw materials were basically reacted after the sample was sent for central control. 585 mL of anhydrous ethanol was added in a water bath at 55°C, the temperature was naturally lowered, and the mixture was stirred in an ice-water bath for 1 h, and crystallized thoroughly. The mixture was filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 75.36 g of a yellow solid, i.e., 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, add 250g of compound C, 87.78g of K2CO3, and 1000mL of dioxane into a 2000mL four-necked bottle, stir mechanically, and react for 30min; add 119.92g of 2,6-difluorobenzyl chloride into the system, heat to 75-85°C, the solution system is yellow-green, and react for 4h; post-treatment: add 3V (3000mL) of water and EA (1000mL) to the reaction system for extraction, and after separation, the aqueous phase is back-extracted with EA (1250mL); combine the organic phases, and concentrate the organic phase under reduced pressure to obtain a yellow oil. Add 1250mL of n-heptane to the residue, and stir the mixture at 50°C for 1 hour, then cool to 0-10°C and stir for 1 hour. Filter, wash with n-heptane / ethyl acetate = 5 / 1, and dry under reduced pressure at 45°C to obtain 300.2g of yellow solid, that is, the yield is 93.4% and the purity is 97.36%.

[0112] Step 5. Synthesis of ethyl 2-((2,6-difluorobenzyl)(isobutoxycarbonyl)amino)-5-(4-(3-methoxyureido)phenyl)-4-methylthiophene-3-carboxylate (Compound E):

[0113] At room temperature, 50.0g of compound D, 11.93g of N-methoxyurea and 150mL of dimethyl sulfoxide were stirred and dissolved, and then 198.17mg of Pd(OAc)2, 420.79mg of Xphos, 25.3g of potassium carbonate were added, nitrogen was replaced three times, the temperature was raised to 80-85°C, the reaction was stirred for 8h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 150mL of ammonium chloride solution was added to quench the reaction, and 100mL of ethyl acetate was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, 150mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 40.38g of yellow solid, i.e., a yield of 79.42% and a purity of 96.87%.

[0114] Example 3: Preparation of the relugolix 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 to a four-necked bottle in sequence, mechanically stirred to dissolve, and the temperature was raised to 30°C; 57.26 g of 1-methylimidazole was added dropwise, and the temperature was controlled at 25-35°C for reaction for about 72 hours; post-treatment: 700 mL of pure water was added dropwise under an ice-water bath, and the temperature was controlled to be below 20°C; the pH was adjusted to neutral with 40% KOH under an ice-water bath, and extracted twice with 500 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was distilled under reduced pressure to obtain 268 g of light yellow liquid, i.e., 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 1L four-necked bottle, 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, stirred for 2 hours, and 23.7 g of triethylamine was added dropwise. The solution system changed from a yellow turbid state to a reddish brown solution. After reacting for 4 hours, the raw materials were basically reacted completely; heating was stopped, the temperature was naturally cooled and crystallized, and the temperature was cooled to room temperature and transferred to an ice water bath, and the reaction was kept warm for 1 hour; suction was filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 137.3 g of a yellow solid, i.e., 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 into the system, and the reaction was carried out for 3 h. The sample was sent for central control, and the reaction of the raw materials was basically complete. 585 mL of anhydrous ethanol was added in a water bath at 55°C, and the temperature was naturally lowered. The mixture was stirred in an ice-water bath for 1 h, and crystallized thoroughly. The mixture was filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 71.96 g of a yellow solid, i.e., 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, add 250g of compound C, 156.98g of K2CO3, and 1000mL of tetrahydrofuran into a 2000mL four-necked bottle, stir mechanically, and react for 30min; add 119.92g of 2,6-difluorobenzyl chloride into the system, heat to 65°C, the solution system is yellow-green, and react for 6h; post-treatment, add 1V (1000mL) of water and EA (1000mL) to the reaction system for extraction, and after separation, the aqueous phase is back-extracted with EA (1250mL); combine the organic phases, and concentrate the organic phase under reduced pressure to obtain a yellow oil. Add 1250mL of n-heptane to the residue, and stir the mixture at 50°C for 1 hour, then cool to 0-10°C and stir for 1 hour. Filter, wash with n-heptane / ethyl acetate = 5 / 1, and dry under reduced pressure at 45°C to obtain 253g of yellow solid, that is, the yield is 78.8% and the purity is 96.65%.

[0123] Step 5. Synthesis of ethyl 2-((2,6-difluorobenzyl)(isobutoxycarbonyl)amino)-5-(4-(3-methoxyureido)phenyl)-4-methylthiophene-3-carboxylate (Compound E):

[0124] At room temperature, 50.0g of compound D, 11.93g of N-methoxyurea and 150mL of dioxane were stirred and dissolved, and then 457mg of Pd2(dba)3, 233.32mg of RuXphos, 43.14g of cesium carbonate were added, nitrogen was replaced three times, the temperature was raised to 80-85°C, the reaction was stirred for 8h, and sampling was monitored. After the reaction was completed, it was cooled to room temperature, 150mL of ammonium chloride solution was added to quench the reaction, 150mL of dichloromethane was extracted twice, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, 150mL of n-heptane was added for pulping, filtered, washed with ice ethanol, and dried under reduced pressure at 45°C to obtain 43.6g of yellow solid, i.e., a yield of 85.82% and a purity of 91.38%.

[0125] In summary, the present invention provides a new method for preparing a relugolix intermediate, which has simpler operation, fewer side reactions, mild reaction conditions, high yield and purity, easy product purification, low production cost, and is more suitable for commercial-scale production.

Claims

1. A method for preparing a relugolix intermediate, characterized in that: Its synthetic route is: The specific steps include: (1) Under the conditions of a catalyst, acetic anhydride and acetic acid, p-bromophenylacetic acid reacts to generate compound A; (2) Compound A reacts with ethyl cyanoacetate and elemental sulfur under the action of a base to generate compound B; (3) Compound B reacts with isobutyl chloroformate to generate compound C; (4) Compound C reacts with 2,6-difluorobenzyl chloride under the action of a base to generate compound D; (5) Compound D reacts with N-methoxyurea in the presence of metal palladium, a ligand and a base to generate 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, elemental sulfur and alkali is 1:(0.8-1.5):(0.8-1.5); the reaction temperature is 20-80° C. and the reaction time is 1-10 h.

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; and 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° C.; the reaction time is 1-10 h; and the reaction 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° C.; and the reaction time is 1-10 h.

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

7. The preparation method according to claim 1, characterized in that: In step (5), the molar ratio of compound D, N-methoxyurea, metal 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, 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 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.

9. A compound E, characterized in that: It is prepared according to the method for preparing the key intermediate of relugolix according to claim 1.

Images