A method of synthesizing relugolix

Abstract

The application provides a synthesis method of relugolix, comprising the following steps: reacting compound 2 with di-tert-butyl dicarbonate to obtain compound 3; reacting compound 3 with dibromohydantoin to obtain compound 4; reacting compound 4 with dimethylamine hydrochloride to obtain compound 5; hydrolyzing compound 5 to obtain compound 6; condensing compound 6 with 6-methoxy-3-aminopyridazine to obtain compound 7; deprotecting the amino group of compound 7 to obtain compound 8; performing reductive amination on compound 8 with 2,6-difluorobenzaldehyde to obtain compound 9; performing nitro reduction on compound 9 to obtain compound 10; and reacting compound 10 in the presence of carbonyldiimidazole and methoxyamine hydrochloride to obtain relugolix. The synthesis method is more efficient than prior art, avoids potential genotoxic impurities in the prior art, has mild process conditions, high reaction yield in each step, effectively reduces industrial production cost and safety risk, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically to a method for synthesizing relugoli. Background Technology

[0002] Relugolix, CAS No. 737789-87-6, chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, is a small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist co-developed by Myovant and Takeda. It has potential applications in uterine fibroids, endometriosis, and prostate cancer. Its chemical structure is shown in Formula I.

[0003]

[0004] Formula I

[0005] Takeda Pharmaceutical disclosed a method for preparing regrugolide in patent CN100360538C. This method is described in synthetic route 1 below. However, the pyridazine condensation step has a yield of only 26%. Both the nitro reduction step and the penultimate deprotection step use 10% palladium on carbon as a catalyst and hydrogen pressure to prepare key intermediates. During debenzylation, some difluorobenzyl groups are also removed, forming unwanted process impurities. Therefore, the selection of the benzyl protecting group for the amino group is inappropriate. The final methylation step requires highly toxic methylating agents such as iodomethane, with a yield of only 17%. Furthermore, there are problems with the difficult removal of potential metal and genotoxic impurities.

[0006]

[0007] Synthesis Route 1

[0008] Takeda Pharmaceutical Co., Ltd. reported a synthetic method for regrugoline in J. Med. Chem. 2011, 54, 4998-5012. This method, described in synthetic route 2 below, involves nitro reduction, nucleophilic substitution, hydrolysis, acylated amine decyclization, demethoxyethylation, and N-methylation to prepare regrugoline. This method uses 10% palladium on carbon. During debenzylation, some difluorobenzyl groups are also removed, forming unwanted process impurities, making product quality control difficult. Furthermore, the yield of this route is low, limiting its industrial application value.

[0009]

[0010] Synthesis Route 2

[0011] Takeda Pharmaceutical disclosed a method for preparing regrangolide in patent CN104703992A, as shown in synthetic route 3 below. This method requires harsh reaction conditions, including heating and pressurization, and places high demands on the equipment. Moreover, many intermediates in this route are oily substances with poor physical properties, requiring purification by column chromatography, which is cumbersome, costly, and difficult to industrialize.

[0012]

[0013] Synthesis Route 3

[0014] Patent CN114685468A discloses a process for synthesizing a nitro compound of relugoli intermediate. This process involves first brominizing thiophene methyl, then condensing it with dimethylamine to obtain compound B. Compound B is then subjected to an N-alkylation reaction with benzyl difluorochloro. Since the basicity of the dimethylamino group at the 4-position of thiophene is much stronger than that of the amino group protected by the benzyloxycarbonyl group at the 2-position of thiophene, the inventors of this invention mainly obtained quaternary ammonium salt compound D when repeating this technical solution. The expected conversion rate of compound C was very low. Therefore, the actual operability and feasibility of this route are very low.

[0015]

[0016] In summary, the existing technology has the following shortcomings:

[0017] 1) The selection of the benzyl protecting group of amino group in the synthetic route of patent CN100360538C is inappropriate. The final synthesis step of the active pharmaceutical ingredient requires the use of highly toxic iodomethane reagent, and the methylation yield is low, resulting in high production cost of the active pharmaceutical ingredient and making it difficult to control the quality of the active pharmaceutical ingredient.

[0018] 2) The selection of the methoxyethyl protecting group of the amino group in the synthetic route of J.Med.Chem.2011,54,4998-5012 is inappropriate. The final synthetic step of the active pharmaceutical ingredient requires the use of chloroethyl chloroformate, a potentially genotoxic substance, which is not conducive to controlling the quality of the active pharmaceutical ingredient.

[0019] 3) The intermediate design in the synthetic route of patent CN114685468A has certain defects. The intermediates are not easy to purify, the quality control is difficult, and the industrial production cost is high. Summary of the Invention

[0020] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing relugoli.

[0021] Research has revealed that the key to the synthesis of regrugoli lies in the construction of the thienocyclic urea heterocycle. Existing techniques mainly involve the cyclization of pyridazinamide with a carbamate protected by ortho-difluorobenzylamine under strongly basic conditions. A process using the direct condensation cyclization of pyridazinamide and difluorobenzylamine has not been reported. This invention is based on the strategy of direct condensation cyclization of pyridazinamide and difluorobenzylamine to efficiently construct the regrugoli backbone.

[0022] Specifically, the technical solution of the synthesis method of relugoli provided by the present invention is as follows:

[0023] A method for synthesizing relugoli includes the following steps:

[0024]

[0025] Step 1: Under alkaline conditions, compound 2 reacts with di-tert-butyl dicarbonate ((Boc)₂O) to give compound 3.

[0026] Step 2: In an organic solvent, compound 3 undergoes a bromination reaction with dibromohydantoin to yield compound 4.

[0027] Step 3: Under the condition of triethylamine as an acid-binding agent, compound 4 undergoes an alkylation reaction with dimethylamine hydrochloride to obtain compound 5.

[0028] Step 4: In the presence of a base, compound 5 is hydrolyzed to obtain compound 6.

[0029] Step 5: Under the action of propyl phosphoric anhydride (T3P), compound 6 condenses with 6-methoxy-3-aminopyridazine to give compound 7.

[0030] Step 6: In the presence of acid, the tert-butyl-protected amino group in compound 7 is deprotected to obtain compound 8.

[0031] Step 7: Under the action of sodium borohydride, compound 8 undergoes reductive ammoniation with 2,6-difluorobenzaldehyde to obtain compound 9.

[0032] Step 8: Compound 9 undergoes nitro reduction to obtain compound 10.

[0033] Step 9: Compound 10 was reacted in the presence of carbonyl diimidazole and methoxyamine hydrochloride to give relugoli.

[0034] According to the method of the present invention, in step 1, the molar ratio of compound 2 to ditert-butyl dicarbonate is 1:2.2 to 2.8, preferably 1:2.5.

[0035] According to the method of the present invention, in step 1, the base is triethylamine and / or 4-dimethylaminopyridine.

[0036] According to the method of the present invention, in step 1, the reaction temperature is 55-70°C, preferably 60-65°C.

[0037] According to the method of the present invention, in step 1, the reaction is carried out in an organic solvent, wherein the organic solvent is 1,4-dioxane; the mass-volume ratio (g / mL) of compound 2 to the organic solvent is 1:5 to 1:7, preferably 1:6.

[0038] According to the method of the present invention, in step 1, after the reaction is completed, the solvent is removed under reduced pressure, ethanol is added and stirred, filtered, and dried to obtain compound 3.

[0039] According to the method of the present invention, in step 2, the molar ratio of compound 3 and dibromohydantoin is 1:0.5 to 0.6, preferably 1:0.55.

[0040] According to the method of the present invention, in step 2, the reaction temperature is 30-40°C, preferably 33-37°C.

[0041] According to the method of the present invention, in step 2, the organic solvent is dichloromethane, and the mass-volume ratio (g / mL) of compound 3 to organic solvent is 1:5 to 1:7, preferably 1:6.

[0042] According to the method of the present invention, in step 2, the reaction is carried out under light.

[0043] According to the method of the present invention, in step 2, after the reaction is completed, the reaction solution is cooled to room temperature, washed with saturated sodium bicarbonate solution, and then the aqueous layer is extracted with dichloromethane. The dichloromethane layers are combined, the solvent is removed under reduced pressure, and the solution is dried to obtain compound 4.

[0044] According to the method of the present invention, in step 3, the molar ratio of compound 4, triethylamine and dimethylamine hydrochloride is 1:2.5 to 3.0:1.3 to 1.6, preferably 1:2.6:1.5.

[0045] According to the method of the present invention, in step 3, the reaction temperature is 15-30°C, preferably 20-25°C.

[0046] According to the method of the present invention, in step 3, the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass-to-volume ratio (g / mL) of compound 4 to the organic solvent is 1:8 to 1:12, preferably 1:10.

[0047] According to the method of the present invention, in step 3, after the reaction is completed, the solvent is removed under reduced pressure, washed, dehydrated, and dried to obtain compound 5.

[0048] According to the method of the present invention, in step 4, the reaction temperature is 60-70°C.

[0049] According to the method of the present invention, in step 4, the base is sodium hydroxide and / or potassium hydroxide, wherein the molar ratio of compound 5 to the base is 1:3 to 1:5, preferably 1:4.

[0050] According to the method of the present invention, in step 4, the reaction is carried out in a solvent, wherein the solvent is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 4:1; and the mass-volume ratio (g / mL) of compound 5 to solvent is 1:2.5.

[0051] According to the method of the present invention, in step 4, after the reaction is completed, the pH is adjusted to 2-3 with hydrochloric acid, a solid precipitates out, and the solid is filtered and dried to obtain compound 6.

[0052] According to the method of the present invention, in step 5, the molar ratio of compound 6, 6-methoxy-3-aminopyridazine, and propylphosphoanhydride is 1:1.1 to 1.3:2.2 to 2.5, preferably 1:1.2:2.4.

[0053] According to the method of the present invention, in step 5, the reaction temperature is 55-60°C, preferably 53-57°C.

[0054] According to the method of the present invention, in step 5, the reaction is carried out in an organic solvent, wherein the organic solvent is DMF, and the mass-volume ratio (g / mL) of compound 6 to the organic solvent is 1:7.

[0055] According to the method of the present invention, in step 5, after the reaction is completed, the pH is adjusted to 7.5-8.5, water is added, a solid precipitates out, the mixture is filtered, dried, and compound 7 is obtained.

[0056] According to the method of the present invention, in step 6, the reaction temperature is 40-50°C, preferably 43-46°C.

[0057] According to the method of the present invention, in step 6, the acid is hydrochloric acid, and the molar ratio of compound 7 to acid is 1:10 to 1:14, preferably 1:12.

[0058] According to the method of the present invention, in step 6, the reaction is carried out in an organic solvent, wherein the organic solvent is THF, and the mass-volume ratio (g / mL) of compound 7 to the organic solvent is 1:8 to 1:12, preferably 1:10.

[0059] According to the method of the present invention, in step 6, after the reaction is completed, the pH is adjusted to 7-8, and the solution is removed under reduced pressure until dry to obtain compound 8.

[0060] According to the method of the present invention, in step 7, the molar ratio of compound 8,2,6-difluorobenzaldehyde and sodium borohydride is 1:1.1 to 1.3:1.5 to 1.8, preferably 1:1.2:1.6.

[0061] According to the method of the present invention, in step 7, the reaction temperature is 15-30°C, preferably 20-25°C.

[0062] According to the method of the present invention, in step 7, after the reaction is completed, the reaction solution is added to a dilute hydrochloric acid aqueous solution, extracted with dichloromethane, and the organic layer is removed to obtain compound 9.

[0063] According to the method of the present invention, in step 8, the reaction temperature is 35-50°C, preferably 40-45°C.

[0064] According to the method of the present invention, in step 8, the reaction is carried out in an organic solvent, wherein the organic solvent is methanol; the mass-to-volume ratio (g / mL) of compound 9 to the organic solvent is 1:16 to 1:22, preferably 1:20.

[0065] According to the method of the present invention, in step 8, the catalyst used for nitro reduction is Raney nickel, wherein the mass ratio (g / g) of compound 9 to catalyst is 1:0.4.

[0066] According to the method of the present invention, in step 8, after the reaction is completed, the reaction solution is filtered, and the filtrate is dried to obtain compound 10.

[0067] According to the method of the present invention, in step 9, the molar ratio of compound 10, carbonyl diimidazole and methoxyamine hydrochloride is 1:3.5 to 4.5:1.8 to 2.2, preferably 1:4.0:1.9.

[0068] According to the method of the present invention, in step 9, the reaction temperature is 45-60°C, preferably 50-55°C.

[0069] According to the method of the present invention, in step 9, the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass-to-volume ratio (g / mL) of compound 10 to the organic solvent is 1:4 to 1:6, preferably 1:5.

[0070] According to the method of the present invention, in step 9, after the reaction is completed, the solvent is removed under reduced pressure to obtain relugoli.

[0071] Beneficial effects

[0072] The beneficial effects of this invention are as follows:

[0073] (1) By adjusting the cyclization strategy, the present invention directly cyclizes pyridazinamide and difluorobenzylamine under the action of carbonyl diimidazole to construct rilugoli, and simultaneously constructs branched methoxyurea. The cyclization method is more efficient than the prior art.

[0074] (2) The present invention avoids the use of potential genotoxic impurities such as iodomethane and ethyl chloroformate in the prior art, which is beneficial to the quality control of potential genotoxic impurities in the active pharmaceutical ingredient.

[0075] (3) The process conditions of this invention are mild and the reaction yields of each step are high, which effectively reduces industrial production costs and safety risks and is suitable for industrial production. Detailed Implementation

[0076] The present invention will be further described below through specific embodiments to provide a better understanding of it, but this does not limit the invention to the scope of the described embodiments. Test methods not specified in the following embodiments are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0077] Unless otherwise specified, the instruments used in this invention are conventional instruments, and the reagents used are conventional reagents.

[0078] 1 HNMR was measured using a Bruker Avance 400 nuclear magnetic resonance spectrometer;

[0079] HRMS measurements were performed using a Waters Xevo G2-XS QTof high-resolution mass spectrometer with an ESI source.

[0080] Example 1: Preparation of Compound 3

[0081] Under nitrogen protection, 10 g of compound 2 (32.6 mmol, 1 eq), 17.8 g of Boc₂O (di-tert-butyl dicarbonate) (81.55 mmol, 2.5 eq), 0.2 g of 4-dimethylaminopyridine (DMAP) (0.02 w / w), and 60 mL of 1,4-dioxane (6 V / w) were added to a four-necked flask. The mixture was heated to 60–65 °C and stirred for 10 hours. The solvent was then removed under reduced pressure, and 20 mL of ethanol was added. The mixture was heated to 55–60 °C and stirred for 1 hour. The temperature was then lowered to 0–5 °C and maintained for 1 hour. The mixture was filtered, washed with ethanol, and dried under reduced pressure at 50–55 °C to obtain 15.2 g of compound 3, with a yield of 92%. ESI-HRMS (m / z): C 24 H 31 Theoretical value of N2O8S[M+H+]: 507.1796, measured value: 507.1792.

[0082] Example 2: Preparation of Compound 4

[0083] Under nitrogen protection, 40 g of compound 3 (78.9 mmol, 1 eq), 12.42 g of dibromohydantoin (43.43 mmol, 0.55 eq), 2 g of azobisisobutyronitrile (AIBN) (0.05 w / w), and 240 mL of dichloromethane (6 v / w) were added to a four-necked flask. The mixture was heated to 35 °C and reacted under light for 10 hours. The reaction solution was cooled to room temperature, washed with 320 mL of saturated sodium bicarbonate solution (8 v / w), and the aqueous layer was extracted with 80 mL of dichloromethane (2 v / v). The dichloromethane layers were combined, the solvent was removed under reduced pressure, 120 mL of ethyl acetate (3 v / v) was added, and the mixture was heated to reflux and stirred until dissolved. The mixture was then cooled to 0–5 °C and maintained at this temperature for 1 hour. The mixture was filtered, washed with ethanol, and dried under reduced pressure at 50–55 °C to obtain 43.2 g of compound 4, with a yield of 90%. ESI-HRMS (m / z): C 24 H 30 Theoretical value of BrN2O8S[M+H+]: 585.0901, measured value: 585.0906; 1 H NMR (400MHz, CDCl3):

[0084] 8.40 (2H, J=8Hz, d), 7.86 (2H, J=8Hz, d), 4.82 (2H, s), 4.28 (2H, m), 1.41 (18H, s), 1.30 (3H, m). 13 C-NMR (100MHz, CDCl3): δ161.47, 149.96, 147.99, 146.98, 138.21, 138.16, 133.90, 130.77, 128.14, 124.88, 83.91, 61.50, 27.83, 14.33.

[0085] Example 3: Preparation of Compound 5

[0086] Add 9.4 g of dimethylamine hydrochloride (115.29 mmol, 1.5 eq) and 450 mL of acetonitrile (10 v / w) to a four-necked flask, and add 20.18 g of triethylamine (199.84, 2.6 eq) dropwise while controlling the temperature at 20–25 °C. Stir for 30 minutes. The solution of 45.0 g of compound 4 (76.86 mmol, 1 eq) and 135 ml of acetonitrile (3 v / w) was added dropwise starting at 5–10 °C. After the addition was complete, the reaction was maintained at 20–25 °C until the starting material disappeared. The solvent was removed under reduced pressure, and the mixture was washed with 450 ml of dichloromethane (10 v / w) and 225 ml of water (5 v / w). After drying, 90 ml of isopropyl ether (2 v / w) was added, and the mixture was heated to reflux and stirred until dissolved. The mixture was then cooled to 0–5 °C and maintained at this temperature for 1 hour. After filtration, the mixture was dried under reduced pressure at 40–45 °C to obtain 35.9 g of compound 5, with a yield of 85%. ESI-HRMS (m / z): C 26 H 36Theoretical calculated value of N3O8S[M+H+]: 550.2218, measured value: 550.2215; 1 H NMR (400MHz, d6 DMSO): 8.31 (2H, J=8Hz, d), 7.82 (2H, J=8Hz, d), 4.20 (2H, s), 3.53 (2H, m), 1.99 (6H, s), 1.39 (18H, s), 1.27 (3H, m); 13 C-NMR (100MHz, d6 DMSO): δ162.12, 149.51, 147.08, 138.96, 136.41, 135.30, 130.83, 123.93, 83.08, 60.55, 54.04, 44.19, 27.73, 27.34, 13.90.

[0087] Example 4: Preparation of Compound 6

[0088] 28 g of compound 5 (50.94 mmol, 1 eq), 56 ml of ethanol (2 v / w), 14 ml of water (0.5 v / w), and 11.43 g of potassium hydroxide (203.77 mmol, 4 eq) were added to a four-necked flask. The temperature was raised to 60–65 °C, and the reaction was maintained until the starting material disappeared. The pH was adjusted to 2–3 with hydrochloric acid, and a solid precipitated. The solid was filtered and rinsed with 28 ml of water. The filter cake was mixed with 56 ml of ethyl acetate, filtered, and dried under reduced pressure at 40–45 °C to give 20.3 g of compound 6, yield 95%; ESI-HRMS (m / z): C 19 H 24 Theoretical value of N3O6S[M+H+]: 422.1380, measured value: 422.1385; 1 H NMR (400MHz, d6 DMSO): 11.30 (1H, br), 8.34 (2H, J=8Hz, d), 7.73 (2H, J=8Hz, d), 4.28 (2H, s), 2.56 (6H, s), 1.51 (9H, s); 13 C-NMR (100MHz, d6 DMSO): δ167.30, 152.05, 150.51, 147.55, 139.23, 131.81, 131.25, 126.21, 123.93, 124.60, 114.75, 82.80, 79.71, 53.62, 42.01, 28.20.

[0089] Example 5: Preparation of Compound 7

[0090] Under nitrogen purging and protection, 10 g of compound 6 (23.7 mmol, 1 eq), 70 ml of DMF (7 v / w), and 4.6 g of 6-methoxy-3-aminopyridazine (28.4 mmol, 1.2 eq) were added to a four-necked flask and stirred until dissolved. 15.3 g of diisopropylethylamine (118.6 mmol, 5 eq) was added dropwise at 10–20 °C. After the addition was complete, the temperature was raised to 55 °C, and 36.2 g (56.9 mmol, 2.4 eq) of a 50% propylphosphonic anhydride (T3P) ethyl acetate solution was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 24–30 hours. The pH was adjusted to 7.5–8.5 with 4N sodium hydroxide solution, and 200 ml of water was slowly added dropwise. A solid precipitated out; the solid was filtered, dried, and yielded 9.4 g of compound 7, with a yield of 75%. ESI-HRMS (m / z): C 24 H 29 Theoretical value of N6O6S[M+H+]: 529.1864, measured value: 529.1861.

[0091] Example 6: Preparation of Compound 8

[0092] 2 g of compound 7 (3.78 mmol, 1 eq), 20 ml of THF (10 v / w), and 4.6 g of purified hydrochloric acid (45.3 mmol, 12 eq) were added to a four-necked flask. The mixture was incubated at 45 °C for 12 hours. The pH was adjusted to 7–8 with liquid alkali. The solvent was removed under reduced pressure at 40–50 °C until dry. 200 ml of dichloromethane was added and stirred until dissolved. The mixture was washed twice with 100 ml x 2 of water. The solvent was removed under reduced pressure at 30–40 °C to give 1.54 g of compound 8 as a white solid, with a yield of 95%. ESI-HRMS (m / z): C 19 H 21 Theoretical value of N6O4S[M+H+]: 429.1340, measured value: 429.1345. 1 H-NMR (400MHz, CDCl3): δ14.19 (1H, s), 8.37 (1H, m), 8.28 (1H, m), 7.89 (2H, s), 7.65 (2H, d), 7.23 (1H, d), 3.99 (3H, s), 3.55 (2H, s), 2.23 (6H, s). 13 C-NMR (100MHz, CDCl3): δ165.44, 164.46, 161.73, 153.48, 146.19, 140.71, 13 1.01, 130.86, 123.81, 123.40, 119.17, 118.14, 108.43, 54.22, 54.10, 43.03.

[0093] Example 7: Preparation of Compound 9

[0094] Under nitrogen purging and protection, compound 8 (0.7 g, 1.63 mmol, 1 eq), 2,6-difluorobenzaldehyde (0.28 g, 1.96 mmol, 1.2 eq), and 20 mL THF were added to the reaction flask. The mixture was heated to 45–50 °C and maintained at this temperature for 1 hour. The temperature was then lowered to 20–25 °C, and sodium borohydride (0.1 g, 2.64 mmol, 1.6 eq) was added. 7 mL of methanol was added dropwise, and the reaction was continued at this temperature for 3 hours. After the reaction was complete, the reaction solution was added dropwise to 20 mL of dilute hydrochloric acid aqueous solution, extracted with 20 mL of dichloromethane, and the organic layer was removed. The solution was then eluted by silica gel column chromatography with ethyl acetate:n-hexane (1:4) to give 0.76 g of compound 9 as a solid, yield 85%. ESI-HRMS (m / z): C 26 H 25 Theoretical value of F2N6O4S[M+H+]: 555.1621, measured value: 555.1627. 1 H-NMR (400MHz, CDCl3): 14.34 (1H, s), 9.04 (1H, s), 8.39 (1H, s), 8.24 (2H, m), 7.50 (2 H, m), 7.25 (1H, s), 6.91 (3H, m), 4.51 (2H, s), 4.06 (3H, s), 3.52 (2H, s), 2.30 (6H, s). 13 C-NMR (100MHz, CDCl3): δ166.44, 165.19, 162.32, 160.68, 146.77, 140.97, 132.06, 131.0 8, 130.03, 123.85, 120.22, 118.43, 113.01, 111.61, 108.79, 54.87, 54.55, 43.43, 38.78.

[0095] Example 8: Preparation of Compound 10

[0096] Compound 9 (1.0 g, 1.8 mmol, 1 eq) was added to a four-necked flask along with methanol (20 mL, 20 v / w), Raney nickel (0.4 g, 0.4 w / w), and the mixture was purged with nitrogen and then hydrogen. The reaction was carried out at 40–45 °C under normal pressure for 8 hours. The reaction solution was filtered, and the filtrate was dried to give 0.8 g of compound 10, yield 84%. ESI-HRMS (m / z): C 26 H 27 Theoretical value of F2N6O2S[M+H+]: 525.1879, measured value: 525.1874; 1H NMR (400MHz, d6DMSO): 14.26 (1H, s), 8.95 (1H, s), 8.33 (1H, s), 7.45-7.16 (6H, m), 6 .61(2H,s), 5.34(2H,s), 4.51(2H,s), 3.98(3H,s), 3.42-3.36(2H,m), 2.21(6H,s). 13 C-NMR (100MHz, d6DMSO): δ166.25, 163.30, 162.15, 154.02, 149.14, 131.66, 131.07, 129.05, 1 24.48, 124.03, 119.82, 118.62, 114.12, 112.40, 112.16, 107.60, 55.01, 54.59, 43.59, 38.65.

[0097] Example 9: Preparation of Relugoline

[0098] Under nitrogen protection, 0.8 g of compound 10 (1.53 mmol, 1 eq), 0.99 g of 1,1-carbonyldiimidazole (6.1 mmol, 4.0 eq), and 4 mL of acetonitrile (5 v / w) were added to a four-necked flask. The mixture was heated to 45 °C and stirred for 4 hours. The temperature was then lowered to 10–15 °C, and 0.32 g of triethylamine (3.15 mmol, 2.06 eq) was added. Methoxyamine hydrochloride (0.24 g, 2.9 mmol, 1.9 eq) was added in portions while controlling the temperature. The mixture was heated to 50–55 °C and maintained at this temperature for 18 hours until the reaction was complete. Acetonitrile was removed under reduced pressure. 20 mL of a saturated ammonium chloride aqueous solution and 20 mL of dichloromethane were slowly added to the residue. After stirring for 30 minutes, the mixture was extracted. The dichloromethane layer was separated and removed under reduced pressure. The residue was recrystallized from ethanol to give 0.76 g of relugoline (80% yield). ESI-HRMS (m / z):

[0099] C 29 H 28 Theoretical value of F2N7O5S[M+H+]: 624.1835, measured value: 624.1827; 1 H NMR(CDCl3): δ2.17(6H,s),3.62-3.82(2H,m),3.84(3H,s),4.20(3H,s),5.37(2H ,s),6.94(2H,t,J=8.2Hz),7.14(1H,d,J=8.8Hz),7.22-7.67(7H,m),7.71(1H,s).

[0100] The specific embodiments of the present invention have been described in detail above, but they are only preferred embodiments of the present invention. From a technical perspective, optimizations to the reaction conditions in the described implementation steps and method improvements made to obtain the intermediates involved in the present invention, based on the synthetic route of the present invention, should also be considered within the scope of protection of the present invention. Therefore, the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention.

Claims

1. A method for synthesizing relugoli, comprising the following steps: Step 1: Compound 2 reacts with di-tert-butyl dicarbonate ((Boc)₂O) under alkaline conditions to give compound 3. The molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:2.2~2.

8. The base is triethylamine and / or 4-dimethylaminopyridine. The reaction temperature is 55~70℃. The reaction is carried out in an organic solvent, wherein the organic solvent is 1,4-dioxane. The mass-volume ratio (g / mL) of compound 2 to the organic solvent is 1:5~1:

7. Step 2: In an organic solvent, compound 3 undergoes a bromination reaction with dibromohydantoin to yield compound 4. Step 3: Under the condition of triethylamine as an acid-binding agent, compound 4 undergoes an alkylation reaction with dimethylamine hydrochloride to obtain compound 5. Step 4: In the presence of a base, compound 5 is hydrolyzed to obtain compound 6. Step 5: Under the action of propyl phosphoric anhydride (T3P), compound 6 condenses with 6-methoxy-3-aminopyridazine to give compound 7. Step 6: In the presence of acid, the tert-butyl-protected amino group in compound 7 is deprotected to obtain compound 8. Step 7: Under the action of sodium borohydride, compound 8 undergoes reductive ammoniation with 2,6-difluorobenzaldehyde to obtain compound 9, wherein the molar ratio of compound 8, 2,6-difluorobenzaldehyde and sodium borohydride is 1:1.1~1.3:1.5~1.8, and the reaction temperature is 15~30℃; Step 8: Compound 9 undergoes nitro reduction to obtain compound 10. Step 9: Compound 10 is reacted in the presence of carbonyl diimidazole and methoxyamine hydrochloride to give relugoli, wherein the molar ratio of compound 10, carbonyl diimidazole and methoxyamine hydrochloride is 1:3.5~4.5:1.8~2.2, the reaction temperature is 45~60℃, the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass-volume ratio of compound 10 to organic solvent is 1:4~1:

6.

2. The method according to claim 1, wherein, In step 1, The molar ratio of compound 2 to ditert-butyl dicarbonate is 1:2.5; The reaction temperature is 60~65℃; The mass-to-volume ratio (g / mL) of compound 2 to organic solvent is 1:

6.

3. The method according to claim 2, wherein, In step 1, after the reaction is complete, the solvent is removed under reduced pressure, ethanol is added and stirred, filtered, and dried to obtain compound 3.

4. The method according to any one of claims 1-3, wherein, In step 2, The molar ratio of compound 3 to dibromohydantoin is 1:0.5~0.6; The reaction temperature is 30~40℃; The organic solvent is dichloromethane, wherein the mass-volume ratio of compound 3 to the organic solvent is 1:5 to 1:7; The reaction takes place under light.

5. The method according to claim 4, wherein, In step 2, The molar ratio of compound 3 to dibromohydantoin is 1:0.55; The reaction temperature is 33~37℃; The mass-to-volume ratio of compound 3 to the organic solvent is 1:

6.

6. The method according to claim 4, wherein, In step 2, after the reaction is complete, the reaction solution is cooled to room temperature, washed with saturated sodium bicarbonate solution, and then the aqueous layer is extracted with dichloromethane. The dichloromethane layers are combined, the solvent is removed under reduced pressure, and the solution is dried to obtain compound 4.

7. The method according to any one of claims 1-3, wherein, In step 3, The molar ratio of compound 4, triethylamine, and dimethylamine hydrochloride is 1:2.5~3.0:1.3~1.6; The reaction temperature is 15~30℃; The reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass-to-volume ratio (g / mL) of compound 4 to the organic solvent is 1:8 to 1:

12.

8. The method according to claim 7, wherein, In step 3, The molar ratio of compound 4, triethylamine, and dimethylamine hydrochloride is 1:2.6:1.5; The reaction temperature is 20~25℃; The mass-to-volume ratio (g / mL) of compound 4 to the organic solvent is 1:

10.

9. The method according to claim 7, wherein, In step 3, after the reaction is complete, the solvent is removed under reduced pressure, followed by washing, dehydration, and drying to obtain compound 5.

10. The method according to any one of claims 1-3, wherein, In step 4, The reaction temperature is 60~70℃; The base is sodium hydroxide and / or potassium hydroxide, wherein the molar ratio of compound 5 to the base is 1:3 to 1:5; The reaction is carried out in a solvent, wherein the solvent is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 4:1; and the mass-volume ratio (g / mL) of compound 5 to the solvent is 1:2.

5.

11. The method according to claim 10, wherein, In step 4, The molar ratio of compound 5 to the base is 1:

4.

12. The method according to claim 10, wherein, In step 4, after the reaction is complete, the pH is adjusted to 2-3 with hydrochloric acid, and a solid precipitates out. After filtration and drying, compound 6 is obtained.

13. The method according to any one of claims 1-3, wherein, In step 5, The molar ratio of compound 6, 6-methoxy-3-aminopyridazine, and propylphosphoanhydride is 1:1.1~1.3:2.2~2.5; The reaction temperature is 55~60℃; The reaction is carried out in an organic solvent, wherein the organic solvent is DMF, and the mass-to-volume ratio (g / mL) of compound 6 to the organic solvent is 1:

7.

14. The method according to claim 13, wherein, In step 5, The molar ratio of compound 6, 6-methoxy-3-aminopyridazine, and propylphosphoanhydride is 1:1.2:2.4; The reaction temperature is 53~57℃.

15. The method according to claim 13, wherein, In step 5, after the reaction is complete, the pH is adjusted to 7.5-8.5, water is added, a solid precipitates out, and the solid is filtered, dried, and compound 7 is obtained.

16. The method according to any one of claims 1-3, wherein, In step 6, The reaction temperature is 40~50℃; The acid is hydrochloric acid, wherein the molar ratio of compound 7 to the acid is 1:10 to 1:14; The reaction is carried out in an organic solvent, wherein the organic solvent is THF, and the mass-volume ratio (g / mL) of compound 7 to the organic solvent is 1:8 to 1:

12.

17. The method according to claim 16, wherein, In step 6, The reaction temperature is 43~46℃; The molar ratio of compound 7 to acid is 1:12; The mass-to-volume ratio (g / mL) of compound 7 to the organic solvent is 1:

10.

18. The method according to claim 16, wherein, In step 6, after the reaction is complete, the pH is adjusted to 7-8, and the solution is removed under reduced pressure until dry to obtain compound 8.

19. The method according to any one of claims 1-3, wherein, In step 7, The molar ratio of compound 8, 2,6-difluorobenzaldehyde, and sodium borohydride is 1:1.2:1.6; The reaction temperature is 20~25℃.

20. The method according to claim 19, wherein, In step 7, after the reaction is complete, the reaction solution is added to a dilute hydrochloric acid aqueous solution, extracted with dichloromethane, and the organic layer is removed to obtain compound 9.

21. The method according to any one of claims 1-3, wherein, In step 8, The reaction temperature is 35~50℃; The reaction was carried out in an organic solvent, wherein the organic solvent was methanol; the mass-to-volume ratio (g / mL) of compound 9 to the organic solvent was 1:16 to 1:

22. The catalyst used for nitro reduction is Raney nickel, in which the mass ratio of compound 9 to the catalyst is 1:0.

4.

22. The method according to claim 21, wherein, In step 8, The reaction temperature is 40~45℃; The mass-to-volume ratio (g / mL) of compound 9 to the organic solvent is 1:

20.

23. The method according to claim 21, wherein, In step 8, after the reaction is complete, the reaction solution is filtered, and the filtrate is dried to obtain compound 10.

24. The method according to any one of claims 1-3, wherein, In step 9, The molar ratio of compound 10, carbonyl diimidazole, and methoxyamine hydrochloride is 1:4.0:1.9; The reaction temperature is 50~55℃; The mass-to-volume ratio of compound 10 to the organic solvent is 1:

5.

25. The method according to claim 24, wherein, In step 9, after the reaction is complete, the solvent is removed under reduced pressure to obtain rilugoli.

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