Preparation method of Alasset bulk drug

Abstract

The invention relates to a preparation method of an ilastrant bulk drug, which comprises the following steps: taking a compound 1 as an initial raw material, carrying out Suzuki-Miyaura coupling reaction on the compound 1 and a compound a, and carrying out palladium-carbon reduction to obtain a key intermediate 6, so that the synthesis steps of the intermediate 6 can be shortened; subsequently, the intermediate 6 is subjected to chiral resolution and then is converted into an intermediate c through a Sandmeyer reaction, and a final product can be synthesized through a Buchwald-Harwig coupling reaction and a protection group removal. According to the invention, the reaction route is shortened, the cost is reduced, the reaction yield is improved, and the industrial production of the process is easier to realize.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and preparation of raw materials, and specifically relates to a method for preparing an elastomeric raw material. Background Art

[0002] Elacestrant is an oral selective estrogen receptor degrader indicated for the treatment of postmenopausal women and adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with an estrogen receptor 1 (ESR1) mutation whose disease has progressed after at least one line of endocrine therapy.

[0003] The structural formula of elastatin is shown below: Currently, there are few reports on the preparation method of alacastran. The patent CN113348163A of Yuanyan Company reports the following synthesis route: 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (CAS: 722536-73-4, compound 1) is used as the starting material, and a Miyaura borylation reaction is carried out under palladium catalysis, followed by a Suzuki-Miyaura coupling reaction with an aryl bromide 3 to obtain compound 4, and then the double bond is reduced by palladium hydroxide on carbon, and then the protecting group is removed to obtain compound 6, and the absolute configuration compound 7 is obtained by chiral resolution with D-(+)-dibenzoyltartaric acid, which is subjected to a reductive amination reaction with compound 8, and the carbonyl group is reduced with sodium borohydride to obtain the target product alacastran.

[0004] The original synthesis route is relatively long, and the total reaction yield is low, only 11%, which is not conducive to process costs and difficult to achieve industrial production; sodium borohydride reduction of the ketone carbonyl group of the amide is difficult and requires the addition of more iodine, which is not conducive to environmental protection and cost saving. The reducing agent used for reduction amination is relatively expensive, and the equivalent weight is large, resulting in high cost.

[0005] Chinese patent CN 117229157A reports the following synthetic route: starting from compound 10, the absolute configuration compound 11 is obtained by chiral resolution with D-(+)-dibenzoyltartaric acid, and then reduced and aminated with compound 12 under the action of sodium acetate borohydride to obtain compound 13, trifluoroacetic acid de-Boc is removed to obtain compound 14, and finally reduced and aminated with acetaldehyde to obtain the final product.

[0006] Although the above synthesis scheme has achieved process production, compound 10 is currently difficult to obtain from the market. If compound 10 is synthesized from compound 1, the route involved is still relatively long. A process with a short route, high yield, low cost, and easy industrialization needs to be further developed and improved. Summary of the invention

[0007] In view of the problems existing in the prior art, the present invention provides a method for preparing an elastomeric bulk drug, which not only shortens the reaction route for preparing the final product from compound 1 and reduces the cost, but also improves the reaction yield and makes it easier to realize industrial production of the process.

[0008] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention is: A method for preparing an elastomeric bulk drug, characterized by comprising the following steps: (1) 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 4-methoxy-2-nitrophenylboronic acid undergo Suzuki-Miyaura coupling reaction to obtain compound b; (2) Compound b was subjected to palladium-carbon hydrogenation to reduce the nitro group, carbon-carbon double bond and debenzylate to obtain compound 6; (3) Compound 6 was chiral resolved by D-(+)-dibenzoyltartaric acid to obtain compound 7 with absolute configuration; (4) Compound 7 is reacted with Sandmeyer reaction to obtain compound c; (5) Compound c and the secondary amine of compound d are subjected to Buchwald-Hartwig coupling reaction, and then the Boc protecting group is removed with trifluoroacetic acid to obtain the elastomeric raw material; .

[0009] The preparation route of the present invention is as follows: The present invention uses compound 1 as a starting material, undergoes a Suzuki-Miyaura coupling reaction with compound a, and then undergoes palladium-carbon reduction to obtain a key intermediate 6, thereby shortening the synthesis steps of intermediate 6. After the intermediate 6 is chirally resolved, it is converted into intermediate c through a Sandmeyer reaction, and the final product is synthesized through a Buchwald-Hartwig coupling reaction and then deprotection.

[0010] Preferably, in step (1), the preparation method of compound b is as follows: add a reaction solvent, water, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, replace with nitrogen, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)2Cl2), heat to 80-85°C after addition, stir to react, and perform HPLC detection. After the reaction is completed, cool to room temperature, filter, separate, concentrate the organic phase until no distillation occurs, add water dropwise while stirring, cool to 10-15°C, filter, wash the filter cake with water, and dry the filter cake at 50-60°C to obtain the product; wherein, 7-benzyloxy-3-bromo-1 , the molar ratio of 2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride is 1:1~1.5:1.5~3:0.0002~0.0005; the reaction solvent is selected from one of the following: toluene, 1,4-dioxane, ethanol, and N,N-dimethylformamide.

[0011] Preferably, in step (2), the preparation method of compound 6 is as follows: add the reaction liquid, compound b, and palladium carbon into the hydrogenation kettle, seal the hydrogenation kettle, replace it with nitrogen three times, exhaust the nitrogen, blow in hydrogen, maintain the nitrogen pressure at 1-1.2 MPa, react at 25-35°C, detect by HPLC, and after the reaction is completed, filter and concentrate the mother liquor to obtain compound 6; wherein the mass ratio of compound b to palladium carbon is 1:0.01-0.05; and the reaction liquid is methanol, ethanol, or tetrahydrofuran.

[0012] Preferably, in step (3), the preparation method of compound 7 is as follows: a solvent, dichloromethane, and compound 6 are added to a reactor, heated to 30-50° C., and then D-(+)-dibenzoyltartaric acid ([D-(+)-DBTA]) is added, heated to reflux, the reactor is cooled to room temperature, filtered, the filter cake is washed with dichloromethane, the wet filter cake is added to dichloromethane and refluxed for 0.5-2 h, cooled to room temperature and stirred for 0.5-2 h, filtered, the filter cake is slurried with dichloromethane for 0.5-2 h, filtered, the filter cake is washed with dichloromethane and dried to obtain compound 7; the solvent is methanol, acetonitrile, or ethyl acetate.

[0013] Preferably, in step (4), the preparation method of compound c is as follows: water is added to the reactor, sulfuric acid is added dropwise, the temperature is controlled at 20-25°C, compound 7 is added, the temperature is lowered to -5-0°C, sodium nitrite solution is added dropwise, the temperature is controlled at -5-0°C, stirring is performed for 0.5-2h after the addition is completed, and HPLC detection is performed. After the raw materials react, the reaction solution is added dropwise to a 50-70°C cuprous bromide aqueous solution, the temperature is controlled at 50-70°C, the reaction is completed after the addition is completed, and HPLC detection is performed. After the reaction is completed, the temperature is lowered to 10-15°C, suction filtered, the filter cake is washed with water, and dried at 50-60°C to obtain the product; wherein the molar ratio of compound 7, sodium nitrite, and cuprous bromide is 1:1-1.5:1-1.5.

[0014] Preferably, in step (5), the preparation method of the elastomeric bulk drug is as follows: an organic solvent, compound c, compound d, and potassium carbonate are added to a reactor, the atmosphere is replaced with nitrogen three times, palladium acetate and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene are added, the temperature is raised to 90-95°C, the reaction is performed, and HPLC detection is performed; after the reaction is completed, the temperature is lowered to room temperature, the mixture is filtered, the mother liquor is returned to the kettle, trifluoroacetic acid is added under stirring, sodium carbonate solution is added dropwise to adjust the pH to 7-8, the reaction solution is concentrated until no distillation occurs, water is added to separate the material, the mixture is filtered, the filter cake is dried, slurried with ethyl acetate, filtered, and dried to obtain the product; wherein the molar ratio of compound c, compound d, potassium carbonate, palladium acetate, and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos) is 1:1.2:2:0.001-0.004:0.001-0.008; the organic solvent is selected from one of the following: toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl adipate.

[0015] Preferably, the preparation method of compound d is as follows: methanol, tert-butyl N-{2-[4-(aminomethyl)phenyl]ethyl}aminomethyl ester, and acetaldehyde are added to the reactor, and sodium triacetoxyborohydride is added in batches at a temperature of 5 to 10°C. After the addition, the temperature is moved to 20 to 25°C for reaction, and HPLC detection is performed. After the reaction is completed, saturated ammonium chloride aqueous solution is added dropwise to quench, the reaction is filtered, and the reaction is concentrated until no distillation is produced. After extraction, the organic phases are combined and concentrated to obtain compound d.

[0016] Preferably, in step (1), the molar ratio of 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride is 1:1.2:2:0.0004.

[0017] Preferably, in step (4), the molar ratio of compound 7, sodium nitrite and cuprous bromide is 1:1.05:1.2.

[0018] Preferably, in step (5), the molar ratio of compound c, compound d, potassium carbonate, palladium acetate, and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene is 1:1.2:2:0.0015:0.003.

[0019] The beneficial effects of the present invention are: 1. The present invention uses compound 1 as a starting material, undergoes a Suzuki-Miyaura coupling reaction with compound a, and then undergoes palladium-carbon reduction to obtain a key intermediate 6; intermediate 6 is subsequently chirally resolved and converted into intermediate c through a Sandmeyer reaction, and then undergoes a Buchwald-Hartwig coupling reaction and deprotection to synthesize the final product; the present invention shortens the reaction route for preparing the final product from compound 1 and reduces the process cost; 2. The reaction involved in the present invention is simple and easy to operate, the reaction is stable, the route is safe and the yield is high; 3. The present invention not only shortens the reaction route and reduces the cost, but also improves the reaction yield, making it easier to realize industrial production of the process. DETAILED DESCRIPTION

[0020] The technical scheme of the present invention is further specifically described below through examples, which are provided for the purpose of illustrating the present invention and are not intended to limit the present invention. Based on the examples in this application, all other examples obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0021] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0022] Synthesis of compound d 200 mL of methanol, 40 g (0.160 mol) of tert-butyl N-{2-[4-(aminomethyl)phenyl]ethyl}aminomethyl ester, and 14.8 g (0.336) of acetaldehyde were added to the reactor. 67.8 g (0.320 mol) of sodium triacetoxyborohydride were added in batches at a temperature of 5 to 10 ° C. After the addition, the temperature was moved to 20 to 25 ° C for reaction for 3 h. HPLC detection was performed. After the reaction was completed, 100 g of saturated ammonium chloride aqueous solution was added dropwise to quench, filtered, and concentrated at 50 ° C until no distillation occurred. 50 mL of ethyl acetate was added for extraction three times. The organic phases were combined and concentrated to obtain 47.1 g of compound d with a yield of 96%. 1H NMR(400MHz, DMSO-d): 1.10-1.25 (m, 6H), 1.42 (s,9H), 2.60-2.71 (m, 2H), 2.79-2.85 (m, 2H), 2.96-3.05 (m, 2H), 3.20-3.30 (m,2H), 3.70 (s, 2H), 7.01-7.10 (m,2H), 7.20-7.29 (m,2H), 8.05 (s, 1H). EI-MS m / z:307.23[M+H] ＋ .

[0023] Example 1 (1) Synthesis of compound b Add 300g 1,4-dioxane, 30g water, 50.0g (0.159mol) 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 37.6g (0.191mol) 4-methoxy-2-nitrophenylboric acid (compound a), 43.9g (0.318mol) potassium carbonate into the reactor, replace with nitrogen three times, add 0.05g (0.07mmol) Pd(dppf)2Cl2, raise the temperature to 80-85℃ after addition, stir for 3h, and detect by HPLC. After the reaction is completed, cool to room temperature, filter, separate the liquid, concentrate the organic phase until no distillation occurs, add 500g of water precipitate dropwise while stirring, cool to 10-15℃, filter, wash the filter cake with water, and dry the filter cake at 55℃ to obtain 58.5g of product compound b with a yield of 95%. 1 H NMR(400MHz, DMSO-d): 2.23-2.29 (m, 2H), 2.91-2.98 (m,2H), 3.81-3.89 (s, 3H), 5.10-5.22 (s, 2H), 6.81-6.92 (m, 2H), 7.01-7.06 (s,1H), 7.32-7.48 (m, 7H), 7.70-7.78 (m, 2H). EI-MS m / z:388.15[M+H] ＋ .

[0024] (2) Synthesis of compound 6: Add 100 g methanol, 10 g (0.026 mol) compound b, and 0.2 g palladium carbon into the hydrogenation kettle, seal the hydrogenation kettle, replace it with nitrogen three times, exhaust the nitrogen, blow in hydrogen, maintain the nitrogen pressure at 1-1.2 MPa, react at 30-35 ° C for 5 h, and detect by HPLC. After the reaction is completed, filter and concentrate the mother liquor to obtain 6.86 g compound 6 with a yield of 98%. 1 H NMR (400MHz, DMSO-d): 1.81-2.00 (m, 2H), 2.80-3.02 (m, 5H), 3.71-3.75 (s, 3H), 6.32-6.44 (m, 3H), 6.65-6.72 (m, 2H), 7.11-7.18 (m, 1H), 7.48 (s, 2H), 9.19 (s, 1H). EI-MS m / z:270.15[M+H] ＋ .

[0025] (3) Synthesis of compound 7: 80 mL of acetonitrile, 40 mL of dichloromethane, and 8 g (0.03 mol) of compound 6 were added to the reactor, heated to 40 °C, and 3.87 g (0.015 mol) of D-(+)-dibenzoyltartaric acid [D-(+)-DBTA] was added, heated to reflux, and the reactor was cooled to room temperature, filtered, and the filter cake was washed with 16 mL of DCM. The wet filter cake was added to 64 mL of DCM and refluxed for 1 h, cooled to room temperature and stirred for 1 h, filtered, and the filter cake was slurried with 64 mL of DCM for 1 h, filtered, and the filter cake was washed with 16 mL of DCM and dried to obtain 3.9 g of compound 7 with a yield of 49%. 1 HNMR(400MHz, DMSO-d): 1.82-2.01 (m, 2H), 2.82-3.02 (m, 5H), 3.74 (s, 3H), 6.35-6.46 (m, 3H), 6.66-6.72 (m, 2H), 7.10-7.17 (m, 1H), 7.49-7.55 (s, 2H), 9.22(s, 1H). EI-MS m / z:270.15[M+H] ＋ .

[0026] (4) Synthesis of compound c: Add 60g water to the reactor, slowly add 40g sulfuric acid, control the temperature at 20-25℃, add 10g (0.037mol) of compound 7, cool to -5-0℃, add 2.69g (0.039) sodium nitrite and 8g aqueous solution, control the temperature at -5-0℃, stir for 0.5h after the dropwise addition, and detect by HPLC. After the reaction of the raw materials, slowly add the reaction solution dropwise to 60℃ 6.37g (0.044mol) cuprous bromide and 40g aqueous solution, control the temperature at 60±2℃, react for 30min after the dropwise addition, and detect by HPLC. After the reaction, cool to 10-15℃, filter, wash the filter cake with water, and dry at 55℃ to obtain 11.7g of the product with a yield of 95%. 1 H NMR (400MHz, DMSO-d): 1.83-2.04 (m, 2H), 2.84-3.10 (m, 5H), 3.72 (s, 3H), 6.36-6.46 (m, 3H), 6.65-6.71 (m, 2H), 7.11-7.17 (m, 1H), 9.18 (s, 1H). EI-MS m / z:333.04[M+H] ＋ .

[0027] (5) Synthesis of API Elacestrant: 40mL 1,4-dioxane, 5g (0.015mol) compound c, 5.5g (0.018mol) compound d, 4.1g (0.03mol) potassium carbonate were added to the reactor, nitrogen was replaced three times, 5mg (0.022mmol) Pd(OAc)2, 25.4mg (0.044mmol) XantPhos were added, the temperature was raised to 90-95℃, the reaction was carried out for 5h, and HPLC was used for detection. After the reaction was completed, the temperature was lowered to room temperature, filtered, the mother liquor was returned to the kettle, 3.4g (0.03mol) trifluoroacetic acid was added under stirring, saturated sodium carbonate solution was slowly added dropwise to adjust the pH to 7-8, the reaction solution was concentrated until no distillation was produced, 50g of water was added, filtered, the filter cake was dried, slurried twice with 20mL EA, filtered, and dried to obtain 6.2 g of the product with a yield of 90%. 1H NMR (400MHz, DMSO-d): 0.92-1.10 (m, 6H), 1.64-1.83 (m, 2H), 2.38-2.45 (m, 2H), 2.65-2.89 (m, 8H), 2.88-2.95 (m, 2H), 3.62-3.70 (m,1H),3.79 (s, 3H), 3.94-4.03 (m, 2H), 6.46-6.60 (m, 2H), 6.69-6.75 (m, 2H), 6.94-7.01 (m, 3H), 7.14-7.19 (m, 3H), 8.21(s, 1H), 9.28 (s, 1H). EI-MS m / z:459.30[M+H] ＋ .

[0028] Example 2 (1) Synthesis of compound b Add 300g 1,4-dioxane, 30g water, 50.0g (0.159mol) 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 37.6g (0.191mol) 4-methoxy-2-nitrophenylboric acid, 43.9g (0.318mol) potassium carbonate into the reactor, replace with nitrogen three times, add 0.05g (0.06mmol) Pd(dppf)2Cl2, raise the temperature to 60-65℃ after addition, stir for 3h, and detect by HPLC. After the reaction is completed, cool to room temperature, filter, separate the liquid, concentrate the organic phase until no distillation occurs, add 500g of water precipitate dropwise while stirring, cool to 10-15℃, filter, wash the filter cake with water, and dry the filter cake at 55℃ to obtain 49.5g of the product with a yield of 81%.

[0029] (2) Synthesis of compound 6: Add 100g methanol, 10g (0.026mol) compound b, and 0.2g palladium carbon into the hydrogenation kettle, seal the hydrogenation kettle, replace it with nitrogen three times, exhaust the nitrogen, blow in hydrogen, maintain the nitrogen pressure at 1-1.2Mpa, react at 20-25℃ for 5h, and detect by HPLC. After the reaction is completed, filter and concentrate the mother liquor to obtain 6.2g compound 6 with a yield of 89%.

[0030] (3) Synthesis of compound 7: 80 mL of acetonitrile, 40 mL of dichloromethane, and 8 g (0.03 mol) of compound 6 were added to the reactor, heated to 40 °C, and 3.87 g (0.015 mol) of D-(+)-dibenzoyltartaric acid [D-(+)-DBTA] was added. The reaction was carried out at room temperature, filtered at room temperature, and the filter cake was washed with 16 mL of DCM. The wet filter cake was added to 64 mL of DCM and refluxed for 1 h. The mixture was cooled to room temperature and stirred for 1 h. The filter cake was filtered and slurried with 64 mL of DCM for 1 h. The filter cake was filtered and washed with 16 mL of DCM and dried to obtain 3.3 g of compound 7 with a yield of 41%.

[0031] (4) Synthesis of compound c: Add 60g water to the reactor, slowly add 40g sulfuric acid, control the temperature at 20-25℃, add 10g (0.037mol) compound 7, cool to -5-0℃, add 2.68g (0.039) sodium nitrite and 8g aqueous solution, control the temperature at -5-0℃, stir for 0.5h after adding, and detect by HPLC. After the reaction of the raw materials, slowly add the reaction solution to 6.37g (0.044mol) cuprous bromide and 40g aqueous solution at 40℃, control the temperature at 40±2℃, react for 30min after adding, and detect by HPLC. After the reaction, cool to 10-15℃, filter, wash the filter cake with water, and dry at 55℃ to obtain the product. Product 9.1g, yield 74%.

[0032] (5) Synthesis of the API Elacestrant 40mL 1,4-dioxane, 5g (0.015mol) compound c, 5.5g (0.018mol) compound d, 4.1g (0.03mol) potassium carbonate were added to the reactor, nitrogen was replaced three times, 5mg (0.022mmol) Pd(OAc)2, 25.4mg (0.044mmol) XantPhos were added, the temperature was raised to 70-75℃, the reaction was carried out for 5h, and HPLC was used for detection. After the reaction was completed, the temperature was lowered to room temperature, filtered, the mother liquor was returned to the kettle, 3.4g (0.03mol) trifluoroacetic acid was added under stirring, saturated sodium carbonate solution was slowly added dropwise to adjust the pH to 7-8, the reaction solution was concentrated until no distillation was produced, 50g of water was added, filtered, the filter cake was dried, slurried twice with 20mL EA, filtered, and dried to obtain 5.7g of the product with a yield of 83%.

[0033] Example 3 (1) Synthesis of compound b Add 300g 1,4-dioxane, 30g water, 50.0g (0.159mol) 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 31.3g (0.159mol) 4-methoxy-2-nitrophenylboric acid, 43.9g (0.318mol) potassium carbonate into the reactor, replace with nitrogen three times, add 0.05g (0.06mmol) Pd(dppf)2Cl2, raise the temperature to 80-85℃ after addition, stir for 3h, and detect by HPLC. After the reaction is completed, cool to room temperature, filter, separate the liquid, concentrate the organic phase until no distillation occurs, add 500g of water precipitate dropwise while stirring, cool to 10-15℃, filter, wash the filter cake with water, and dry the filter cake at 55℃ to obtain 50.7g of product with a yield of 50.7%.

[0034] (2) Synthesis of compound 6: Add 100 g methanol, 100 g (0.026 mol) compound b, and 1 g palladium carbon into the hydrogenation kettle, seal the hydrogenation kettle, replace it with nitrogen three times, exhaust the nitrogen, blow in hydrogen, maintain the nitrogen pressure at 1-1.2 MPa, react at 30-35 ° C for 5 h, and detect by HPLC. After the reaction is completed, filter and concentrate the mother liquor to obtain 56.5 g compound 6 with a yield of 81%.

[0035] (3) Synthesis of compound 7: 800 mL of acetonitrile, 400 mL of dichloromethane, and 80 g (0.3 mol) of compound 6 were added to the reactor, heated to 40°C, and then 25.8 g (0.1 mol) of D-(+)-dibenzoyltartaric acid [D-(+)-DBTA] was added and heated to reflux. The reactor was cooled to room temperature, filtered, and the filter cake was washed with 160 mL of DCM. The wet filter cake was added to 640 mL of DCM and refluxed for 1 h. The mixture was cooled to room temperature and stirred for 1 h. The filter cake was filtered and slurried with 640 mL of DCM for 1 h. The filter cake was filtered and washed with 160 mL of DCM and dried to obtain 32.6 g of compound 7 with a yield of 41%.

[0036] 4) Synthesis of compound c: Add 60g water to the reactor, slowly add 40g sulfuric acid, control the temperature at 20-25℃, add 10g (0.037mol) of compound 7, cool to -5-0℃, add 2.68g (0.039) sodium nitrite and 8g aqueous solution, control the temperature at -5-0℃, stir for 0.5h after adding, and detect by HPLC. After the reaction of the raw materials, slowly add the reaction solution to 60℃ 5.3g (0.037mol) cuprous bromide and 40g aqueous solution, control the temperature at 60±2℃, react for 30min after adding, and detect by HPLC. After the reaction, cool to 10-15℃, filter, wash the filter cake with water, and dry at 55℃ to obtain 8.87g of product with a yield of 72%.

[0037] (6) Synthesis of the API Elacestrant 40mL 1,4-dioxane, 5g (0.015mol) compound c, 4.58g (0.015mol) compound d, 4.1g (0.03mol) potassium carbonate were added to the reactor, nitrogen was replaced three times, 5mg (0.022mmol) Pd(OAc)2, 25.4mg (0.044mmol) XantPhos were added, the temperature was raised to 90-95℃, the reaction was carried out for 5h, and HPLC was used for detection. After the reaction was completed, the temperature was lowered to room temperature, filtered, the mother liquor was returned to the kettle, 3.4g (0.03mol) trifluoroacetic acid was added under stirring, saturated sodium carbonate solution was slowly added dropwise to adjust the pH to 7-8, the reaction solution was concentrated until no distillation was produced, 50g of water was added, filtered, the filter cake was dried, slurried twice with 20mL EA, filtered, and dried to obtain 5.6g of the product with a yield of 81%.

[0038] Finally, it should be noted that the above are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

Claims

1. A method for preparing an elastomeric bulk drug, characterized in that The steps include: (1) 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 4-methoxy-2-nitrophenylboronic acid undergo Suzuki-Miyaura coupling reaction to obtain compound b; (2) Compound b was subjected to palladium-carbon hydrogenation to reduce the nitro group, carbon-carbon double bond and debenzylate to obtain compound 6; (3) Compound 6 was chiral resolved by D-(+)-dibenzoyltartaric acid to obtain compound 7 with absolute configuration; (4) Compound 7 is reacted with Sandmeyer reaction to obtain compound c; (5) Compound c and the secondary amine of compound d are subjected to Buchwald-Hartwig coupling reaction, and then the Boc protecting group is removed with trifluoroacetic acid to obtain the elastomeric raw material; 。 2. The method for preparing the elastomeric bulk drug according to claim 1, characterized in that In step (1), the preparation method of compound b is as follows: adding a reaction solvent, water, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, nitrogen replacement, adding [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, heating to 80-85°C after the addition, stirring for reaction, HPLC detection, cooling to room temperature after the reaction, filtering, separating, concentrating the organic phase until no distillation occurs, stirring, adding water dropwise, cooling to 10-15°C, filtering, washing the filter cake with water, and drying the filter cake at 50-60°C to obtain the product; wherein, 7-benzyloxy-3-bromo-1 , the molar ratio of 2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride is 1:1~1.5:1.5~3:0.0002~0.0005; the reaction solvent is selected from one of the following: toluene, 1,4-dioxane, ethanol, and N,N-dimethylformamide.

3. The method for preparing the elastomeric bulk drug according to claim 1, characterized in that In step (2), the preparation method of compound 6 is as follows: add the reaction liquid, compound b, and palladium carbon into the hydrogenation kettle, seal the hydrogenation kettle, replace it with nitrogen three times, exhaust the nitrogen, blow in hydrogen, maintain the nitrogen pressure at 1 to 1.2 MPa, react at 25 to 35°C, and detect by HPLC. After the reaction is completed, filter and concentrate the mother liquor to obtain compound 6; wherein the mass ratio of compound b to palladium carbon is 1:0.01 to 0.05; and the reaction liquid is methanol, ethanol, or tetrahydrofuran.

4. The method for preparing the elastomeric bulk drug according to claim 1, characterized in that In step (3), the preparation method of compound 7 is as follows: add solvent, dichloromethane, and compound 6 to a reactor, heat to 30-50° C., then add D-(+)-dibenzoyltartaric acid, heat to reflux, cool the reactor to room temperature, filter, wash the filter cake with dichloromethane, add the wet filter cake to dichloromethane and reflux for 0.5-2h, cool to room temperature and stir for 0.5-2h, filter, slurry the filter cake with dichloromethane for 0.5-2h, filter, wash the filter cake with dichloromethane and dry to obtain compound 7; the solvent is methanol, acetonitrile, or ethyl acetate.

5. The method for preparing the elastomeric bulk drug according to claim 1, characterized in that In step (4), the preparation method of compound c is as follows: add water to the reactor, add sulfuric acid dropwise, control the temperature at 20 to 25°C, add compound 7, cool to -5 to 0°C, add sodium nitrite solution dropwise, control the temperature at -5 to 0°C, stir for 0.5 to 2h after the addition, and perform HPLC detection. After the raw materials react, add the reaction solution dropwise to a 50 to 70°C cuprous bromide aqueous solution, control the temperature at 50 to 70°C, complete the addition, and perform HPLC detection. After the reaction is completed, cool to 10 to 15°C, filter, wash the filter cake with water, and dry at 50 to 60°C to obtain the product; wherein the molar ratio of compound 7, sodium nitrite, and cuprous bromide is 1:1 to 1.5:1 to 1.

5.

6. The method for preparing the elastomeric bulk drug according to claim 1, characterized in that In step (5), the preparation method of elastomeric bulk drug is as follows: add an organic solvent, compound c, compound d, potassium carbonate to a reactor, replace the atmosphere with nitrogen three times, add palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, heat to 90-95°C, react, and perform HPLC detection; after the reaction is completed, cool to room temperature, filter, return the mother liquor to the kettle, add trifluoroacetic acid under stirring, add sodium carbonate solution dropwise to adjust the pH to 7-8, concentrate the reaction solution until no distillation occurs, add water to precipitate, filter, dry the filter cake, slurry with ethyl acetate, filter, and dry to obtain the product; wherein the molar ratio of compound c, compound d, potassium carbonate, palladium acetate, and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene is 1:1.2:2:0.001-0.004:0.001-0.008; and the organic solvent is selected from one of the following: toluene, 1,4-dioxane, N,N-dimethylformamide, and dimethyl adipate.

7. The method for preparing the elastomeric bulk drug according to claim 6, characterized in that The preparation method of compound d is as follows: methanol, tert-butyl N-{2-[4-(aminomethyl)phenyl]ethyl}aminomethyl ester, and acetaldehyde are added to a reactor, and sodium triacetoxyborohydride is added in batches at a temperature of 5 to 10°C. After the addition, the temperature is moved to 20 to 25°C for reaction, and HPLC detection is performed. After the reaction is completed, saturated ammonium chloride aqueous solution is added dropwise to quench, the reaction is filtered, and the reaction is concentrated until no distillation is produced. After extraction, the organic phases are combined and concentrated to obtain compound d.

8. The method for preparing the elastomeric bulk drug according to claim 2, characterized in that In step (1), the molar ratio of 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, 4-methoxy-2-nitrophenylboric acid, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride is 1:1.2:2:0.0004.

9. The method for preparing the elastomeric bulk drug according to claim 5, characterized in that In step (4), the molar ratio of compound 7, sodium nitrite and cuprous bromide is 1:1.05:1.

2.

10. The method for preparing the elastomeric bulk drug according to claim 6, characterized in that In step (5), the molar ratio of compound c, compound d, potassium carbonate, palladium acetate, and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene is 1:1.2:2:0.0015:0.003.

Images