A method for preparing an intermediate for a therapeutic agent for advanced breast cancer

Abstract

The application discloses a preparation method of an intermediate of a breast cancer treatment drug Irla group, which comprises the following steps: in step 1, 6-hydroxy-3,4-dihydro-1H-2-naphthalenone is first subjected to hydroxyl silylation protection, then subjected to C-C coupling docking reaction with trimethylchlorosilane, and finally subjected to deprotection to obtain the intermediate 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol; in step 2, the product in step 1 is subjected to dehydroxylation reaction to obtain the intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol; and in step 3, the product in step 2 is subjected to nitro reduction reaction to obtain 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol. The new synthesis method of the Irla group has the obvious advantages over the prior art, the reaction is complete, and the by-products are less.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of chemical medicine synthesis, and particularly relates to a preparation method of an intermediate of a breast cancer treatment drug Elacestrant. BACKGROUND

[0002] Breast cancer is a phenomenon of uncontrolled proliferation of breast epithelial cells under the action of various carcinogens. In the early stage of the disease, symptoms such as breast lump, nipple discharge, and axillary lymph node enlargement often occur. In the late stage, due to distant metastasis of cancer cells, multiple organ lesions occur, directly threatening the life of the patient.

[0003] In China, the incidence of breast cancer is increasing year by year, with more than 300,000 women diagnosed with breast cancer each year. In the eastern coastal areas and economically developed large cities, the incidence of breast cancer is increasing particularly significantly. In terms of age of onset, the incidence of breast cancer in China gradually increases from the age of 20, reaching a high value at the age of 45-50. With the popularization of new treatment strategies and methods, the mortality rate of breast cancer worldwide has gradually decreased. However, in China, especially in the vast rural areas, the mortality rate of breast cancer has not shown a significant downward trend.

[0004] Breast cancer has various types, and the severity of the disease, treatment methods, and prognosis of patients are different for different types of breast cancer. According to the protein molecules expressed on the surface of breast cancer cells, breast cancer can be divided into estrogen receptor positive (ER+) breast cancer, human epidermal growth factor receptor 2 positive (HER2+) breast cancer, ER+, HER2- breast cancer, ER+, HER2- breast cancer, and triple-negative breast cancer. Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is a highly dangerous type of breast cancer, accounting for about 20%-30% of breast cancer. HER2-positive breast cancer is characterized by rapid tumor progression, easy lymph node or vascular metastasis, and insensitivity to endocrine therapy, thus having poor prognosis. The survival time of HER2-positive breast cancer patients is only half of that of HER2-negative patients.

[0005] Elacestrant (common name: Elacestrant) is a non-steroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD), which is suitable for treating postmenopausal women or adult men with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative, ESR1 mutant, advanced or metastatic breast cancer after at least one line of endocrine therapy.

[0006] Elacestrant, an oral selective estrogen receptor degrader (SERD), can improve the progression-free survival (PFS) of patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer after treatment with CDK4 / 6 inhibitors. This benefit is more pronounced in patients who have been exposed to CDK4 / 6 inhibitors for a long time and patients with ESR1 mutant disease. Compared with the effect of other hormone therapy, Elacestrant reduces the risk of disease progression and death in postmenopausal breast cancer patients by 30%. Elacestrant is more effective for patients who are insensitive to hormone therapy due to cancer gene mutations, and the risk of cancer progression or death is reduced by 45% compared with standard hormone therapy, which is the best standard of care for the treatment of advanced breast cancer. This drug will benefit a large number of patients with advanced breast cancer.

[0007] The Chinese name of Elacestrant: (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride, molecular formula: C 30 H 40 Cl2N2O2, molecular weight: 531.56, CAS Registry Number: 722533-56-4, and its chemical structure is as follows:

[0008]

[0009] The prior art document patent CN202080011109 reports the synthesis route of Elacestrant as follows:

[0010]

[0011] In the above route, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-5-methoxyacetanilide are used as starting materials to obtain the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) through 4 steps of reaction; the intermediate compound of formula a is first subjected to chiral resolution, then docked with N-ethyl-2-(4-formylphenyl)acetamide, and then subjected to acyl reduction to obtain Elacestrant.

[0012] In the synthesis process of the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a), noble metal catalysts Pd(OH)2 / C and PdCl2(PPh3)2 are used, and hydrogenation reaction is involved. The route is long, the yield is low, and the cost is high.

[0013] The present application provides a new method for obtaining the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of Iralukast by only 3 steps of reaction, with 6-hydroxy-3,4-dihydro-1H-2-naphthalenone and 1-halogen-4-methoxy-2-nitrobenzene (compound of formula b) as starting materials, which has the advantages of short route, cheap and easily purchased starting materials, safe and simple operation, low cost, environmental friendliness and the like. The present application is helpful to reduce the production cost of Iralukast, an advanced breast cancer treatment drug, to alleviate the accessibility problem, and to benefit the vast number of advanced breast cancer patients in China. SUMMARY

[0014] The present application aims to overcome the deficiencies of the prior art, and provides a new preparation method of the intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of Iralukast, which is as follows:

[0015]

[0016] Step 1, 6-hydroxy-3,4-dihydro-1H-2-naphthalenone is first protected by hydroxyl silylation, then subjected to C-C coupling docking reaction with the compound of formula b, and finally subjected to deprotection to obtain the intermediate 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol;

[0017] Step 2, the intermediate 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol is subjected to dehydroxylation reaction to obtain the intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;

[0018] Step 3, the intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol is subjected to nitro reduction reaction to obtain 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a);

[0019] wherein

[0020] X in the compound of formula b is selected from Cl, Br or I.

[0021] The route of the present application is different from the synthesis route of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) reported in the prior art document patent CN202080011109. The present application provides a new method for obtaining the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of Irasposin by using 6-hydroxy-3,4-dihydro-1H-2-naphthalenone and 1-iodo-4-methoxy-2-nitrobenzene as starting materials, only 3 steps of reaction, which has the advantages of short route, cheap and easy-to-buy starting materials, safe and simple operation, low cost, environmental friendliness and the like. After the compound of formula a is split into a single R configuration, and then subjected to a docking reaction with N-ethyl-2-(4-formylphenyl)acetamide, and an acyl reduction reaction, irasposin is obtained.

[0022] The step 1 reaction of the present application includes a three-stage reaction, wherein the first stage reaction is the protection of the hydroxyl group of 6-hydroxy-3,4-dihydro-1H-2-naphthalenone, which is protected by trimethylchlorosilane. The protecting group is sensitive to acid and easy to remove. Triethylamine is used as an acid binding agent in the reaction process, and the reaction efficiency is high. The second stage reaction is a C-C coupling docking reaction. The catalyst in this stage is Grignard reagent, which is selected from isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride, isopropylmagnesium chloride, and tert-butylmagnesium chloride. Among them, isopropylmagnesium chloride-lithium chloride is the most active, and is preferred. Under anhydrous and anaerobic conditions, isopropylmagnesium chloride-lithium chloride is first activated at low temperature to 1-iodo-4-methoxy-2-nitrobenzene, and then subjected to a docking reaction with the hydroxyl protected product. The third stage reaction is deprotection with hydrochloric acid solution. This stage is relatively easy. In the key stage one and stage two reactions, the molar feeding ratio of 6-hydroxy-3,4-dihydro-1H-2-naphthalenone, trimethylchlorosilane, compound of formula b, and Grignard reagent is 1:1-1.2:1-1.2:1-1.4, preferably 1:1.05-1.15:1.05-1.15:1.1-1.3. The reaction can be completely and the by-product can be controlled to the minimum limit. In addition to the control of the material feeding ratio, the control of the reaction conditions is also particularly important in step 1. The anhydrous and anaerobic conditions need to be strictly controlled. In the hydroxyl protection stage of 6-hydroxy-3,4-dihydro-1H-2-naphthalenone, trimethylchlorosilane is added dropwise in dichloromethane solvent with temperature control at 10-20℃, and then the reaction is carried out at room temperature for 3-4h. In the C-C coupling docking reaction stage, the Grignard reagent is added with temperature control at-35 to-15℃, and then the reaction is continued at-25 to-15℃ for 1-1.5h. Then, 6-trimethylsiloxy-3,4-dihydro-1H-2-naphthalenone is added with temperature control at-25 to-15℃ and the reaction is continued for 1-1.5h. In the deprotection stage, 4M hydrochloric acid solution is added and stirred at room temperature for 0.5-1h. The control of the above reaction conditions is also the key to ensure the smooth progress of the reaction and reduce the by-products.

[0023] The catalyst for the dehydroxylation reaction in step 2 of the present application is triethylsilane and boron trifluoride ether complex. Under anhydrous conditions, the molar feed ratio of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol, triethylsilane and boron trifluoride ether complex is 1:1.5-3:1.5-3, preferably 1:1.75-2.5:1.75-2.5, which can make the reaction complete. In order to reduce the generation of by-products, the reaction needs to be strictly controlled in terms of reaction temperature and time. After 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol is dissolved in a mixed solvent of dichloromethane and acetonitrile, triethylsilane is added dropwise at a temperature of-30 to-15°C, and the reaction is continued for about 15 min; then triethylsilane is added dropwise at a temperature of-30 to-15°C, and finally the reaction is carried out at a temperature of-5 to 0°C for 3-4 h, which can control the by-products to a minimum. In addition, step 2 can also remove the hydroxyl group by refluxing in an isopropanol-hydrogen chloride system, but the yield is lower and the impurities are more, so it is not the first choice.

[0024] In step 3 of the present application, the nitrobenzene is reduced to aniline, which can be carried out by using a reduced iron powder-hydrochloric acid solution system, a palladium carbon pressurized hydrogenation system or an active nickel pressurized hydrogenation system, but the reduced iron powder-hydrochloric acid solution system is the most economical and does not involve pressurized reaction, so it is the first choice. In this reduction system, the molar feed ratio of 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, reduced iron powder and 4M hydrochloric acid solution is 1:3-4:3-4, preferably 1:3.25-3.75:3.25-3.75, which can ensure the reaction to be complete and the by-products to be less.

[0025] The present application provides a new synthesis method for the key intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of Irasposim, which has a short route, high yield and environmental friendliness, and has obvious advantages over the prior art documents and can benefit from them. Specific implementation method

[0026] The technical solutions in the embodiments of the present application will be described in detail below with reference to the embodiments of the present application, but the following embodiments are only used to understand the present application, and cannot limit the present application, which can be implemented in various different ways limited and covered by the claims.

[0027] The new synthesis method for the key intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of Irasposim and the advantages of the method will be further described below with reference to Examples 1-10 and Comparative Examples of the present application.

[0028] Example 1: Synthesis of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene- 2,6-diol, Method 1

[0029]

[0030] Into a 1 L three-necked flask, was placed 6-hydroxy-3,4-dihydro-1H-2-naphthalenone (81.0 g, 0.5 mol), triethylamine (55.7 g, 0.55 mol), dichloromethane 400 ml, under nitrogen atmosphere, trimethylsilyl chloride (59.8 g, 0.55 mol) was added dropwise at 10-20 °C, after the addition was completed, the reaction was continued at room temperature for 3 h. The reaction was quenched by the addition of water 300 ml at 20 °C or below, the mixture was stirred and partitioned, the organic phase was washed successively with water 200 ml, saturated sodium chloride solution 200 ml, the organic phase was dried over anhydrous sodium sulfate 30 g for 2 h, filtered, the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in tetrahydrofuran (BASF reagent, 300 ml) and used as a hydroxyl protected material.

[0031] Into a 2 L three-necked flask, was placed 1-iodo-4-methoxy-2-nitrobenzene (compound of formula b-I, 153.5 g, 0.55 mol), tetrahydrofuran (BASF reagent, 300 ml), under nitrogen atmosphere, the flask was cooled to -35 °C, 1.3 M isopropylmagnesium chloride lithium chloride solution in tetrahydrofuran (550 ml, 0.6 mol) was added dropwise at -35 to -15 °C, after the addition was completed, the reaction was continued at -25 to -15 °C for 1 h. The reaction was cooled to -25 °C, 1.3 M isopropylmagnesium chloride lithium chloride solution in tetrahydrofuran (550 ml, 0.6 mol) was added dropwise at -25 to -15 °C, after the addition was completed, the reaction was continued at -25 to -15 °C for 1 h. The reaction was quenched by the addition of 4 M hydrochloric acid solution (150 ml), the reaction was stirred at room temperature for 0.5 h, 1.2 L water was added, the mixture was extracted with ethyl acetate twice (1 L each time), the combined organic phase was washed with water 1 L, the organic phase was stirred with 1 M sodium hydroxide solution 600 ml, the mixture was partitioned, the aqueous phase was extracted with ethyl acetate 800 ml, the organic phase was adjusted to acidic by the addition of 2 M hydrochloric acid solution 350 ml, the mixture was partitioned, the organic phase was washed successively with water 600 ml, saturated brine 600 ml, the organic phase was dried over anhydrous sodium sulfate 40 g for 2 h, filtered, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in anhydrous ethanol 200 ml, the mixture was stirred and partitioned, the filter cake was dried under vacuum to give 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (126.1 g, 80% yield, 97.8% purity). Ms m / z 316.1 (M+1), 1H NMR (300 MHz, d6-DMSO): 1.93 - 2.15 (m, 2H), 2.77 - 2.87 (m, 2H), 3.19 - 3.40 (m, 2H), 3.89 (s, 3H), 6.03 (s, H), 6.42 (d, 1H), 6.60 (d, 1H), 6.78 (d, 1H), 7.26 (d, 1H), 7.56 (d, 1H), 7.72 (s, 1H).

[0032] Example 2: Synthesis of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalen-2,6-diol, Method 2

[0033]

[0034] Under nitrogen protection, 6-hydroxy-3,4-dihydro-1H-2-naphthalenone (32.4 g, 0.2 mol), triethylamine (22.3 g, 0.22 mol), dichloromethane 200 ml were added into a 500 ml three-necked flask, trimethylsilyl chloride (23.9 g, 0.22 mol) was added dropwise at 10-20 °C, after dropwise addition, the reaction was carried out at room temperature for 3 h. Under temperature control below 20 °C, the reaction was quenched by adding water 150 ml, and then the mixture was stirred and separated into two phases. The organic phase was washed successively with water 80 ml and saturated sodium chloride solution 80 ml. Then, 12 g of anhydrous sodium sulfate was added to the organic phase, which was dried for 2 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in tetrahydrofuran (BASF reagent, 120 ml) and used as a hydroxyl-protected material.

[0035] Into a 1 L three-necked flask, 1-bromo-4-methoxy-2-nitrobenzene (compound of formula b-II, 51.0 g, 0.22 mol), tetrahydrofuran (BASF reagent, 120 ml) were added under nitrogen atmosphere, and the mixture was cooled to -35 °C. Then, 1.3 M isopropylmagnesium chloride lithium chloride solution in tetrahydrofuran (220 ml, 0.24 mol) was added dropwise at -35 to -15 °C. After the addition, the reaction was continued to stir for 1.5 h at -25 to -15 °C. The mixture was cooled to -25 °C, and the above prepared hydroxyl-protecting agent was added dropwise at -25 to -15 °C. After the addition, the reaction was continued to stir for 1.5 h at -25 to -15 °C. The reaction was stopped, and 4 M hydrochloric acid solution (60 ml) was added to the reaction mixture. The mixture was stirred for 0.5 to 1 h at room temperature, and 500 ml of water was added. The mixture was extracted with ethyl acetate (400 ml x 2), and the combined organic phase was washed with water (400 ml x 1). The organic phase was stirred with 1 M sodium hydroxide solution (240 ml) to separate into two layers. The aqueous phase was extracted with ethyl acetate (350 ml), and the pH was adjusted to be acidic by adding 2 M hydrochloric acid solution (140 ml). The mixture was stirred to separate into two layers. The organic phase was washed with water (250 ml x 2), and then with saturated brine (250 ml). The organic phase was dried over anhydrous sodium sulfate (15 g) for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in 80 ml of anhydrous ethanol, and the mixture was stirred to separate into two layers. The precipitate was filtered, and the filter cake was dried under vacuum to obtain 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (45.4 g, 72% yield, 96.1% purity).

[0036] Example 3: Synthesis method 3 of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

[0037]

[0038] Into a 200 ml three-necked flask, 6-hydroxy-3,4-dihydro-1H-2-naphthalenone (16.2 g, 0.1 mol), triethylamine (11.1 g, 0.11 mol), and dichloromethane (80 ml) were added under nitrogen atmosphere, and the mixture was cooled to 10 to 20 °C. Then, trimethylsilyl chloride (12.0 g, 0.11 mol) was added dropwise at 10 to 20 °C. After the addition, the reaction was continued to stir for 3 h at room temperature. The reaction was quenched by adding 60 ml of water, and the mixture was stirred to separate into two layers. The organic phase was washed with water (50 ml x 1), and then with saturated sodium chloride solution (50 ml x 1). The organic phase was dried over anhydrous sodium sulfate (6 g) for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in 60 ml of tetrahydrofuran (BASF reagent), and the mixture was used as a hydroxyl-protecting agent.

[0039] Into a 500 ml dry three-necked flask, 1-chloro-4-methoxy-2-nitrobenzene (compound of formula b-III, 20.6 g, 0.11 mol), tetrahydrofuran (BASF reagent, 60 ml) were added under nitrogen atmosphere, and the mixture was cooled to -35 °C. Then, 1.3 M isopropylmagnesium chloride lithium chloride solution in tetrahydrofuran (110 ml, 0.12 mol) was added dropwise at -35 to -15 °C. After the addition, the reaction was continued to stir for 1.5 h at -25 to -15 °C. The mixture was cooled to -25 °C, and the above prepared hydroxyl protecting agent was added dropwise at -25 to -15 °C. After the addition, the reaction was continued to stir for 1.5 h at -25 to -15 °C. The reaction was stopped, and 4 M hydrochloric acid solution (30 ml) was added to the reaction mixture. The mixture was stirred for 0.5 h at room temperature, and then 250 ml of water was added. The mixture was extracted with ethyl acetate (200 ml x 2), and the combined organic phase was washed with water (200 ml). The organic phase was separated with 1 M sodium hydroxide solution (120 ml). The aqueous phase was extracted with ethyl acetate (150 ml), and the pH was adjusted to acidic with 2 M hydrochloric acid solution (70 ml). The mixture was separated, and the organic phase was washed with water (150 ml) and saturated brine (150 ml) successively. The organic phase was dried with anhydrous sodium sulfate (8 g) for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in anhydrous ethanol (40 ml), and the mixture was stirred to disperse. The mixture was filtered, and the filter cake was recrystallized with a mixture of anhydrous ethanol (40 ml) and water (60 ml). The recrystallized product was dried to obtain 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (20.5 g, 65% yield, 96.9% purity).

[0040] Example 4: Synthesis method 4 of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

[0041]

[0042] Into a 1 L three-necked flask, 6-hydroxy-3,4-dihydro-1H-2-naphthalenone (40.5 g, 0.25 mol), triethylamine (27.8 g, 0.275 mol), and dichloromethane (200 ml) were added under nitrogen atmosphere, and the mixture was cooled to 10 to 20 °C. Then, trimethylsilyl chloride (30.0 g, 0.275 mol) was added dropwise at 10 to 20 °C. After the addition, the reaction was continued to stir for 3 h at room temperature. The reaction was quenched by adding water (150 ml), and the mixture was separated. The organic phase was washed with water (150 ml) and saturated sodium chloride solution (150 ml) successively. The organic phase was dried with anhydrous sodium sulfate (15 g) for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in tetrahydrofuran (BASF reagent, 150 ml) to prepare a hydroxyl protecting agent.

[0043] Under nitrogen atmosphere, 1-iodo-4-methoxy-2-nitrobenzene (compound of formula b-III, 51.5 g, 0.275 mol), tetrahydrofuran (BASF reagent, 150 ml) were added into a 1 L dry three-necked flask, cooled to -35 °C, and 1 M isopropylmagnesium bromide in tetrahydrofuran (300 ml, 0.3 mol) was added dropwise at -35 to -15 °C. After the addition was completed, the reaction was continued to stir at -25 to -15 °C for 1.5 h. The reaction was cooled to -25 °C again, and the above prepared hydroxyl protecting agent was added dropwise at -25 to -15 °C. After the addition was completed, the reaction was continued to stir at -25 to -15 °C for 1.5 h. The reaction was stopped, 4 M hydrochloric acid solution (75 ml) was added into the reaction solution, and the reaction was stirred at room temperature for 0.5 h. 600 ml of water was added, and the mixture was extracted twice with 500 ml of ethyl acetate each time. The organic phase was washed once with 500 ml of water. The organic phase was stirred with 300 ml of 1 M sodium hydroxide solution to separate the phases. The aqueous phase was stirred with 400 ml of ethyl acetate, and the pH was adjusted to be acidic by adding about 170 ml of 2 M hydrochloric acid solution. The phases were separated by stirring. The organic phase was washed with 400 ml of water and 400 ml of saturated brine successively. The organic phase was dried with 20 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dispersed by stirring in 100 ml of anhydrous ethanol, filtered, and the filter cake was recrystallized from a mixture of 100 ml of anhydrous ethanol and 150 ml of water. The product was dried to obtain 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (59.1 g, yield 75%, purity 97.6%).

[0044] Example 5: Synthesis of 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0045]

[0046] Under nitrogen atmosphere, 1-iodo-4-methoxy-2-nitrobenzene (compound of formula b-III, 51.5 g, 0.275 mol), tetrahydrofuran (BASF reagent, 150 ml) were added into a 1 L dry three-necked flask, cooled to -35 °C, and 1 M isopropylmagnesium bromide in tetrahydrofuran (300 ml, 0.3 mol) was added dropwise at -35 to -15 °C. After the addition was completed, the reaction was continued to stir at -25 to -15 °C for 1.5 h. The reaction was cooled to -25 °C again, and the above prepared hydroxyl protecting agent was added dropwise at -25 to -15 °C. After the addition was completed, the reaction was continued to stir at -25 to -15 °C for 1.5 h. The reaction was stopped, 4 M hydrochloric acid solution (75 ml) was added into the reaction solution, and the reaction was stirred at room temperature for 0.5 h. 600 ml of water was added, and the mixture was extracted twice with 500 ml of ethyl acetate each time. The organic phase was washed once with 500 ml of water. The organic phase was stirred with 300 ml of 1 M sodium hydroxide solution to separate the phases. The aqueous phase was stirred with 400 ml of ethyl acetate, and the pH was adjusted to be acidic by adding about 170 ml of 2 M hydrochloric acid solution. The phases were separated by stirring. The organic phase was washed with 400 ml of water and 400 ml of saturated brine successively. The organic phase was dried with 20 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was dispersed by stirring in 100 ml of anhydrous ethanol, filtered, and the filter cake was recrystallized from a mixture of 100 ml of anhydrous ethanol and 150 ml of water. The product was dried to obtain 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (59.1 g, yield 75%, purity 97.6%).

[0047] The reaction solution was added dropwise to saturated sodium bicarbonate solution to adjust the pH to 7-8, and the organic solvent was evaporated under reduced pressure. The concentrate was added to water 200 ml, extracted with ethyl acetate 3 times (250 ml / time), the organic phase was combined, washed with purified water 2 times (300 ml / time), and the organic phase was concentrated under reduced pressure until no distillate was obtained. Anhydrous ethanol (150 ml)-water (200 ml) was added to the concentrate to reflux and dissolve, and the crystals were separated by natural cooling, filtered, and the filter cake was dried to obtain 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (77.2 g, yield 86%, purity 98.2%). Ms m / z 300.1 (M+1), 1 H NMR (300 MHz d6-DMSO): 1.78-2.03 (m, 2H), 2.75-2.89 (m, 3H), 3.05-3.29 (m, 2H), 3.90 (s, 3H), 6.41 (d, 1H), 6.59 (m, 1H), 6.77 (d, 1H), 7.28 (d, 1H), 7.55 (d, 1H), 7.73 (s, 1H).

[0048] Example 6: Synthesis method 2 of 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0049]

[0050] Under nitrogen protection, 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol (63.1 g, 0.2 mol), 1 mol / L isopropyl alcohol hydrogen chloride solution 400 ml were added to a 1 L three-necked flask, and the reaction was refluxed for 4 h, slightly cooled, and the solvent was evaporated under reduced pressure. The residue was recrystallized twice with anhydrous ethanol (100 ml)-water (200 ml) mixed solvent, filtered, and the filter cake was dried to obtain 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (41.2 g, yield 69%, purity 94.3%), Ms m / z 300.1 (M+1).

[0051] Example 7: Synthesis method 1 of 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a)

[0052]

[0053] A three-necked flask was charged with 6-(4-methoxy-2-nitrophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (59.9 g, 0.2 mol), absolute ethanol 400 ml and 5% Pd / C (8.5 g, 4 mmol). The flask was replaced with air and pressurized to 0.5-1 MPa. The temperature was controlled at 30-40 °C and the reaction was allowed to proceed for 10 h. The pressure was released and the catalyst was filtered off. The filtrate was concentrated to dryness. The residue was dissolved in 300 ml of ethyl acetate and 300 ml of water. Concentrated hydrochloric acid (20 ml) was added. The mixture was stirred and separated. The aqueous phase was extracted with 300 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase was separated. The aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phase was dried over 10 g of anhydrous sodium sulfate for 2 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of absolute ethanol and stirred to disperse. The mixture was filtered and the filter cake was dried in an oven to give 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (42 g, 78% yield, 98.2% purity).

[0054] Example 8: Synthesis method 2 of the compound of formula a

[0055]

[0056] A three-necked flask was charged with 6-(4-methoxy-2-nitrophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (59.9 g, 0.2 mol), absolute ethanol 400 ml and 5% Pd / C (8.5 g, 4 mmol). The flask was replaced with air and pressurized to 0.5-1 MPa. The temperature was controlled at 30-40 °C and the reaction was allowed to proceed for 10 h. The pressure was released and the catalyst was filtered off. The filtrate was concentrated to dryness. The residue was dissolved in 300 ml of ethyl acetate and 300 ml of water. Concentrated hydrochloric acid (20 ml) was added. The mixture was stirred and separated. The aqueous phase was extracted with 300 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase was separated. The aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phase was dried over 10 g of anhydrous sodium sulfate for 2 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of absolute ethanol and stirred to disperse. The mixture was filtered and the filter cake was dried in an oven to give 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (42 g, 78% yield, 98.2% purity).

[0057] Example 9: Synthesis method 3 of the compound of formula a

[0058]

[0059] Into a pressure vessel, 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (29.9 g, 0.1 mol), absolute ethanol 200 ml and Raney-Ni (2.9 g, 10 mmol) were placed, the air was replaced and pressurized to 0.5-1 MPa, and the temperature was controlled at 30-40 °C for 10 h. After depressurization, the mixture was filtered. The filtrate was concentrated to dryness, and the residue was added to 150 ml of ethyl acetate and 150 ml of water, and 10 ml of concentrated hydrochloric acid was added. After stirring and separation, the aqueous phase was added to 150 ml of ethyl acetate, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phase was dried with 5 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The residue was added to 25 ml of absolute ethanol and stirred to disperse. The filtrate was filtered and the filter cake was dried to obtain 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (20.2 g, 75% yield, 97.8% purity).

[0060] Example 10: Synthesis of Elacridar

[0061]

[0062] Reference to the operation of steps 4, 5, and 6 in "Preparation of Compound 1·2HCl" in Comparative Document CN202080011109 "Scheme 1".

[0063] Step 1, Synthesis of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0064] Into a 5 L three-necked flask, the compound of formula a (134.7 g, 0.5 mol), acetonitrile 1.8 L and dichloromethane 600 ml were placed, heated to 40 °C, and (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 89.6 g, 0.25 mol] was added and heated to reflux. After cooling to 50 °C for 1 h, it was further cooled to 40 °C for 1 h, and then to 25 °C for 1 h. Filtration was performed, and the filter cake was washed with 250 ml of dichloromethane. The filter cake was added to 1 L of dichloromethane and refluxed for 1 h. Cooling was performed at a rate of 15 °C / h to 25 °C, and stirring was performed at 25 °C for 1.5 h. Filtration was performed, and the filter cake was washed with 200 ml of dichloromethane. The filter cake was again slurried with 1 L of dichloromethane at room temperature for 1 h, filtered, washed with 200 ml of dichloromethane, and dried to obtain (+)-DBTA salt 149.0 g.

[0065] A mixture of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (53.9 g, 0.2 mol), 4A molecular sieves (50 g), 1.2 L THF was stirred at room temperature for 3 h. Filtered through celite and rinsed with 600 ml of THF. To the filtrate was added N-ethyl-2-(4-formylphenyl)acetamide (45.9 g, 0.24 mol), 400 ml of n-heptane and (+)-DBTA (1 g) and heated to reflux. The mixture was concentrated to about 500 ml, 150 ml of heptane and 350 ml of THF was added and concentrated to about 500 ml. The solution was cooled to 20 °C to crystallize and stirred for 8 h. Filtered, rinsed with 200 ml of heptane, the filter cake was dissolved in 2 L of dry THF, NaBH(OAc)3 (190.7 g, 0.9 mol) was added and heated to 50 °C for 20 h, cooled to 20 °C, quenched with 3 M NaOH and adjusted the pH to 8-9, stirred for another 1 h, the aqueous layer was separated, the organic layer was concentrated to about 300 ml, 500 ml of ethyl acetate was added and concentrated to about 300 ml. 500 ml of ethyl acetate and 300 ml of saturated NaCl solution was added, stirred and separated, the organic phase was dried over sodium sulfate, filtered and concentrated to about 200 ml, 500 ml of n-heptane was added and concentrated to about 200 ml; the above operation was repeated 2 more times, concentrated to about 200 ml, 500 ml of THF was added and concentrated to 200 ml, the above operation was repeated once more and finally concentrated to about 200 ml for the next reaction.

[0066] Step 2, synthesis of (R)-N-ethyl-3-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)propanamide

[0067] A mixture of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (53.9 g, 0.2 mol), 4A molecular sieves (50 g), 1.2 L THF was stirred at room temperature for 3 h. Filtered through celite and rinsed with 600 ml of THF. To the filtrate was added N-ethyl-2-(4-formylphenyl)acetamide (45.9 g, 0.24 mol), 400 ml of n-heptane and (+)-DBTA (1 g) and heated to reflux. The mixture was concentrated to about 500 ml, 150 ml of heptane and 350 ml of THF was added and concentrated to about 500 ml. The solution was cooled to 20 °C to crystallize and stirred for 8 h. Filtered, rinsed with 200 ml of heptane, the filter cake was dissolved in 2 L of dry THF, NaBH(OAc)3 (190.7 g, 0.9 mol) was added and heated to 50 °C for 20 h, cooled to 20 °C, quenched with 3 M NaOH and adjusted the pH to 8-9, stirred for another 1 h, the aqueous layer was separated, the organic layer was concentrated to about 300 ml, 500 ml of ethyl acetate was added and concentrated to about 300 ml. 500 ml of ethyl acetate and 300 ml of saturated NaCl solution was added, stirred and separated, the organic phase was dried over sodium sulfate, filtered and concentrated to about 200 ml, 500 ml of n-heptane was added and concentrated to about 200 ml; the above operation was repeated 2 more times, concentrated to about 200 ml, 500 ml of THF was added and concentrated to 200 ml, the above operation was repeated once more and finally concentrated to about 200 ml for the next reaction.

[0068] Step 3, synthesis of elacridar

[0069] To the reactor was added 350 ml THF and NaBH4(18.9 g, 0.5 mol), cooled to -10 to 0 °C, and the solution was added dropwise with temperature control below 5 °C. After the addition was completed, the solution was cooled to -25 °C. A solution of I2(50.8 g, 0.2 mol) in 100 ml THF was added with temperature control below -10 °C. After the addition was completed, the solution was stirred for 1 h with temperature control below -10 °C, and then heated to reflux for 4 h. The reaction mixture was cooled to ≤5 °C, quenched with concentrated hydrochloric acid, and adjusted to a pH of less than 1.5. 1 L of water was added, and most of the solvent was removed under reduced pressure. The residue was cooled to 15-25 °C and stirred for 6 h. The mixture was filtered, and the filter cake was added to 800 ml of EtOAc. The pH was adjusted to 8-9 with 1 M NaOH, and the mixture was stirred at 10-20 °C for 20 min. The mixture was separated, and the organic layer was removed. The aqueous layer was re-extracted with 400 ml of ethyl acetate, and the combined organic phases were washed with 500 ml of a 5% sodium thiosulfate solution. The organic phase was washed with 500 ml of a 10% NaCl solution four times. Most of the solvent was removed from the organic phase by concentration, and 800 ml of anhydrous ethanol was added. The volume was concentrated to about 250 ml. The above operation was repeated three times, and the final volume was about 250 ml. After drying with Na2SO4, the mixture was filtered, and the filtrate was added to 100 ml of EtOAc. 150 ml of a 3% HCl-EtOH solution was added, and the mixture was stirred at 15-25 °C for 3 h. The volume was concentrated to 300 ml, and 1 L of EtOAc was added. The mixture was stirred at 15-25 °C for 3 h to crystallize, and the mixture was filtered. The filter cake was washed with 250 ml of EtOAc. The filter cake was dried and recrystallized with anhydrous ethanol / ethyl acetate (100 ml / 300 ml) to obtain the finished product of irasugeng (62.4 g, the yield of two steps of step 2 and step 3 was 68%, the chemical purity was 99.1%, and the ee value was 98.9%).

[0070] Embodiments 1-9 of the present application have shorter routes and higher yields compared to prior art documents, and provide a new preparation method of the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound of formula a) of irasugeng. The intermediate is industrialized, and is of great significance for subsequent reduction of the production cost of irasugeng.

[0071] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. The present application can be variously changed and modified by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing an intermediate of ellastrant, a drug for the treatment of advanced breast cancer, characterized in that, The method is as follows: Step 1: 6-hydroxy-3,4-dihydro-1H-2-naphthone is first protected by hydroxysilanization, then subjected to CC coupling docking reaction with compound b, and finally deprotected to obtain intermediate 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphth-2,6-diol. Step 2: The intermediate 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol undergoes a dehydroxylation reaction to obtain the intermediate 6-(4-methoxy-2-nitrophenyl)-5,6,7,8-tetrahydronaphthalene-2-ol; in In compound b, X is selected from Cl, Br, or I.

2. The preparation method according to claim 1, characterized in that, In step 1, the catalyst for the CC coupling reaction is a Grignard reagent, which is selected from isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride, isopropyl magnesium chloride, and tert-butyl magnesium chloride.

3. The preparation method according to claim 2, characterized in that, The catalyst for the CC coupling docking reaction in step 1 is a Grignard reagent, which is selected from isopropyl magnesium chloride-lithium chloride.

4. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of 6-hydroxy-3,4-dihydro-1H-2-naphthone, trimethylchlorosilane, compound b, and Grignard reagent is 1:1 to 1.2:1 to 1.2:1 to 1.

4.

5. The preparation method according to claim 4, characterized in that, In step 1, the molar ratio of 6-hydroxy-3,4-dihydro-1H-2-naphthone, trimethylchlorosilane, compound b, and Grignard reagent is 1:1.05-1.15:1.05-1.15:1.1-1.

3.

6. The preparation method according to claim 1, characterized in that, The catalyst for step 2 is a triethylsilane and boron trifluoride diethyl ether complex.

7. The preparation method according to claim 1 or 4, characterized in that, In step 2, the molar ratio of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol, triethylsilane, and boron trifluoride diethyl ether complex is 1:1.5–3:1.5–3.

8. The preparation method according to claim 7, characterized in that, In step 2, the molar ratio of 2-(4-methoxy-2-nitrophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol, triethylsilane, and boron trifluoride diethyl ether complex is 1:1.75-2.5:1.75-2.5.

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