Process for the preparation of an intermediate of elacridar

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an intermediate of Iaroxilumab. The preparation method comprises the following steps: step 1, a substitution reaction is carried out between a compound of formula VIII and a halogenated benzyl to obtain a compound of formula VII; step 2, a reduction reaction is carried out on the compound of formula VII under the action of a reducing agent to obtain a compound of formula VI; step 3, a halogenation reaction is carried out on the compound of formula VI to obtain a compound of formula V; step 4, a boronization reaction is carried out on the compound of formula V to obtain a compound of formula IV; step 5, a Suzuki coupling reaction is carried out between the compound of formula IV and a compound of formula III to obtain a compound of formula II; and step 6, the compound of formula II is debenzylated to obtain a compound of formula I. The synthesis route is short, and the method has the advantages of efficacy, low cost and high yield, and has a good application prospect.

Description

TECHNICAL FIELD

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

[0002] Elacestrant (Chinese name: Elacestrant or Elacestrant) is an oral selective estrogen receptor degrader (SERD) developed by Radius. On October 20, 2021, Menarini / Radius jointly announced that Elacestrant achieved positive results for ER+ / HER2- advanced or metastatic breast cancer patients. On January 27, 2023, the FDA approved Elacestrant (Elacestrant, Orserdu) for use in postmenopausal women or adult men with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer who have experienced disease progression after at least one endocrine therapy. The molecular weight of Elacestrant is 458.65, and the molecular formula is C 30 H 38 N2O2, the structure is as follows,

[0003]

[0004] 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol is an important intermediate for the synthesis of Elacestrant. The CAS number is 722520-42-5, the molecular weight is 297.40, and the molecular formula is C 19 H 23 NO2, the structure is as follows,

[0005]

[0006] At present, the preparation method of 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol is only reported in WO2004058682. 6-methoxy-1-tetralone (compound A) is used as the starting material, demethylation is carried out under the action of hydrogen bromide to obtain compound B, then benzyl protection is carried out on the hydroxyl group to obtain compound C, then bromination reaction of compound D occurs, then carbonyl reduction to obtain compound E, intramolecular dehydration to obtain compound F, then Ullmann coupling reaction with 4-bromo-3-nitrobenzyl ether (compound G) to obtain compound H, then reduction of nitro and debenzyl under the action of hydrogen to obtain compound I, then reaction with acetic anhydride to obtain compound J, then under the action of a reducing agent to obtain 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol.

[0007]

[0008] However, the above synthetic route has many reaction steps, which is not conducive to the total yield of synthesis and the cost of process. In summary, there are few reported preparation methods of 6-(2-(ethylamino)-4-methoxyphenyl)-5, 6, 7, 8-tetrahydronaphthalen-2-ol, and there are few commercial suppliers, and the existing process still has many shortcomings, which limits its wide application in the field of drug synthesis. Therefore, it is of great significance to study a synthesis method of 6-(2-(ethylamino)-4-methoxyphenyl)-5, 6, 7, 8-tetrahydronaphthalen-2-ol with high yield, short synthesis steps, low cost and suitable for industrial production. SUMMARY

[0009] In view of the problems of the prior art, the purpose of the present application is to provide a preparation method of 6-(2-(ethylamino)-4-methoxyphenyl)-5, 6, 7, 8-tetrahydronaphthalen-2-ol.

[0010] A preparation method of an intermediate of elacestrant, comprising the following steps:

[0011]

[0012] Step 1: taking the compound of formula VIII as a starting material, substitution reaction with halogenated benzyl to obtain the compound of formula VII;

[0013] Step 2: the compound of formula VII undergoes reduction reaction under the action of a reducing agent to obtain the compound of formula VI;

[0014] Step 3: the compound of formula VI undergoes halogenation reaction to obtain the compound of formula V;

[0015] Step 4: the compound of formula V undergoes boronization reaction to obtain the compound of formula IV;

[0016] Step 5: the compound of formula IV and the compound of formula III undergo Suzuki coupling reaction to obtain the compound of formula II;

[0017] Step 6: after debenzylization of the compound of formula II, the compound of formula I is obtained.

[0018] Preferably, in step 1, the halogenated benzyl is selected from at least one of chlorinated benzyl or brominated benzyl;

[0019] And / or, the substitution reaction is carried out under the action of a base selected from at least one of potassium carbonate or sodium carbonate;

[0020] And / or, the solvent of the substitution reaction is selected from at least one of N, N-dimethylformamide, acetonitrile or dichloromethane;

[0021] And / or, the temperature of the substitution reaction is 20-30℃.

[0022] and / or, the compound of formula VIII is used in a ratio of 1 : (1.1-1.2) molar ratio with the benzyl halide;

[0023] and / or, the substitution reaction is carried out in the presence of a base, and the compound of formula VIII is used in a ratio of 1 : (1.4-2) molar ratio with the base.

[0024] Preferably, in step 2, the reducing agent is selected from at least one of sodium borohydride, lithium borohydride or lithium aluminum hydride;

[0025] and / or, the solvent of the reduction reaction is selected from at least one of methanol, ethanol or tetrahydrofuran;

[0026] and / or, the temperature of the reduction reaction is 0-10°C;

[0027] and / or, the compound of formula VII is used in a ratio of 1 : (0.5-1.5) molar ratio with the reducing agent.

[0028] Preferably, in step 3, the halogenating agent of the halogenation reaction is selected from at least one of carbon tetrabromide or phosphorus oxybromide;

[0029] and / or, the solvent of the halogenation reaction is selected from at least one of dichloromethane, dichloroethane or toluene;

[0030] and / or, the temperature of the halogenation reaction is 0-40°C.

[0031] Preferably, in step 4, it specifically comprises the following steps:

[0032] Step 4.1, reacting the compound of formula V with magnesium to form a Grignard reagent;

[0033] Step 4.2, reacting the Grignard reagent with trimethyl borate, and adding an acid to obtain the compound of formula IV.

[0034] Preferably, in step 4.1, the solvent of the reaction is selected from at least one of diethyl ether or tetrahydrofuran;

[0035] and / or, the temperature of the reaction is 20-50°C.

[0036] Preferably, in step 4.2, the solvent of the reaction is selected from at least one of diethyl ether or tetrahydrofuran;

[0037] and / or, the temperature of the reaction is -75 to -80°C;

[0038] and / or, the acid is selected from hydrochloric acid, sulfuric acid.

[0039] Preferably, in step 5, the Suzuki coupling reaction is carried out in the presence of a catalyst selected from at least one of 1,1-bis(diphenylphosphino)ferrocene palladium dichloride or tetrakis(triphenylphosphine)palladium;

[0040] and / or, the Suzuki coupling reaction is carried out in the presence of a base selected from at least one of potassium carbonate, sodium carbonate or cesium carbonate;

[0041] and / or, the Suzuki coupling reaction is carried out in a solvent selected from at least one of N,N-dimethylformamide or 1,4-dioxane;

[0042] and / or, the Suzuki coupling reaction is carried out at a temperature of 80-100°C;

[0043] and / or, the molar ratio of the compound of formula IV to the compound of formula III is 1:0.9-1.2;

[0044] and / or, the molar ratio of the compound of formula IV to the catalyst is 1:0.005-0.01.

[0045] Preferably, in step 6, the debenzylization is carried out in the presence of a catalyst selected from 10% palladium on carbon;

[0046] and / or, the debenzylization is carried out in a solvent selected from at least one of methanol or ethanol;

[0047] and / or, the debenzylization is carried out at a temperature of 20-60°C;

[0048] and / or, the mass ratio of the compound of formula II to the catalyst is 1:0.05-0.1.

[0049] Preferably, in step 1, the benzyl halide is selected from benzyl bromide; the substitution reaction is carried out in the presence of a base selected from at least one of potassium carbonate; the substitution reaction is carried out in a solvent selected from N,N-dimethylformamide; the substitution reaction is carried out at a temperature of 20-30°C; the molar ratio of the compound of formula VIII to the benzyl halide is 1:1.1; the molar ratio of the compound of formula VIII to the base is 1:1.4;

[0050] and / or, in step 2, the reducing agent is selected from sodium borohydride; the reducing reaction is carried out in a solvent selected from methanol; the reducing reaction is carried out at a temperature of 0-5°C; the molar ratio of the compound of formula VII to the reducing agent is 1:(0.5-1);

[0051] and / or, in step 3, the halogenating agent of the halogenation reaction is selected from carbon tetrabromide; the halogenation reaction is carried out in a solvent selected from dichloromethane; the halogenation reaction is carried out at a temperature of 0-5°C;

[0052] and / or, in step 4, specifically comprising the following steps:

[0053] Step 4.1, reacting the compound of formula V with magnesium to form a Grignard reagent;

[0054] Step 4.2, reacting the Grignard reagent with trimethyl borate, and treating with an acid to obtain the compound of formula IV;

[0055] In step 4.1, the solvent of the reaction is selected from at least one of diethyl ether or tetrahydrofuran; and the temperature of the reaction is 20-50℃.

[0056] In step 4.2, the solvent of the reaction is selected from at least one of diethyl ether or tetrahydrofuran; the temperature of the reaction is -78℃; and the acid is selected from hydrochloric acid.

[0057] and / or, in step 5, the Suzuki coupling reaction is carried out in the presence of a catalyst selected from 1,1-bis(diphenylphosphino)ferrocene palladium dichloride; the Suzuki coupling reaction is carried out in the presence of a base selected from potassium carbonate; the solvent of the Suzuki coupling reaction is selected from N,N-dimethylformamide; the temperature of the Suzuki coupling reaction is 80℃; the molar ratio of the compound of formula IV to the compound of formula III is 1:1.19; and the molar ratio of the compound of formula IV to the catalyst is 1:0.01.

[0058] and / or, in step 6, the debenzylization is carried out in the presence of a catalyst selected from 10% palladium on carbon; the solvent of the debenzylization is selected from methanol; the temperature of the debenzylization is 20℃; and the mass ratio of the compound of formula II to the catalyst is 1:0.05.

[0059] The present application establishes a new synthetic route for the preparation of the intermediate 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol of iralespun, and optimizes the process conditions of each reaction step. The present application reduces the nine-step reaction of the existing preparation method of 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol to six-step reaction, which can improve the efficiency of the process, reduce the production cost, and provide the total yield of synthesis. Therefore, the present application has good application prospect.

[0060] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and common means in the art, other various forms of modifications, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0061] The above summary of the present application is further elaborated in the following detailed description of the application in the form of examples. However, it should be understood that the above summary of the present application is not intended to be limited to the following examples. Any technology based on the above summary of the present application falls within the scope of the present application. DETAILED DESCRIPTION

[0062] The reagents and materials used in the following examples are commercially available.

[0063] Example 1:

[0064] First Step: Preparation of compound of formula VII

[0065] The compound of formula VIII (100 g, 0.62 mol) was dissolved in DMF (500 mL) and stirred to dissolve. Potassium carbonate (120 g, 0.87 mol) was added and stirred for 5 min. Benzyl bromide (117 g, 0.68 mol) was added at room temperature and the reaction was stirred for 4 h. The reaction was monitored by TLC and the starting material was consumed. 1500 mL of water was added to the reaction mixture to precipitate the solid which was filtered and the filter cake was dried at 50 °C under vacuum for 12 h to obtain 148 g of compound of formula VII with a molar yield of 95%. The product was used for the next step without further purification. MS (ESI + m / z 253 [M+H] + .

[0066] Second Step: Preparation of compound of formula VI

[0067] The crude compound VII (100 g, 0.40 mol) from the previous step was dissolved in 500 mL of methanol. Sodium borohydride (7.6 g, 0.20 mol) was added at 0-5 °C and the reaction was stirred for 4 h. The reaction was monitored by TLC and the starting material was consumed. The reaction was quenched by the addition of 500 mL of saturated aqueous ammonium chloride solution. The reaction mixture was extracted with 1500 mL of dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was dried at 50 °C under vacuum to obtain 98.5 g of compound of formula VI with a molar yield of 97%. MS (ESI + m / z 255 [M+H] + .

[0068] Third Step: Preparation of compound of formula V

[0069] Into a reaction flask equipped with a stir bar, under argon atmosphere, was added compound VI (80 g, 0.315 mol), carbon tetrabromide (114 g, 0.343 mol), dichloromethane (800 mL), and the mixture was stirred until the compound was dissolved. To the mixture was added triphenylphosphine (dissolved in 100 mL of dichloromethane) (91 g, 0.346 mmol) slowly at 0 °C to 5 °C. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 10 h. The reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution and the organic phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give 86 g of compound of formula V in 86% molar yield; HPLC purity 98%; MS (ESI + m / z 318 [M+H] +

[0070] Fourth Step: Preparation of compound of formula IV

[0071] Into a reaction flask equipped with a stir bar, under argon atmosphere, was added magnesium turnings (5.3 g, 0.25 mol, 1.0 eq), followed by dry diethyl ether (50 mL), and a small portion of a solution of compound of formula V (80 g, 0.25 mol, 1.0 eq, dissolved in 400 mL of diethyl ether) (10 mL). The reaction mixture was activated by the addition of iodine (20 mg) and heating. The remaining solution of compound of formula V (390 mL) was added dropwise to the reaction mixture over a period of 4 h. The reaction mixture was heated to reflux for 2 h. The reaction mixture was allowed to stir at room temperature for 17 h. The reaction mixture was added to a solution of trimethyl borate (26 g, 0.25 mol) in diethyl ether (1000 mL) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by the dropwise addition of HCl (10 wt.%) (400 mL). The reaction mixture was extracted with diethyl ether (2 x 200 mL). The reaction mixture was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 63 g of compound of formula IV in 90% molar yield; MS (ESI + m / z 283 [M+H] + .

[0072] Fifth Step: Preparation of compound of formula II

[0073] The crude compound of formula IV (60 g, 0.21 mol), compound III (58 g, 0.25 mol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (1.5 g, 2.1 mmol), potassium carbonate (72 g, 0.53 mol), DMF (500 mL) and water (50 mL) were taken in a reaction flask and heated to 80 °C for 8 h under nitrogen atmosphere. The reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude compound of formula II. The crude compound of formula II was dissolved in a small quantity of ethyl acetate and heated to reflux with stirring. Petroleum ether was added slowly and the stirring was continued at reflux for 1 h. The crystals were allowed to separate on cooling to room temperature. The product was filtered and the filter cake was dried under vacuum to get 70 g of pure compound of formula II with 86% molar yield and 99.2% HPLC purity; MS (ESI + )m / z 388 [M+H] + .

[0074] Sixth step: Preparation of compound of formula I

[0075] The compound of formula II (60 g, 0.155 mol) was dissolved in methanol (500 mL) and 10% palladium on carbon (3 g) was added. After purging with nitrogen three times, the reaction mixture was purged with hydrogen three times and stirred at 100 psi of H2at room temperature for 12 h. The reaction was monitored by TLC. The reaction mixture was filtered through celite and the filtrate was washed with methanol (100 mL) and 3 g of activated carbon was added to remove palladium. The mixture was stirred for 2 h and filtered. The filtrate was concentrated to 200 mL and EtOAc (700 mL) was added. The mixture was concentrated to 200 mL under vacuum at <45 °C. The temperature was adjusted to 20 °C and the mixture was stirred at 20 °C for 1 h. The product was collected by filtration and washed with ethyl acetate (100 mL). The filter cake was dried at 45 °C to get 44 g of compound of formula I with 96% molar yield and 99.3% HPLC purity; 1 H-NMR (400 MHz, CDC13) δ 7.03 (d, 1H), 6.98 (d, 1H), 6.66-6.62 (m, 2H), 6.29 (dd, 1H), 6.26 (d, 1H), 4.55 (s, 1H), 3.81 (s, 3H), 3.63 (br s, 1H), 3.19 (q, 2H), 3.03-2.89 (m, 3H), 2.86-2.78 (m, 1H), 2.72 (dd, 1H), 2.13-2.06 (m, 1H), 2,00-1.90 (m, 1H), 1.29 (t, 3H);

[0076] MS (ESI + )m / z 298 [M+H] + .

[0077] Example 2:

[0078] First step: Preparation of compound of formula VII

[0079] Compound of formula VIII (2 kg, 12.3 mol) was dissolved in DMF (10 L), the solution was stirred, then potassium carbonate (2.4 kg, 17.2 mol) was added and stirred for 20 min, benzyl bromide (2.3 kg, 13.6 mol) was added at room temperature, and the reaction was stirred for 4 h. The reaction was monitored by TLC, and the starting material was substantially consumed. Water (7.5 L) was added to the reaction solution to precipitate the solid, which was filtered, and the filter cake was dried at 50 °C under vacuum for 12 h to obtain 2.97 kg of compound of formula VII with a molar yield of 96%; without further purification, the next step was directly performed; MS (ESI + )m / z 253 [M+H] + .

[0080] Second step: Preparation of compound of formula VI

[0081] The crude compound VII (2 kg, 7.94 mol) from the previous step was dissolved in methanol (10 L), and sodium borohydride (150 g, 3.97 mol) was slowly added in batches at 0-5 °C, and the reaction was stirred for 4 h. The reaction was monitored by TLC, and the starting material was consumed. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (500 mL), and dichloromethane (6 L) was added to extract the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and finally dried at 50 °C under vacuum to obtain 1.94 kg of compound of formula VI with a molar yield of 96%; MS (ESI + )m / z 255 [M+H] + .

[0082] Third step: Preparation of compound of formula V

[0083] Under argon protection, compound VI (1.5 kg, 5.9 mol), carbon tetrabromide (2.1 kg, 6.5 mol), and dichloromethane (15 L) were sequentially added to a reaction flask equipped with a stirrer, and the mixture was fully dissolved. Then, triphenylphosphine (dissolved in 5 L of dichloromethane) (1.7 kg, 6.5 mmol) was slowly added to the system at 0-5 °C, and the reaction was allowed to recover to room temperature and stirred for 10 h. The reaction was monitored by TLC, and the starting material was substantially consumed. The reaction was quenched by saturated ammonium chloride solution, and the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary evaporated. Purification was performed on a silica gel column to obtain 1.7 kg of compound of formula V with a molar yield of 84%; the HPLC purity was 98%; MS (ESI + )m / z 318 [M+H] +

[0084] Fourth step: Preparation of compound of formula IV

[0085] Magnesium turnings (113 g, 4.7 mol, 1.0 eq) were taken in an argon purged dry reaction flask followed by addition of dry diethyl ether (500 mL) and a small quantity of a solution of compound V (1.5 kg, 4.7 mol, 1.0 eq dissolved in 10 L of diethyl ether) (100 mL) was added. The reaction was activated by addition of iodine (200 mg) and heating. The remaining solution of compound V (9.5 L) was added drop wise to the reaction mixture over a period of 8 h. The reaction mixture was heated to reflux for 2 h. The reaction mixture was continued to be stirred at room temperature for 16 h. The above reaction mixture was added to a solution of trimethyl borate (498 g, 4.7 mol) in diethyl ether (5 L) at -78 °C under argon atmosphere and the reaction was stirred at -78 °C for 2 h. The reaction mixture was quenched by drop wise addition of HCl (10 wt%, 6 L). The reaction mixture was extracted with diethyl ether (2 x 2 L). The reaction mixture was dried over anhydrous sodium sulphate. The solvent was removed under vacuum to obtain 1.2 kg of compound of formula IV with 91% molar yield; MS (ESI + )m / z 283 [M+H] + .

[0086] Fifth step: Preparation of compound of formula II

[0087] The crude compound of formula IV (1 kg, 3.55 mol), compound III (980 g, 4.26 mol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (26 g, 3.55 mmol), potassium carbonate (1.2 kg, 8.9 mol), DMF (10 L) and water (1 L) were taken in a reaction flask and heated to 80 °C for 8 h under nitrogen atmosphere. The reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound II. The crude compound II was taken in a small quantity of ethyl acetate and heated to reflux and stirred till it dissolved. Petroleum ether was added slowly and the stirring was continued at reflux for 1 h. The crystals were allowed to separate on cooling to room temperature. It was filtered and the filter cake was dried under vacuum to obtain 1.2 kg of compound of formula II with 87% molar yield and 99.1% HPLC purity; MS (ESI + )m / z 388 [M+H] + .

[0088] Sixth step: Preparation of compound of formula I

[0089] Dissolve compound of formula II (1 kg, 2.58 mol) in methanol (10 L), add 10% palladium on carbon (50 g), replace with nitrogen for 3 times, replace with hydrogen for 1 time, stir the reaction mixture at 100 psi H2for 12 hours at room temperature, monitor the reaction completion by TLC. Filter through celite, wash the filtrate with methanol (1 L), add 50 g of activated carbon (to remove palladium), stir for 2 h, filter, concentrate the filtrate to 2 L, add ethyl acetate (7 L) and concentrate to 2 L under vacuum at <45 °C, adjust the temperature to 20 °C, stir for 1 h at 20 °C, collect the product by filtration, wash with ethyl acetate (1 L), dry the filter cake at 45 °C to get 736 g of compound of formula I with 96% molar yield and 99.1% HPLC purity; MS (ESI + m / z 298 [M+H] + .

[0090] The technical solutions of the present application are further described by experiments below.

[0091] Preferred process conditions of experimental example

[0092] The present application provides several comparative experimental groups, in which some process parameters or raw materials are changed on the basis of Example 1, and other experimental steps and process parameters not specifically described are the same as those of Example 1.

[0093] The specific conditions and the influence on the reaction results are shown in the following table:

[0094] Table 1 Preferred process conditions for the first step reaction

[0095]

[0096]

[0097] Table 2 Preferred process conditions for the second step reaction

[0098] Second step Reductant amount Reductant type Molar yield Purity Example 1 0.5 eq Sodium borohydride 97％ \ Comparative test group 3 0.5 eq Lithium borohydride 85％ \ Comparative test group 4 0.5 eq Lithium aluminum hydride 55％ \ Comparative test group 5 0.3 eq Sodium borohydride 80％ \ Comparative test group 6 1.0 eq Sodium borohydride 95％ \

[0099] Table 3 Preferred process conditions for the third step reaction

[0100] Third step Halogenated reagent amount Halogenated reagent type Molar yield Purity Example 1 1.1 eq Carbon tetrabromide 86％ 98.0％ Comparative test group 7 1.0 eq Phosphorus tribromide 46％ 97.2％ Comparative test group 8 1.0 eq Carbon tetrabromide 65％ 96.5％ Comparative test group 9 1.2 eq Carbon tetrabromide 70％ 95.6％

[0101] Table 4 Preferred process conditions for the fourth step reaction

[0102] Fourth step Boron reagent amount Boron reagent type Molar yield Purity Example 1 1.0 eq Trimethyl borate 91％ \ Comparative test group 10 1.0 eq Trimethyl borate 78％ \ Comparative test group 11 1.0 eq Triacetic acid borate 65％ \

[0103] Table 5 Preferred process conditions for the fifth step reaction

[0104]

[0105] Table 6 Preferred process conditions for the sixth step reaction

[0106]

[0107]

[0108] From the data in the above table, it can be seen that the process parameters and raw materials used in Example 1 can achieve the best molar yield and product purity.

[0109] From the above examples and experimental examples, it can be seen that the present application provides a preparation method of 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, which has the advantages of short synthesis route, efficacy, low cost, high yield and high product purity, and good application prospect.

Claims

1. A method for preparing an elastostat intermediate, characterized in that: The steps include: Step 1: Using the compound of formula VIII as a starting material, a substitution reaction is carried out with a benzyl halide to obtain a compound of formula VII; Step 2, the compound of formula VII undergoes a reduction reaction under the action of a reducing agent to obtain a compound of formula VI; Step 3, the compound of formula VI undergoes a halogenation reaction to obtain a compound of formula V; Step 4, the compound of formula V undergoes borylation reaction to obtain a compound of formula IV; Step 5, Suzuki coupling reaction of the compound of formula IV and the compound of formula III to obtain the compound of formula II; Step 6, after debenzylation of the compound of formula II, the compound of formula I is obtained; In step 2, the reducing agent is selected from sodium borohydride or lithium borohydride; In step 3, the halogenating agent of the halogenation reaction is selected from carbon tetrabromide; Step 4 specifically includes the following steps: Step 4.1, reacting the compound of formula V with magnesium to prepare a Grignard reagent; Step 4.2, reacting the Grignard reagent with trimethyl borate, and treating with acid to obtain a compound of formula IV; In step 4.2, the reaction solvent is selected from at least one of diethyl ether and tetrahydrofuran; the reaction temperature is -75 to -80°C; In step 5, the Suzuki coupling reaction is carried out under the action of a catalyst, and the catalyst is selected from 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride; the Suzuki coupling reaction is carried out under the action of a base, and the base is selected from at least one of potassium carbonate, sodium carbonate or cesium carbonate; the solvent of the Suzuki coupling reaction is selected from at least one of N,N-dimethylformamide or 1,4-dioxane; the temperature of the Suzuki coupling reaction is 80-100° C.; the molar ratio of the compound of formula IV to the compound of formula III is 1:0.9-1.2; and the molar ratio of the compound of formula IV to the catalyst is 1:0.

01.

2. The preparation method according to claim 1, characterized in that: In step 1, the benzyl halide is selected from at least one of benzyl chloride and benzyl bromide; And / or, the substitution reaction is carried out under the action of a base, wherein the base is selected from at least one of potassium carbonate and sodium carbonate; and / or, the solvent for the substitution reaction is selected from at least one of N,N-dimethylformamide, acetonitrile or dichloromethane; and / or, the temperature of the substitution reaction is 20-30° C.; and / or, the molar ratio of the compound of formula VIII to the benzyl halide is 1:(1.1-1.2); And / or, the substitution reaction is carried out under the action of a base, and the molar ratio of the compound of formula VIII to the base is 1:(1.4-2).

3. The preparation method according to claim 1, characterized in that: In step 2, the solvent for the reduction reaction is selected from at least one of methanol, ethanol or tetrahydrofuran; and / or, the temperature of the reduction reaction is 0-10° C.; And / or, the molar ratio of the compound of formula VII to the reducing agent is 1:(0.5-1.5).

4. The preparation method according to claim 1, characterized in that: In step 3, the solvent for the halogenation reaction is selected from at least one of dichloromethane, dichloroethane or toluene; And / or, the temperature of the halogenation reaction is 0-40°C.

5. The preparation method according to claim 1, characterized in that: In step 4.1, the reaction solvent is selected from at least one of diethyl ether and tetrahydrofuran; And / or, the reaction temperature is 20-50°C.

6. The preparation method according to claim 1, characterized in that: In step 4.2, the acid is selected from hydrochloric acid and sulfuric acid.

7. The preparation method according to claim 1, characterized in that: In step 6, the debenzylation is carried out under the action of a catalyst, and the catalyst is selected from 10% palladium on carbon; And / or, the debenzylation solvent is selected from at least one of methanol and ethanol; and / or, the debenzylation reaction temperature is 20-60° C.; And / or, the mass ratio of the compound of formula II to the catalyst is 1:0.05-0.

1.

8. The preparation method according to any one of claims 1 to 7, characterized in that: In step 1, the benzyl halide is selected from benzyl bromide; the substitution reaction is carried out in the presence of a base, and the base is selected from at least one of potassium carbonate; the solvent for the substitution reaction is selected from N,N-dimethylformamide; the temperature for the substitution reaction is 20-30° C.; the molar ratio of the compound of formula VIII to the benzyl halide is 1:1.1; and the molar ratio of the compound of formula VIII to the base is 1:1.

4. And / or, in step 2, the reducing agent is selected from sodium borohydride; the solvent for the reduction reaction is selected from methanol; the temperature for the reduction reaction is 0-5° C.; the molar ratio of the compound of formula VII to the reducing agent is 1:(0.5-1); And / or, in step 3, the solvent for the halogenation reaction is selected from dichloromethane; the temperature for the halogenation reaction is 0-5°C; And / or, in step 4.1, the reaction solvent is selected from at least one of diethyl ether and tetrahydrofuran; the reaction temperature is 20-50°C; In step 4.2, the reaction solvent is selected from at least one of diethyl ether and tetrahydrofuran; the reaction temperature is -78°C; and the acid is selected from hydrochloric acid; And / or, in step 5, the Suzuki coupling reaction is carried out under the action of a base, the base is selected from potassium carbonate; the solvent of the Suzuki coupling reaction is selected from N,N-dimethylformamide; the temperature of the Suzuki coupling reaction is 80° C.; the molar ratio of the compound of formula IV to the compound of formula III is 1:1.19; And / or, in step 6, the debenzylation is carried out under the action of a catalyst, the catalyst is selected from 10% palladium on carbon; the solvent for the debenzylation is selected from methanol; the reaction temperature for the debenzylation is 20° C.; and the mass ratio of the compound of formula II to the catalyst is 1:0.05.

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