A process for the synthesis of elacridar and intermediate compounds

Abstract

The application provides a method for synthesizing elacridar, comprising the following steps: S1), coupling reaction of compound 11 and compound 16 to obtain compound 12; S2), removing a deamination protection group from compound 12 to obtain compound 13; S3), obtaining compound 14 from compound 13; S4), reducing compound 14 to obtain compound 15 elacridar; wherein R1 represents a hydroxyl protection group, R2 represents an amino protection group, and X represents halogen. The method has the advantages of novel route, mild reaction condition, convenient post-treatment, low cost, high yield and suitability for industrial production. The reaction formula is as follows:

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a method for synthesizing elacestrant and an intermediate compound. BACKGROUND

[0002] Breast cancer is one of the most common malignant tumors in women, with an incidence of 7-10% of all malignant tumors. In the past, lung cancer has always been at the top of the cancer incidence list, but in 2020, the number of new cases of breast cancer was more than that of lung cancer, becoming the largest cancer in the world.

[0003] Elacestrant is an estrogen receptor antagonist that can bind to estrogen receptor-alpha (ERa). In ER-positive (ER+) HER2-negative (HER2-) breast cancer cells, elacestrant inhibits 17beta-estradiol-mediated cell proliferation at concentrations that induce ERa protein degradation through the proteasome pathway. Elacestrant has shown antitumor activity in vitro and in vivo, and as an oral selective estrogen receptor degrader, has shown promise in clinical studies over standard second-line treatments such as fulvestrant, and has been approved by the FDA in January 2023 for the treatment of metastatic hormone receptor-positive breast cancer patients and has been officially put into clinical use.

[0004] Patent application US20060116364A1 discloses the preparation of compounds with selective estrogen receptor modulator activity, including elacestrant (310 pages of the specification, example 736) and numerous structural analogs. The compounds obtained by this preparation method are all in milligram level, which is not suitable for large-scale production and has very low application value.

[0005] Patent application CN113348163 A discloses a method for preparing elacestrant (compound 1 in the specification is elacestrant). The starting compound is expensive and difficult to purchase. The hydrogenation step from intermediate b to c requires pressure, and the experimental conditions are harsh. It is difficult to scale up production and has a high safety risk. Both couplings involve noble metal reagents, and the production cost is high. The reaction route is shown below:

[0006]

[0007] Therefore, it is of great significance to develop a new method for synthesizing elacestrant. SUMMARY

[0008] The purpose of the present application is to provide a method for synthesizing elacestrant, which is novel in route, cheap and easy to obtain in material, mild in reaction conditions, convenient in post-treatment, low in cost, high in safety, and very suitable for industrial production.

[0009] The present application provides the following technical solutions:

[0010] In one aspect, the present application provides a method for synthesizing intermediate compound 11 of elacridar, comprising the steps of:

[0011] 1) compound 1 is subjected to a demethylation reaction to obtain compound 2;

[0012] 2) compound 2 is subjected to a bromination reaction to obtain compound 3;

[0013] 3) compound 3 is subjected to a hydroxyl protection reaction to obtain compound 4;

[0014] 4) compound 4 is subjected to a reduction reaction to obtain compound 5;

[0015] 5) compound 5 is subjected to an elimination reaction to obtain compound 6;

[0016] 6) compound 6 is subjected to a coupling reaction to obtain compound 7;

[0017] 7) compound 7 is subjected to a nitro reduction reaction to obtain compound 8;

[0018] 8) compound 8 is subjected to a substitution reaction to obtain compound 9

[0019] 9) compound 9 is subjected to a reduction reaction to obtain compound 10;

[0020] 10) compound 10 is subjected to a chiral resolution to obtain compound 11;

[0021] The reaction formula is as follows:

[0022]

[0023] wherein R1 represents a hydroxyl protection group.

[0024] The method comprises one or more of the following features:

[0025] In one embodiment, in step 1), compound 1 is subjected to a demethylation reaction in the presence of an acid to obtain compound 2; the acid is selected from at least one of hydrobromic acid, hydroiodic acid, hydrochloric acid, and sulfuric acid;

[0026] In one embodiment, in step 1), the reaction temperature is 100-130°C, and after the reaction is completed, the reaction solution is cooled to precipitate a solid, which is filtered to obtain compound 2;

[0027] In one embodiment, in step 2), compound 2 is subjected to a bromination reaction with a bromination reagent to obtain compound 3. Preferably, the bromination reagent is copper bromide;

[0028] In one embodiment, in step 2), the molar ratio of compound 2 to the bromination reagent is 1:2;

[0029] In one embodiment, in step 2), the reaction solvent is ethyl acetate, and the reaction temperature is 60-100 °C.

[0030] In one embodiment, in step 3), compound 3 is reacted with R1X in the presence of a base to obtain compound 4; wherein R1represents a hydroxyl protecting group selected from TMS, TES, TBS, TIPS, TBDPS, TBDMS, t-Bu, methyl, benzyl, PMB, Boc, Cbz, Fmoc, MOM, SEM, pivaloyl; and X represents halogen selected from fluorine, chlorine, bromine, iodine.

[0031] In one embodiment, in step 3), the base is triethylamine; and R1X is pivaloyl chloride.

[0032] In one embodiment, in step 3), the molar ratio of compound 3 to R1X is 1:(1-2), preferably 1:1.5, and the molar ratio of compound 3 to the base is 1:(1-2), preferably 1:(1-1.5), more preferably 1:1.1.

[0033] In one embodiment, in step 3), the reaction solvent is dichloromethane, and the reaction temperature is 0-20 °C.

[0034] In one embodiment, in step 4), compound 4 is reduced with a reducing agent to obtain compound 5, wherein the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, lithium aluminum hydride.

[0035] In one embodiment, in step 4), the molar ratio of compound 4 to the reducing agent is 1:(1-2), preferably 1:1.3.

[0036] In one embodiment, in step 4), the reaction solvent is anhydrous ethanol.

[0037] In one embodiment, in step 5), compound 5 is subjected to an elimination reaction in the presence of an acid to obtain compound 6, wherein the acid is p-toluenesulfonic acid.

[0038] In one embodiment, in step 5), the reaction solvent is toluene, and the reaction temperature is 110-130 °C, for example 120 °C.

[0039] In one embodiment, in step 6), compound 6 is coupled with 4-bromo-3-nitroanisole in the presence of a transition metal to obtain compound 7, wherein the transition metal is a combination of Pd(dppf)2Cl2and Cu.

[0040] In one embodiment, in step 6), the reaction solvent is dimethyl sulfoxide; and the reaction temperature is 50-70 °C.

[0041] In an embodiment, in step 7), compound 7 is subjected to a reduction reaction in the presence of a transition metal and a reducing agent to obtain compound 8; preferably, the transition metal is a palladium catalyst and the reducing agent is hydrogen gas;

[0042] In an embodiment, in step 7), the transition metal is selected from at least one of Pd(PPh3)4, Pd2(dba)3, PdCl2(PPh3)2, Pd(OAc)2, Pd-C, preferably Pd-C;

[0043] In an embodiment, in step 7), the reaction can be carried out under pressurized or non-pressurized (atmospheric pressure) conditions, preferably under atmospheric pressure conditions;

[0044] In an embodiment, in step 7), the reaction solvent is selected from one or any combination of ethyl acetate, petroleum ether, tetrahydrofuran, ethanol, methanol, n-hexane, preferably a mixture of tetrahydrofuran and ethanol; the reaction temperature is 40-100°C, preferably 50-70°C, for example 55-65°C;

[0045] In an embodiment, in step 8), compound 8 is reacted with iodoethane in the presence of a base to obtain compound 9; the base can be selected from at least one of potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, cesium carbonate, sodium hydride;

[0046] In an embodiment, in step 8), the molar ratio of compound 8 to iodoethane is 1:(1-10), preferably 1:5, and the molar ratio of compound 8 to base is 1:(1-10), preferably 1:5;

[0047] In an embodiment, in step 8), the reaction solvent is tetrahydrofuran;

[0048] In an embodiment, in step 9), compound 9 is subjected to a reduction reaction in the presence of a transition metal and a reducing agent to obtain compound 10; preferably, the transition metal is a palladium catalyst and the reducing agent is hydrogen gas;

[0049] In an embodiment, in step 9), the transition metal is selected from at least one of Pd(PPh3)4, Pd2(dba)3, PdCl2(PPh3)2, Pd(OAc)2, Pd-C, preferably Pd-C;

[0050] In an embodiment, in step 9), the reaction can be carried out under pressurized or non-pressurized (atmospheric pressure) conditions, preferably under atmospheric pressure conditions;

[0051] In an embodiment, in step 9), the reaction solvent can be selected from one or any combination of ethyl acetate, petroleum ether, tetrahydrofuran, ethanol, methanol, n-hexane, preferably a mixed solvent of tetrahydrofuran and ethanol; and the reaction temperature can be room temperature.

[0052] In an embodiment, in step 10), compound 10 is obtained by coupling with a chiral reagent to obtain chiral compound 11; the chiral reagent is D-(+)-dibenzoyl tartaric acid.

[0053] In an embodiment, in step 10), the reaction solvent can be selected from one or any combination of acetonitrile, dichloromethane, tetrahydrofuran, ethanol, methanol, preferably a mixed solvent of acetonitrile and dichloromethane; and the reaction temperature can be 50-80°C, preferably 60-70°C.

[0054] Further, the present application provides a method for synthesizing elacridar, comprising the steps of:

[0055] S1) coupling reaction of compound 11 with compound 16 to obtain compound 12;

[0056] S2) deprotection of compound 12 to obtain compound 13;

[0057] S3) obtaining compound 14 from compound 13;

[0058] S4) reducing compound 14 to obtain compound 15;

[0059] The reaction formula is as follows:

[0060]

[0061] wherein, R1 represents a hydroxyl protecting group, R2 represents an amino protecting group, and X represents halogen.

[0062] In an embodiment, the hydroxyl protecting group is selected from TMS, TES, TBS, TIPS, TBDPS, TBDMS, t-Bu, methyl, benzyl, PMB, Boc, Cbz, Fmoc, MOM, SEM, pivaloyl; the amino protecting group is selected from tert-butyloxycarbonyl (Boc), Cbz, Fmoc, PMB, benzyl, trityl, p-toluenesulfonyl (Tos), propenoxycarbonyl; and the halogen is selected from fluorine, chlorine, bromine, iodine.

[0063] In an embodiment, in step S1), compound 11 is coupled with compound 16 in the presence of a base to obtain compound 12, and the base can be at least one of an inorganic base and an organic base.

[0064] In one embodiment, in step S1), the molar ratio of compound 11 to compound 16 ranges from 1 : (1-2), preferably 1 : 1.2, and the molar ratio of compound 11 to base ranges from 1 : (1-4), preferably 1 : 2;

[0065] In one embodiment, in step S1), the reaction solvent is an aprotic solvent, such as acetonitrile, dimethylsulfoxide, dimethylformamide, and the reaction temperature is in the range of 70-140 °C, such as 85-110 °C, for example 95 °C;

[0066] In one embodiment, in step S1), R1represents pivaloyl, R2represents tert-butyloxycarbonyl (Boc), and X represents Br;

[0067] In one embodiment, in step S2), compound 12 is deprotected from the amino protecting group under acidic conditions to obtain compound 13, and the acid is trifluoroacetic acid;

[0068] In one embodiment, in step S2), the reaction solvent is dichloromethane, and the reaction temperature is in the range of 10-50 °C;

[0069] In one embodiment, in step S3), compound 13 is reacted with acetic anhydride under basic conditions to obtain compound 14, and the base is selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), preferably triethylamine;

[0070] In one embodiment, in step S3), the reaction solvent is anhydrous dichloromethane, and the reaction temperature is room temperature;

[0071] In one embodiment, in step S3), the molar ratio of compound 13 to acetic anhydride is 1 : (1-2), and the molar ratio of compound 13 to base is 1 : (1-5);

[0072] In one embodiment, in step S4), compound 14 is reacted with a reducing agent to obtain compound 15, and the reducing agent can be selected from at least one of lithium aluminum hydride, sodium borohydride, potassium borohydride, preferably lithium aluminum hydride; preferably, the reaction is carried out under a nitrogen atmosphere;

[0073] In one embodiment, in step S4), the reaction solvent is tetrahydrofuran, and the reaction temperature is in the range of 30-80 °C, such as 50-60 °C, for example 55 °C;

[0074] Further, the present application provides a method for preparing compound 16, comprising the steps of:

[0075] i) compound 17 is subjected to a reduction reaction to obtain compound 18;

[0076] ii) compound 18 is subjected to an amino protection reaction to obtain compound 19;

[0077] iii) Compound 19 is subjected to bromination to obtain Compound 16;

[0078] The reaction formula is as follows:

[0079]

[0080] In one embodiment, in step i), Compound 17 is subjected to reduction with a reducing agent to obtain Compound 18, and the reducing agent is borane;

[0081] In one embodiment, in step i), the molar ratio of Compound 17 to the reducing agent is 1:3;

[0082] In one embodiment, in step i), the reaction solvent is tetrahydrofuran, and the reaction temperature is 60-80°C;

[0083] In one embodiment, in step ii), Compound 18 is subjected to reaction with (R2)20 under basic conditions to obtain Compound 19, and the base is sodium carbonate; preferably, R2 is a Boc group.

[0084] In one embodiment, in step ii), the molar ratio of Compound 18 to (R2)20 is 1:(1-3), and the molar ratio of Compound 18 to the base is 1:(1-8);

[0085] In one embodiment, in step ii), the reaction solvent is a mixed solvent of tetrahydrofuran and water, and the reaction temperature is room temperature;

[0086] In one embodiment, in step iii), Compound 19 is subjected to reaction with a halogenating agent under the condition of a catalyst to obtain Compound 16; preferably, the halogenating agent is NBS; preferably, the catalyst is triphenylphosphine;

[0087] In one embodiment, in step iii), the molar ratio of Compound 19 to the halogenating agent ranges from 1:(1-2), and the molar ratio of Compound 19 to the catalyst ranges from 1:(1-3), preferably 1:3;

[0088] In one embodiment, in step iii), the reaction solvent is dichloromethane, and the reaction temperature is room temperature.

[0089] The present application also provides a novel intermediate compound of elacridar.

[0090] In one embodiment, the present application provides Compound 12, the structural formula of which is as follows:

[0091]

[0092] wherein R1 is as defined above.

[0093] In one embodiment, the present application provides compound 13, whose structural formula is shown as follows:

[0094]

[0095] wherein R1 is as defined above.

[0096] In a preferred embodiment, in the above-mentioned intermediate compounds, R1 is pivaloyl; and R2 is tert-butyloxycarbonyl.

[0097] The raw materials (e.g. starting material 6-methoxy-1-tetralone) used in the preparation method of the present application are cheap and readily available, and the hydrogenation steps for preparing intermediate compounds 8 and 10 can be operated without pressure, which is convenient and mild. In the process of preparing compound 13 from compound 10, the route is novel, and does not require column chromatography, which is convenient for post-treatment and is very suitable for industrial production. DETAILED DESCRIPTION

[0098] The features and advantages of the present application are further illustrated by the following examples, which are for illustrative purposes only and are not intended to limit the scope of the present application. Unless otherwise specified, the materials and reagents used in the examples are commercially available. Unless otherwise specified, the steps of the methods used in the examples are conventional operations.

[0099] Abbreviations Chinese Name Abbreviations Chinese Name Pd Palladium on carbon TIPS Triisopropylsilyl (Boc)20 Di-tert-butyl dicarbonate TBDPS Tert-butyldiphenylsilyl [Pd(dppf)2Cl2] 1,1-Bis(diphenylphosphino) ferrocene palladium dichloride TBDMS Tert-butyldimethylsilyl [Pd(PPh3)4] Tetrakis(triphenylphosphine) palladium t-Bu Tert-butyl [Pd2(dba)3] Tris(dibenzylideneacetone) dipalladium PMB p-Methoxybenzyl [PdCl2(PPh3)2] Bis(triphenylphosphine) palladium dichloride Boc Tert-butyloxycarbonyl [Pd(OAc)2] Palladium acetate Cbz Benzyloxycarbonyl TMS Trimethylsilyl Fmoc 9-Fluorenylmethoxycarbonyl TE Triethylsilyl MOM Methoxymethyl TBS Dimethyl-tert-butylsilyl SEM (Silyl)ethoxymethyl

[0100] The reaction route in the following examples is shown as follows:

[0101]

[0102]

[0103] Example 1: Preparation of compound 7a

[0104] Step 1: Compound 1 (13 g, 73.8 mmol) was mixed with hydrobromic acid (47%, 130 mL) and stirred while heating to 126°C for 3 h. The reaction solution was cooled to room temperature, and solid was precipitated. The solid was filtered and dried to obtain compound 2 (10.2 g, 85.2%).

[0105] Step 2: Copper bromide (10 g, 44.8 mmol) was added to 100 mL of ethyl acetate, and compound 2 (14.5 g, 89.5 mmol) was added while heating to reflux. The reaction was carried out at reflux for 3 h. The reaction solution was cooled to room temperature, and solid was precipitated. The solid was filtered and washed with petroleum ether to obtain compound 3 (21 g, 95.7%).

[0106] Step 3: Compound 3 (10.0 g, 41.5 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (5.50 g, 45.6 mmol, 5.6 mL) was added dropwise with stirring. The temperature was lowered to below 10 °C, and tert-butyl chloroformate (6.3 g, 62.2 mmol) was added dropwise, with the temperature controlled to not exceed 20 °C. After the dropwise addition was complete, the reaction was allowed to proceed for 5 min, and then water (50 mL) was added to quench the reaction. The mixture was stirred and allowed to stand, and the phases were separated. The aqueous phase was back-extracted with 25 mL of dichloromethane three times, and the combined organic phases were washed with 25 mL of saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with 25 mL of petroleum ether twice. The mother liquor was concentrated under reduced pressure at 40 °C. The residue was slurried in 75 mL of petroleum ether for 30 min, filtered, and dried to give compound 4a (13.2 g, 97.9%).

[0107] Step 4: Compound 4a (10.0 g, 30.8 mmol) was mixed with 100 mL of anhydrous ethanol, and the mixture was cooled to 5 °C in an ice-salt bath. Sodium borohydride (1.3 g, 33.8 mmol) was added in portions (with the temperature controlled to not exceed 10 °C), and the reaction was allowed to proceed for 30 min. Then 50 mL of water was slowly added to the reaction mixture while stirring, and the mixture was filtered to give yellow solid compound 5a (8.3 g, 82.5%).

[0108] Step 5: Compound 5a (5.0 g, 15.3 mmol) was dissolved in 50 mL of toluene, and p-toluenesulfonic acid (526.0 mg, 9.9 mmol) was added with stirring. The mixture was heated to 120 °C and allowed to react for 2 h. After the reaction was complete, a light yellow solid was obtained, which was compound 6a (3.9 g, 82.5%).

[0109] Step 6: Compound 6a (5 g, 16.2 mmol), 4-bromo-3-nitroanisole (4.5 g, 19.4 mmol), copper (3.1 g, 48.5 mmol), Pd(dppf)2Cl2(393.2 mg, 485.1 umol), and 25 mL of DMSO were added to a 100 mL flask, which was replaced with nitrogen three times. The mixture was transferred to an oil bath and heated to 60 °C, and the reaction was allowed to proceed overnight. After the reaction was complete, the mixture was cooled, 50 mL of water and 50 mL of ethyl acetate were added with stirring, and the mixture was filtered through diatomite. The filter cake was rinsed with 25 mL of ethyl acetate three times, and the combined organic phases were concentrated at 45 °C. The residue was dried and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give yellow solid compound 7a (5.1 g, 82.6%).

[0110] 1H NMR (600 MHz, CHLOROFORM-d) δ 7.46 (d, J = 2.6 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.88 - 6.83 (m, 2H), 6.44 (s, 1H), 3.00 - 2.90 (m, 2H), 2.47 (t, J = 7.9 Hz, 2H), 1.36 (s, 9H).

[0111] The total yield of the above six steps is: 44.9%

[0112] Referring to the above method, the reaction reagent pivaloyl chloride in step 3) is replaced by the same molar amount of benzyloxy carbonyl chloride (CbzCl), that is, the hydroxyl protecting group of compounds 4a to 7a is changed from pivaloyl to benzyloxy carbonyl, and the yield of steps 3 to 6 is: 85.4%; 72.2%; 75.5%; 62.8%; the total yield of six steps is 23.8%; the reaction reagent pivaloyl chloride in step 3) is replaced by the same molar amount of chloromethyl methyl ether (MOMCl), that is, the hydroxyl protecting group of compounds 4a to 7a is changed from pivaloyl to methoxymethyl ether, and the yield of steps 3 to 6 is: 92.4%; 80.3%; 52.8%; 73.5%; the total yield of six steps is 23.5%.

[0113] Example 2: Preparation of compound 11a

[0114] Step 7: Compound 7a (10 g, 0.03 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and ethanol (50 mL), Pd-C (1 g, 10%) was added, and the temperature was raised to 62°C under hydrogen atmosphere, extracted with ethyl acetate (100 mL), washed with water (100 mL), and dried to obtain crude compound 8a (8.3 g).

[0115] Step 8: Compound 8a (10 g, 0.03 mmol) was dissolved in tetrahydrofuran (60 mL), iodomethane (22 g, 0.14 mmol) and potassium carbonate (19.3 g, 0.14 mmol) were added, after the reaction was completed, extracted with ethyl acetate (150 mL), washed with water (150 mL), and the organic phase was dried to obtain crude compound 9a (8.5 g).

[0116] Step 9: Compound 9a (10 g, 0.026 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and ethanol (50 mL), Pd-C (1 g, 10%) was added, and the temperature was raised to 62°C under hydrogen atmosphere, extracted with ethyl acetate (100 mL), washed with water (100 mL), and the organic phase was dried to obtain compound 10a (7.5 g, total yield of three steps 75.0%).

[0117] Referring to the above method, when the pivaloyl group of compound 7a is replaced with the same molar amount of benzyloxycarbonyl (Cbz), i.e., the hydroxyl protecting group of compound 7a to 10a is changed from pivaloyl to benzyloxycarbonyl (Cbz), the total yield of three steps is 55%. When the pivaloyl group of compound 7a is replaced with the same molar amount of methoxymethyl ether (MOM), i.e., the hydroxyl protecting group of compound 7a to 10a is changed from pivaloyl to methoxymethyl ether (MOM), the total yield of three steps is 65%. The preferred hydroxyl protecting group is pivaloyl.

[0118] Step 10: Compound 10a (10 g, 26.21 mmol) was dissolved in 100 mL of acetonitrile / dichloromethane (v / v = 1:1), after stirring to dissolve, D-(+)-dibenzoyl tartaric acid (4.70 g, 13.11 mol) was added, after stirring to dissolve, the temperature was raised to 65°C and refluxed for 3 h, slowly cooled to room temperature, a solid was precipitated, the solid was filtered, the filter cake was washed with dichloromethane (30 mL) twice, the filter cake was dispersed in dichloromethane (30 mL) and refluxed for 1 h, then filtered and washed again, the filter cake was repeated the above operation once again, and finally the filter cake was vacuum dried to obtain the D-(+)-dibenzoyl tartaric acid salt of compound 10a. The D-(+)-dibenzoyl tartaric acid salt of compound of formula II was dissolved in water / acetonitrile (10 mL, v / v = 2:1), after stirring to dissolve, 25% sodium bicarbonate aqueous solution (30 mL) was added, stirred at room temperature for 2 h, a solid was precipitated, the solid was filtered, the filter cake was washed with water twice, the obtained filtrate was adjusted to pH≥8 with sodium bicarbonate solution, a solid was precipitated again, the solid was filtered and washed, the filter cakes obtained in two times were combined, the filter cake was washed with water (10 mL) and n-heptane (10 mL) twice, and vacuum dried at 50°C to obtain compound 11a (4.63 g, yield 46%).

[0119] 1H NMR (600 MHz, CHLOROFORM-d) δ 7.09 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.94 (ddd, J = 24.1, 15.5, 5.2 Hz, 4H), 6.81 (dd, J = 11.8, 3.7 Hz, 2H), 6.33 - 6.22 (m, 2H), 3.80 (s, 3H), 3.65 (s, J = 32.1 Hz, 1H), 3.18 (dt, J = 7.2, 3.1 Hz, 2H), 3.04 (dd, J = 15.9, 2.3 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 - 2.73 (m, 2H), 2.09 (d, J = 1.9 Hz, 1H), 1.95 (s, 1H), 1.35 (d, J = 9.8 Hz, 9H), 1.31 - 1.24 (m, 3H).

[0120] Example 3: Preparation of Elacridar

[0121] Compound 11a (20 g, 52.42 mmol) was dissolved in 240 mL of acetonitrile, to which compound 16a (24.71 g, 78.63 mmol) and potassium carbonate (14.49 g, 104.84 mmol) were added. The reaction was refluxed at about 95 °C overnight; TLC monitoring (PE:EA = 9:1) showed that the reaction was nearly complete. Water 200 mL was added to the reaction, and extracted with ethyl acetate (200 mL*3), the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound 12a (26.0 g, yield 80.6%).

[0122] 1 H NMR (400 MHz, CHLOROFORM-d) = 7.14 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.4 Hz, 2H), 7.09-6.97 (m, 3H), 6.85-6.75 (m, 3H), 6.70 (dd, J = 2.2, 8.4 Hz, 1H), 5.30 (s, 1H), 4.52 (br. s., 1H), 3.99 (s, 2H), 3.80 (s, 3H), 3.75-3.64 (m, 1H), 3.34 (d, J = 5.5 Hz, 2H), 2.97-2.83 (m, 4H), 2.74 (t, J = 7.0 Hz, 4H), 1.84-1.64 (m, 2H), 1.43 (s, 9H), 1.36 (s, 9H), 0.94 (t, J = 6.8 Hz, 3H)

[0123] The crude compound 12a (20 g, 32.53 mmol) was dissolved in 200 mL of dichloromethane, and 50 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. TLC monitoring (petroleum ether: ethyl acetate = 9:1) showed that the reaction was complete, and the product was salted out. The reaction was spin-dried, diluted with water (100 mL), extracted with ethyl acetate (100 mL), the aqueous phase was adjusted to weak alkaline, extracted with ethyl acetate (150 mL*2), the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound 13a (14.7 g, yield 87.8%).

[0124] 1H NMR (400 MHz, CHLOROFORM-d) = 8.01 (br. s., 2 H), 7.20 - 7.09 (m, 3 H), 7.07 - 6.95 (m, 3 H), 6.84 - 6.74 (m, 3 H), 6.70 (d, J = 8.2 Hz, 1 H), 3.98 (br. s., 2 H), 3.83 - 3.73 (m, 3 H), 3.70 - 3.53 (m, 1 H), 3.15 - 3.03 (m, 2 H), 2.99 - 2.80 (m, 6 H), 2.78 - 2.63 (m, 2 H), 1.83 - 1.64 (m, 2 H), 1.38 - 1.29 (m, 9 H), 0.93 (t, J = 6.8 Hz, 3 H)

[0125] The crude compound 13a was dissolved in 200 mL of dry dichloromethane, acetic anhydride (5.16 g, 50.51 mmol) and triethylamine (9.83 g, 97.14 mmol) were added under ice bath, then the reaction was carried out at room temperature for 3 hours. TLC monitoring (ethyl acetate) showed that the reaction was complete. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (400 mL*3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give compound 14a (13.5 g, 85.0%).

[0126] 1 H NMR (400 MHz, CHLOROFORM-d) = 7.22 - 7.11 (m, 3 H), 7.09 - 6.99 (m, 3 H), 6.85 - 6.76 (m, 3 H), 6.70 (dd, J = 2.5, 8.4 Hz, 1 H), 5.47 (br. s., 1 H), 4.12 (q, J = 7.0 Hz, 2 H), 3.99 (s, 2 H), 3.80 (s, 3 H), 3.75 - 3.63 (m, 1 H), 3.47 (q, J = 6.7 Hz, 2 H), 2.99 - 2.85 (m, 4 H), 2.82 - 2.72 (m, 4 H), 2.04 (s, 3 H), 1.92 (s, 3 H), 1.84 - 1.71 (m, 2 H), 1.36 (s, 9 H), 1.26 (t, J = 7.2 Hz, 4 H), 0.94 (t, J = 7.0 Hz, 3 H)

[0127] Compound 14a (20 g, 35.92 mmol) was dissolved in 400 mL of tetrahydrofuran, lithium aluminum hydride (4.77 g, 125.73 mmol) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hours and then heated to 55 °C overnight. TLC monitoring (ethyl acetate) showed that the reaction was complete. The quenched reaction solution was filtered with 250 mL of water and 250 mL of 15% sodium hydroxide successively under ice bath. The quenched reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was rotary evaporated to dryness. Water (100 mL) and ethyl acetate (100 mL*3) were added to extract the product, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain compound 15 elacridar (11.7 g, 71.0%).

[0128] Example 4: Synthesis of compound 16

[0129]

[0130] Compound 17 (20 g, 0.11 mmol) was dissolved in tetrahydrofuran (100 mL), and borane (9.13 g, 3 eq) was added. The mixture was heated to 70 °C and stirred overnight. After the reaction was complete, the solvent was rotary evaporated to dryness to obtain crude compound 18.

[0131] Compound 18 (15.8 g, 0.11 mmol) was dissolved in tetrahydrofuran (100 mL), water (50 mL) was added, and di-tert-butyl dicarbonate (Boc)2O (37.37 g, 0.17 mmol) and sodium carbonate (17.5 g, 0.16 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate was added, and the mixture was washed with water (100 mL). The organic phase was rotary evaporated to dryness to obtain crude compound 19a.

[0132] Compound 19a (23.6 g, mmol) was dissolved in dichloromethane (200 mL), triphenylphosphine (37.5 g, 0.14 mmol), and N-bromosuccinimide (23.5 g, 0.13 mmol) were added. The mixture was stirred for 1 hour. After the reaction was complete, ethyl acetate (100 mL) was added, the mixture was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain compound 16a (24.2 g, total yield of three steps 67.7%).

[0133] Referring to the above method, di-tert-butyl dicarbonate was replaced with the same molar amount of p-toluenesulfonyl acid, i.e., the amino protecting group Boc in compound 19a was replaced with Tos, and the total yield after completing the three-step reaction was 58%; di-tert-butyl dicarbonate was replaced with the same molar amount of p-methoxybenzyl chloride, i.e., the amino protecting group Boc in compound 19a was replaced with PMB, and the total yield after completing the three-step reaction was 62%.

Claims

1. A method for synthesizing compound 11, comprising the steps of: 1) demethylation of compound 1 to obtain compound 2; 2) bromination of compound 2 to obtain compound 3; 3) hydroxyl protection of compound 3 to obtain compound 4; 4) reduction of compound 4 to obtain compound 5; 5) elimination of compound 5 to obtain compound 6; 6) coupling of compound 6 to obtain compound 7; 7) nitro reduction of compound 7 to obtain compound 8; 8) substitution of compound 8 to obtain compound 9; 9) reduction of compound 9 to obtain compound 10; and 10) chiral resolution of compound 10 to obtain compound 11; and the reaction formula is as follows: wherein R1 represents a hydroxyl protecting group.

2. The method of claim 1, wherein one or more of the following features is included: in step 1), the demethylation of compound 1 is carried out in the presence of an acid to obtain compound 2, and the acid is selected from at least one of hydrobromic acid, hydroiodic acid, hydrochloric acid, and sulfuric acid; and / or in step 2), the bromination of compound 2 is carried out with a bromination reagent to obtain compound 3, and the bromination reagent is copper bromide; and / or R1 represents a hydroxyl protecting group selected from at least one of TMS, TES, TBS, TIPS, TBDPS, TBDMS, t-Bu, methyl, benzyl, PMB, Boc, Cbz, Fmoc, MOM, SEM, and pivaloyl; and X represents a halogen selected from at least one of fluorine, chlorine, bromine, and iodine; and / or in step 4), the reduction of compound 4 is carried out in the presence of a reducing agent to obtain compound 5, and the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, and lithium aluminum hydride; and / or in step 5), the elimination of compound 5 is carried out in the presence of an acid to obtain compound 6, and the acid is p-toluenesulfonic acid; and / or in step 6), the coupling of compound 6 is carried out with 4-bromo-3-nitroanisole in the presence of a transition metal to obtain compound 7, and the transition metal is a combination of Pd(dppf)2Cl2 and Cu; and / or in step 7), the reduction of compound 7 is carried out in the presence of a transition metal and a reducing agent to obtain compound 8, and the transition metal is a palladium catalyst and the reducing agent is hydrogen; and / or in step 8), the reaction of compound 8 is carried out with iodoethane in the presence of a base to obtain compound 9, and the base is selected from at least one of potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, cesium carbonate, and sodium hydride; and / or in step 9), the reduction of compound 9 is carried out in the presence of a transition metal and a reducing agent to obtain compound 10, and the transition metal is a palladium catalyst and the reducing agent is hydrogen; and / or in step 10), the chiral resolution of compound 10 is carried out with a chiral resolution reagent to obtain chiral compound 11, and the chiral resolution reagent is D-(+)-dibenzoyltartaric acid.

3. The method of claim 2, wherein one or more of the following features is included: in step 2), the molar ratio of compound 2 to the bromination reagent is 1:2; and / or in step 2), the reaction solvent is ethyl acetate, and the reaction temperature is 60-100°C; and / or ​ ​ ​ ​ ​ ​ ​ ​ ​ ； ​ ​ ​ ​ In Step 3), compound 3 is reacted with R1X in the presence of a base to give compound 4; wherein, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ In step 3), compound 3 is reacted with pivaloyl chloride in the presence of triethylamine to obtain compound 4; the molar ratio of compound 3 to pivaloyl chloride is 1:(1-2), and the molar ratio of compound 3 to base is 1:(1-2); In step 4), the molar ratio of compound 4 to reducing agent is 1:(1-2); In step 7), the transition metal is at least one selected from Pd(PPh3)4, Pd2(dba)3, PdCl2(PPh3)2, Pd(OAc)2, and Pd-C; In step 7), the reaction is carried out under pressure or without pressure; In step 7), the reaction solvent is a mixed solvent of tetrahydrofuran and / or ethanol; In step 8), the molar ratio of compound 8 to iodoethane is 1:(1-10), and the molar ratio of compound 8 to base is 1:(1-10); In step 9), the transition metal is at least one selected from Pd(PPh3)4, Pd2(dba)3, PdCl2(PPh3)2, Pd(OAc)2, and Pd-C; In step 9), the reaction is carried out under pressure or without pressure; In step 9), the reaction solvent is a mixed solvent of tetrahydrofuran and ethanol; the reaction temperature is room temperature; and / or In step 10), the reaction solvent is a mixed solvent of dichloromethane and acetonitrile.

4. A method for synthesizing elacridar, comprising the steps of: S1) coupling compound 11 with compound 16 to obtain compound 12; S2) removing the amino protecting group from compound 12 to obtain compound 13; S3) obtaining compound 14 from compound 13; S4) obtaining compound 15 from compound 14 through a reduction reaction; The reaction formula is as follows: ； wherein R1 represents a hydroxyl protecting group, R2 represents an amino protecting group, and X represents halogen; The hydroxyl protecting group is at least one selected from TMS, TES, TBS, TIPS, TBDPS, TBDMS, t-Bu, methyl, benzyl, PMB, Boc, Cbz, Fmoc, MOM, SEM, and pivaloyl; the amino protecting group is at least one selected from tert-butyloxycarbonyl (Boc), Cbz, Fmoc, PMB, benzyl, trityl, p-toluenesulfonyl (Tos), and propenoxycarbonyl; and the halogen is at least one selected from fluorine, chlorine, bromine, and iodine.

5. The method of claim 4, wherein one or more of the following features is included: In step S1), compound 11 is coupled with compound 16 in the presence of a base to obtain compound 12, and the base is at least one selected from inorganic bases and organic bases; and / or In step S2), the amino protecting group of compound 12 is removed under acidic conditions to obtain compound 13, and the acid is trifluoroacetic acid; and / or In step S3), compound 13 is reacted with acetic anhydride under basic conditions to obtain compound 14, and the base is at least one selected from triethylamine, pyridine, and 4-dimethylaminopyridine (DMAP); and / or In step S4), compound 14 is reacted with a reducing agent to obtain compound 15, and the reducing agent is at least one selected from lithium aluminum hydride, sodium borohydride, and potassium borohydride.

6. The method of claim 5, wherein one or more of the following features is included: In step S1), R1represents tert-pivaloyl, R2represents tert-butyloxycarbonyl (Boc), and X represents Br; and / or In step S1), the reaction solvent is an aprotic solvent; and / or In step S1), the molar ratio of compound 11 to compound 16 is 1: (1-2), and the molar ratio of compound 11 to base is 1: (1-4); and / or In step S2), the reaction solvent is dichloromethane; and / or In step S3), the molar ratio of compound 13 to acetic anhydride is 1: (1-2), and the molar ratio of compound 13 to base is 1: (1-5); and / or In step S3), the reaction solvent is anhydrous dichloromethane; and / or In step S4), the reducing agent is lithium aluminum hydride; and / or the reaction is carried out under a nitrogen atmosphere; and / or In step S4), the reaction solvent is tetrahydrofuran.

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