Intermediate of elacestrant, method for preparing the intermediate, and method for preparing elacestrant

Abstract

The application discloses a method for preparing Iaroxime and salts thereof, and corresponding intermediates and a preparation method of the intermediates. The method is simple, safe, environmentally friendly, and mild in process operation and post-treatment, and is not harsh in a reaction process, and obviously improves product yield and quality, solves operation difficulties in a production process and other work problems, and is beneficial to industrialization expansion.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to ellastrant intermediates, methods for preparing the intermediates, and methods for preparing ellastrant using the intermediates. Background Technology

[0002] Breast cancer has become one of the most common cancers worldwide in recent years, with a year-on-year increasing trend and a persistently high mortality rate. It has now surpassed lung cancer to become the fifth leading cause of cancer death globally.

[0003] In January 2023, the FDA approved elacestrant (Orserdu, elextron, RAD1901) for postmenopausal women or adult men with ER+, HER2-, ESR1-mutant advanced or metastatic breast cancer whose disease has progressed after at least one line of prior endocrine therapy. Compared to fulvestrant or aromatase inhibitors, elacestrant, as the first oral SERD drug, has better safety and efficacy, is more convenient to use, and has better adherence. It has now been included in the NCCN (2023.V2) guidelines for breast cancer.

[0004] Ilasma group free compound, (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol, CAS number 722533-56-4, molecular formula C 30 H 38 N2O2, with a molecular weight of 458.64 (C 30 H 38 N2O2). Irasulane dihydrochloride, CAS number 1349723-93-8, molecular formula C 30 H 40 Cl2N2O2, with a molecular weight of 531.56, has the following structure:

[0005]

[0006] However, globally, reports on its preparation methods are relatively scarce. The original manufacturer of Eisai, CN202080011109.9, discloses the following preparation route:

[0007]

[0008] The process involves harsh and complex reaction conditions, cumbersome post-processing, multiple steps, high risk, long reaction and processing times, poor conversion rate, low overall yield, and is environmentally unfriendly, making it unsuitable for industrial scale-up.

[0009] Patent application CN202311194779.0 discloses the following preparation route:

[0010]

[0011] The starting materials in this process are difficult to purify, have low yields, and high production costs. Furthermore, the subsequent processes use acetaldehyde, which is volatile, highly toxic, and environmentally unfriendly, making it unsuitable for industrial scale-up.

[0012] Therefore, for allergic groups, there is an urgent need to develop a process route that has high yield, stable process, simple operation, green process, and is conducive to industrial scale-up. Summary of the Invention

[0013] To achieve the objectives of this invention, the following technical solution is adopted:

[0014] A method for preparing a compound of formula (I) includes the following steps:

[0015]

[0016] Compound V is catalytically reduced in the first solvent to yield compound I.

[0017] The reducing agent can be one or more of elemental iodine, lithium aluminum hydride, sodium borohydride, and potassium borohydride. In some embodiments, the reducing agent is elemental iodine.

[0018] The catalyst may be one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, diborane, nonaborane, borane and its complexes, lithium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. In some embodiments, the reducing agent is one or more of sodium borohydride, lithium triethylborohydride, and sodium triacetoxyborohydride.

[0019] The molar ratio of compound V to reducing agent can be 1-20, preferably 1-10, and more preferably 1-3.

[0020] The reaction temperature can be -50℃ to 150℃, preferably 0℃ to 100℃, and more preferably 40℃ to 80℃.

[0021] Furthermore, a method for preparing a compound of formula (I) further includes the following steps:

[0022]

[0023] Compound IV reacts with an ethylating agent in a second solvent in the presence of a catalyst and a reducing agent to yield compound V.

[0024] The ethylating agent may be bromoethane, iodoethane, chloroethane, diethyl carbonate, diethyl sulfate, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate, ethylaluminum, diazonium ethane, potassium ethyltrifluoroborate, ethyl magnesium bromide, ethyl zinc iodide, ethylboric acid, sodium ethoxide, potassium ethoxide, or combinations thereof. In some embodiments, the ethylating agent is bromoethane, iodoethane, diethyl carbonate, or combinations thereof.

[0025] The catalyst can be one or more of organic acids, inorganic acids, organic bases, and inorganic bases. The organic acid can be one or more of formic acid, acetic acid, propionic acid, p-toluenesulfonic acid, and benzoic acid, preferably formic acid and acetic acid, and more preferably acetic acid. The inorganic acid can be one or more of hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base can be one or more of triethylamine and DIPEA, preferably triethylamine. The inorganic base can be one or more of ammonia, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably ammonia.

[0026] The reducing agent may be sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, diborane, nonaborane, borane and its complexes, triethylborohydride, lithium triethylborohydride, triacetoxyborohydride, sodium cyanoborohydride, or combinations thereof. In some embodiments, the reducing agent is triethylborohydride, lithium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, or combinations thereof.

[0027] The molar ratio of Formula IV to the ethylating agent can be 1-10, preferably 2-8, and more preferably 2-5.

[0028] The reaction temperature can be -20℃ to 120℃, preferably 0℃ to 80℃, and more preferably 10℃ to 50℃.

[0029] Furthermore, a method for preparing a compound of formula (I) further includes the following steps:

[0030]

[0031] Compound II and compound III react in a third solvent in the presence of a catalyst to give compound IV.

[0032] The catalyst can be one or more of organic acids, inorganic acids, organic bases, and inorganic bases. The organic acid can be one or more of formic acid, acetic acid, propionic acid, p-toluenesulfonic acid, and benzoic acid, preferably formic acid and acetic acid, and more preferably acetic acid. The inorganic acid can be one or more of hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base can be one or more of triethylamine and DIPEA, preferably triethylamine. The inorganic base can be one or more of ammonia, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably ammonia.

[0033] The molar ratio of Formula II to Formula III can be in the range of 0.9-1.1, preferably 0.95-1.1, and more preferably 1-1.1.

[0034] The reaction temperature can be 20℃-120℃, preferably 30℃-120℃, and more preferably 50℃-120℃.

[0035] The first solvent, second solvent, and third solvent are each independently selected from alkanes, haloalkanes, ethers, esters, alcohols, amides, sulfones, ketones, nitriles, benzenes, or combinations thereof; the alkanes are selected from one or more of methane, ethane, butane, and pentane; the haloalkanes are selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, and toluene; the ethers are selected from one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, phenethyl ether, and 1,4-dioxane; the esters are selected from ethyl acetate, methyl acetate, ethyl formate, and ethyl acetate. The following compounds are selected from one or more of methyl formate, triethyl orthoformate, and trimethyl orthoformate; the alcohols are selected from one or more of methanol, ethanol, isopropanol, propanol, n-butanol, isobutanol, n-pentanol, and isopentanol; the amides are selected from one or more of N,N-dimethylformamide, N,N-diethylformamide, and benzamide; the sulfones are selected from one or more of dimethyl sulfoxide and sulfolane; the ketones are selected from one or more of acetone, methyl isobutyl ketone, and acetophenone; the nitriles are selected from acetonitrile; and the benzenes are selected from one or more of benzene, toluene, and xylene.

[0036] In some embodiments, a method for preparing a compound of formula (I) includes the following steps:

[0037]

[0038] Compounds of formula IV and V are used as intermediates to prepare compound (I):

[0039]

[0040] The enantiomeric excess of compounds of formula IV and V is >50%, and in some embodiments, the enantiomeric excess is >50%, >60%, >70%, >80%, >90%, >95%, >98%, or >99%.

[0041] This invention addresses the shortcomings of existing methods for preparing alastra and its salts by optimizing and improving upon them, providing a novel synthetic route and employing a novel intermediate:

[0042] 1. The reaction of compound II with compound III yields compound IV. A single solvent and catalyst are used, and the product is inexpensive and readily available. After the reaction, the product crystallizes in situ, resulting in good quality and high conversion and yield.

[0043] 2. Compounds of Formula IV are prepared into compounds of Formula V using a one-pot condensation process, which significantly improves the conversion rate. The reaction conditions are mild and not harsh, making it more environmentally friendly, simplifying the process, and improving the quality and yield.

[0044] 3. The reaction of compound V yields compound I, which is a simple process with mild conditions, high yield, and excellent quality.

[0045] In summary, the process and post-processing of this invention are simple, safe, and environmentally friendly, with mild conditions and a non-harsh reaction process. The product yield and quality are significantly improved, solving operational difficulties in the production process and facilitating industrial scale-up. Attached Figure Description

[0046] Figure 1 The HPLC reaction chromatogram of the reaction solution of compound IV;

[0047] Figure 2 The HPLC chromatogram of the solid crystal of compound IV is shown.

[0048] Figure 3 MS spectrum of compound IV;

[0049] Figure 4 The 1H-NMR spectrum of compound IV;

[0050] Figure 5 MS spectrum of compound V;

[0051] Figure 6 The 1H-NMR spectrum of compound V;

[0052] Figure 7 The HPLC chromatogram of compound I in Example 3-1 is shown below.

[0053] Figure 8 MS spectrum of compound I;

[0054] Figure 9 The HPLC chromatogram of compound I in Example 3-2 is shown below.

[0055] Figure 10 Examples 3-3 show the HPLC chromatograms of compounds of formula I.

[0056] Figure 11 Compare the HPLC chromatogram of the reaction solution in Example 2;

[0057] Figure 12 Compare the solid HPLC reaction chromatograms of the compound in Example 2;

[0058] Figure 13 Comparative Example 2: MS spectrum of imine compound;

[0059] Figure 14Compare the 1H-NMR spectra of the imine compound in Example 2;

[0060] Figure 15 Comparative Example 2 shows the HPLC reaction chromatogram of compound I. Detailed Implementation

[0061] The following detailed description of specific embodiments further illustrates the above-mentioned content of the present invention, but should not be construed as limiting the scope of protection of the present invention in any way. All technical solutions implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. The present invention provides a general and / or specific description of the materials and test methods used in the experiments.

[0062] Summary of experimental instruments:

[0063] The structures of the compounds in this application were identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Neo 400M or Bruker Ascend 400 NMR spectrometer, with deuterated chloroform (CDCl3) and heavy water (D2O) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0064] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-DAD-MSD mass spectrometer with an Agilent ZORBAX Rx-C8 (5 μm, 4.6 × 250 mm) column (electrospray ionization source). High-performance liquid chromatography (HPLC) was performed using a Waters ARC-2489-2998 mass spectrometer with an Agilent ZORBAX Rx-C8 (5 μm, 4.6 × 150 mm) column.

[0065] The starting materials used in the embodiments of this application are known and commercially available, or can be synthesized using methods known in the art. Unless otherwise specified, all reactions in this application are carried out under continuous magnetic stirring and a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius or °C. Unless otherwise specified, room temperature refers to 25 ± 5 °C.

[0066] Preparation of Formula IV compounds

[0067]

[0068] Example 1-1

[0069] Add 19.1 g (0.1 mol) of Formula II, 95 ml of ethanol, 26.9 g (0.1 mol) of Formula III, and 3.0 g (0.05 mol) of glacial acetic acid to a 500 ml reaction flask. Heat the system to reflux and maintain the reaction temperature for 1 h. Take a sample for analysis (CYA250218-2-1, such as...). Figure 1 (As shown), the system was cooled to 15±5℃, and filtered to obtain 40.1g of compound IV, with a purity as shown. Figure 2 As shown, the yield is 90.5%.

[0070] Target compound (MS (m / z): 443.2 (M+H)) (e.g.) Figure 3 (As shown).

[0071] 1 HNMR(CDCl3)δ: 1.66-1.74(m,2H), 1.79(s,3H), 2.53-2.69(m,7H), 3.22-3.28(m,3H), 3.51-3.64(s,3H), 6.26-6.31(d, 1H), 6.35-6.56(s,2H), 6.57-6.76(m,3H), 6.95-7.29(m,3H), 7.57-7.63(s,2H), 8.15-8.20(s,1H), 8.27-8.32(s,1H)(such as Figure 4 (As shown).

[0072] Examples 1-2

[0073] Add 34.5 g (0.18 mol) of Formula II, 350 ml of toluene, 48.55 g (0.18 mol) of Formula III, and 5.5 g (0.09 mol) of glacial acetic acid to a 500 ml reaction flask. Heat the system to reflux and maintain the temperature for 1 h. Cool the system to 15 ± 5 °C and filter to obtain 74.19 g of Formula IV compound, with a yield of 93.0%.

[0074] Examples 1-3

[0075] Add 34.5 g (0.18 mol) of Formula II, 350 ml of methyl tert-butyl ether, 48.55 g (0.18 mol) of Formula III, and 9.1 g (0.09 mol) of triethylamine to a 500 ml reaction flask. Heat the system to reflux and maintain the reaction temperature for 1 h. Cool the system to 15 ± 5 °C and filter to obtain 71.00 g of compound IV, with a yield of 89.0%.

[0076] Preparation of Compound V

[0077]

[0078] Example 2-1

[0079] Add 20 g (45 mmol) of compound IV and 200 ml of toluene to a reaction flask, then add 9.58 g (45 mmol) of sodium triethoxyborohydride and react for 1 h. Next, add 8.13 g (0.14 mol) of glacial acetic acid and 12.03 g (0.11 mol) of bromoethane and maintain the temperature at 20-30 °C for 1 h. Distill the system until solvent-free, and crystallize to obtain compound V.

[0080] 19.22g, yield 90%.

[0081] Target compound (MS (m / z): 473.5 (M+H)) (e.g.) Figure 5 (As shown).

[0082] 1 H NMR (400MHz, CDCl3): δ7.21-7.28(dd,2H),7.16-7.28(s,1H),7.06-7.08(dd,2H), 6.91-6.93(s,1H),6.81-6.82(s,1H),6.67-6.73(s,3H),6.33(s,1H),5.61-5.63(s ,1H),3.82-4.02(s,2H),3.69-3.70(s,3H),3.63-3.64(m,1H),3.47-3.52(m,2H),2 .86-2.98(m,2H),2.77-2.84(m,6H),2.11(s,3H),1.77-1.99(m,1H),1.12(t,3H)(such as Figure 6 (As shown).

[0083] Example 2-2

[0084] 35 g (79 mmol) of compound IV and 350 ml of ethyl acetate were added to a reaction flask. 50.32 g (0.24 mol) of sodium triethoxyborohydride was then added, and the reaction was allowed to proceed for 1 h. Next, 14.24 g (0.24 mol) of glacial acetic acid and 12.94 g (0.12 mol) of bromoethane were added, and the mixture was kept at 20-30 °C for 1 h. The system was then evaporated until solvent-free, and crystallization yielded 34.38 g of compound V, with a yield of 92.0%.

[0085] Example 2-3

[0086] Add 75 g (0.17 mol) of compound IV and 1.5 L of acetonitrile to a reaction flask, then add 107.87 g (0.51 mol) of sodium triethoxyborohydride and react for 3 h. Next, add 30.53 g (0.51 mol) of glacial acetic acid and 27.73 g (0.25 mol) of bromoethane and maintain the temperature at 20-30 °C for 1 h. Distill the system until solvent-free, and crystallize to obtain compound V.

[0087] 72.88g, yield 91.0%.

[0088] Preparation of Compound I

[0089]

[0090] Example 3-1

[0091] Add 23.6 g (0.05 mol) of compound V, 120 ml of tetrahydrofuran, 120 ml of ethanol, 9.6 g (0.075 mol) of iodine, and 1.9 g (0.05 mol) of sodium borohydride to a 500 ml reaction flask, and incubate at 60 ± 5 °C for 5 h. Distill the system until solvent-free, add 200 ml of ethyl acetate and 100 ml of purified water, stir, and separate the liquids, retaining the organic phase. Distill the organic phase until solvent-free.

[0092] Add 50 ml of ethyl acetate to the concentrated system, stir well, then add 50 ml of 4M ethyl acetate hydrochloride solution. Stir at 25 ± 5 °C for 3 h until the reaction is complete. Filter, wash the filter cake with 25 ml of ethyl acetate, and dry to obtain 24.7 g of compound I with a purity of 99.80% (API 250306-1-1, as shown). Figure 7 As shown), the yield was 92.9%. Target compound (MS (m / z): 459.3 [M+H]) (as shown) Figure 8 (As shown).

[0093] Example 3-2

[0094] Add 40.0 g (0.085 mol) of compound V, 200 ml of tetrahydrofuran, 200 ml of ethanol, 16.2 g (0.127 mol) of iodine, and 3.2 g (0.085 mol) of sodium borohydride to a 500 ml reaction flask, and incubate at 60 ± 5 °C for 5 h. Distill the system until solvent-free, add 300 ml of ethyl acetate and 150 ml of purified water, stir, and separate the liquids, retaining the organic phase. Distill the organic phase until solvent-free.

[0095] Add 85 ml of ethyl acetate to the concentrated system, stir well, then add 85 ml of 4M dioxane hydrochloride solution. Stir at 25±5℃ for 1 h until the reaction is complete. Filter, rinse the filter cake with 50 ml of dioxane, and dry to obtain 42.7 g of compound I with a purity of 99.73% (API 250305-3-1, as shown). Figure 9 (As shown), the yield was 95.0%.

[0096] Example 3-3

[0097] Add 40.0 g (0.085 mol) of compound V, 200 ml of tetrahydrofuran, 200 ml of ethanol, 16.2 g (0.127 mol) of iodine, and 3.2 g (0.085 mol) of sodium borohydride to a 500 ml reaction flask, and incubate at 60 ± 5 °C for 5 h. Distill the system until solvent-free, add 300 ml of ethyl acetate and 150 ml of purified water, stir, and separate the liquids, retaining the organic phase. Distill the organic phase until solvent-free.

[0098] Add 85 ml of ethyl acetate to the concentrated system, stir well, then add 170 ml of 2M isopropanol hydrochloride solution. Stir at 25±5℃ for 1 h until the reaction is complete. Filter, rinse the filter cake with 50 ml of dioxane, and dry to obtain 44.1 g of compound I with a purity of 99.69% (API 250305-1-1, as shown). Figure 10 (As shown), the yield was 98.0%.

[0099] Comparative Examples

[0100] Comparative Example 1

[0101] Original patent CN202080011109.9 Synthesis route:

[0102]

[0103] Preparation of compound (g):

[0104] At room temperature, 10.0 g (37 mmol) of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (e), 8.52 g (44.5 mmol) of N-ethyl-2-(4-formylphenyl)acetamide (f), 125 mg (0.35 mmol) of D-(+)-dibenzoyl tartaric acid, 100 mL of tetrahydrofuran, and 75 mL of n-heptane were added to a reaction flask in that order. After the addition was complete, the reaction system was purged with nitrogen, and the reaction solution was heated to 70 °C with stirring. The reaction was monitored by TLC after 4 hours to indicate completion. The reaction system was then concentrated under reduced pressure at 40 °C until no more droplets flowed out, yielding (R,E)-N-ethyl- 2-(4-((2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)imino)methyl)phenyl)acetamide (imine intermediate) was added to tetrahydrofuran (800 mL) and sodium acetylborohydride (82.0 g, 0.37 mol). The reaction system was purged with nitrogen, and the reaction solution was heated to 68 °C with stirring under controlled temperature. After 16 hours, the reaction was monitored by TLC to ensure complete reaction. The reaction system was cooled to 25 °C, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate and separated. The organic phase was washed with water and separated. The organic phase was concentrated under reduced pressure at 40 °C until no more droplets flowed out, yielding 12.9 g of the target compound, with a molar yield of 73.6%.

[0105] Preparation of compound 1:

[0106] At room temperature, 1.1 g (29 mmol) of sodium borohydride and 40 mL of tetrahydrofuran were added to a reaction flask. Under nitrogen protection, the mixture was cooled to -20 °C. Separately, 5.4 g (11.4 mmol) of (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide was dissolved in 30 mL of tetrahydrofuran and added dropwise to the reaction flask under controlled temperature of -20 °C to 0 °C. After the addition was complete, 2.9 g (11.4 mmol) of iodine was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction flask under controlled temperature of -20 °C to 0 °C. After the addition was complete, the reaction system was heated to 65 °C and stirred for 20 hours. LC-MS showed that the reaction was incomplete, with a large amount of raw material remaining.

[0107] Target compound MS and Figure 8 Consistent.

[0108] Comparative Example 2

[0109] Add (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (e) 2.0 g (7.4 mmol), N-ethyl-2-(4-formylphenyl)acetamide (f) 1.58 g (8.3 mmol), glacial acetic acid 0.22 g (0.5 mmol), and toluene (20 mL) to the reaction flask in that order. Reflux for 1 h, and then take a sample for analysis (NBA250313-1-1, such as...). Figure 11 (As shown), the system was cooled to 15±5℃ and filtered to obtain 2.57g of imine compound with the purity shown. Figure 12 As shown, the yield was 78.4%.

[0110] Target compound (MS (m / z): 443.2 (M+H)) Figure 13 (As shown).

[0111] 1H NMR (400MHz, CD3SOCD3): δ9.02(s,1H),8.53(s,1H),8.07-8.08(s,1H),7.36-7.38(dd,2H),7.23(dd,2H),7.21(dd,1H),6.77-6.83(m, 2H),6.64-6.55(d,1H),6.48-6.49(dd,2H),3.77(s,3H),3.33-3.44(t,2H),2.51-2.79(m,4H),1.83-1.92(dt,2H),0.99-1.03(s,3H)(such as Figure 14 (As shown).

[0112] 2 g (4.5 mmol) of an imine compound and 20 mL of toluene were added to a reaction flask. Then, 0.95 g (4.5 mmol) of sodium triethoxyborohydride was added, and the reaction was allowed to proceed for 1 h. Next, 0.84 g (14 mmol) of glacial acetic acid and 1.20 g (11 mmol) of bromoethane were added, and the reaction was maintained at 20-30 °C for 1 h. The system was then evaporated until solvent-free, and crystallization yielded 1.63 g of the compound, with a yield of 76.2%.

[0113] Add 1.5 g (3.2 mmol) of compound (g), 7.5 ml of tetrahydrofuran, 7.5 ml of ethanol, 1.2 g (4.7 mmol) of iodine, and 0.12 g (3.2 mmol) of sodium borohydride to a reaction flask, and incubate at 60 ± 5 °C for 5 h. Distill the system until solvent-free, add 12.5 ml of ethyl acetate and 6.25 ml of purified water, stir, and separate the liquid, retaining the organic phase. Distill the organic phase until solvent-free.

[0114] Add 5 ml of ethyl acetate to the concentrated system, stir well, then add 5 ml of 4M ethyl acetate hydrochloride solution. Stir at 25±5℃ for 5 h until the reaction is complete. Filter, wash the filter cake with 3 ml of ethyl acetate, and dry to obtain 1.21 g of compound I with a purity of 96.21% (API 250324-2-1, as shown). Figure 15 (As shown), yield 71.9%. Target compound (MS (m / z): 459.3 [M+H]).

Claims

1. A method for preparing a compound of formula I, characterized in that, Includes the following steps: Compound V is catalytically reduced in the first solvent to yield compound I.

2. The preparation method according to claim 1, characterized in that, The reducing agent is one or more of elemental iodine, lithium aluminum hydride, sodium borohydride, and potassium borohydride; and / or the catalyst is one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, diborane, nonaborane, borane and its complexes, triethyllithium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

3. The preparation method according to any one of the preceding claims, characterized in that, Further steps include the following: Compound IV reacts with an ethylating agent in a second solvent in the presence of a catalyst and a reducing agent to yield compound V.

4. The preparation method according to claim 3, characterized in that, The ethylating agent is bromoethane, iodoethane, chloroethane, diethyl carbonate, diethyl sulfate, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate, ethylaluminum, diazonium ethane, potassium ethyltrifluoroborate, ethyl magnesium bromide, zinc ethyl iodide, ethylboric acid, sodium ethoxide, potassium ethoxide, or combinations thereof; and / or, the catalyst is one or more of organic acids, inorganic acids, organic bases, and inorganic bases; and / or, the reducing agent is sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, diborane, nonaborane, borane and its complexes, sodium triethylborohydride, lithium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, or combinations thereof.

5. The preparation method according to any one of the preceding claims, characterized in that, Further steps include the following: Compound II and compound III react in a third solvent in the presence of a catalyst to give compound IV.

6. The preparation method according to claim 5, characterized in that, The catalyst is one or more of organic acids, inorganic acids, organic bases, and inorganic bases.

7. The preparation method according to any one of the preceding claims, characterized in that, The first solvent, the second solvent, and the third solvent are each independently selected from alkanes, haloalkanes, ethers, esters, alcohols, amides, sulfones, ketones, nitriles, benzenes, or combinations thereof.

8. A compound selected from:

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