Tetrahydronaphthalene derivative and synthesis of intermediate thereof

Abstract

The invention discloses synthesis of a tetrahydronaphthalene derivative and an intermediate thereof. The invention provides a synthesis method of a compound I. The synthesis method comprises the following step: in a solvent, in the presence of acid and a palladium catalyst, and in the presence of a reducing agent, carrying out hydroxyl reduction reaction on a compound IV to prepare the compound I. The preparation method has one or more of the following advantages: (1) good reaction selectivity, (2) mild and easy-to-control reaction, (3) high reaction yield, (4) good product purity, and (5) easily available materials, simple and convenient reaction operation, and good application prospect and value.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to the synthesis of a tetrahydronaphthalene derivative and its intermediates. Background Technology

[0002] Breast cancer is the most common type of cancer among women worldwide and the second leading cause of cancer-related death. Estrogen is considered a significant factor promoting the growth of most breast cancers. Breast cancer is a heterogeneous disease with three subtypes: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Overexpression of ER is found in many breast cancer patients. ER-positive (ER+) breast cancer accounts for two-thirds of all breast cancers. Estrogen receptor alpha-positive (ERα+) breast cancer is the most common subtype, accounting for approximately 70% of breast cancers. These patients can initially be treated with endocrine blockade therapy, but as the disease progresses, the tumor develops resistance to this therapy and accumulates many mutations, making treatment difficult. ESR1 mutations occur late in the treatment of advanced / metastatic breast cancer and are one of the most difficult mechanisms for acquiring resistance to treat.

[0003] Elacestrant is a selective estrogen receptor modulator (SERD). Unlike modulators that inhibit estrogen activity, it dose-dependently degrades estrogen receptor α (ERα / ESR1), inhibiting estradiol-dependent ER-guided gene transcription and tumor growth, and can address resistance caused by estrogen receptor mutations. Following FDA approval on January 27, 2023, Elacestrant (Orserdu) was included in the NCCN (2023.V2) guidelines for breast cancer on February 7, 2023, for the treatment of ER-related tumors that have progressed after at least one line of endocrine therapy. + HER2 - This drug is indicated for postmenopausal women or adult men with advanced or metastatic breast cancer who have ESR1 mutations. It is the first oral SERD approved by the FDA. Previously, fulvestrant was the only approved SERD targeted therapy, but it could only be administered via intramuscular injection. Compared to the injectable form of fulvestrant, allergan offers better treatment convenience and patient compliance.

[0004]

[0005] Eisai Corporation's patent WO2004058682A1 first disclosed the synthetic method of Elacestrant (route 1). Starting with 6-methoxy-3,4-dihydronaphthyl-1(2H)-one (1), the product undergoes demethoxylation, benzyl protection, and then reacts with bromine to convert it into an alkenyl brominated intermediate (3). Under the co-catalysis of triphenylphosphine palladium chloride and copper, intermediate (3) undergoes a coupling reaction with 4-bromo-3-nitrobenzene ether (4) to obtain intermediate (5). Under palladium carbon hydrogenation conditions, the nitro group and double bond of intermediate (5) are reduced while simultaneously debenzylated to obtain... The process proceeds to intermediate (6), which is then acetylated with amino groups and reduced with lithium aluminum hydride to obtain intermediate (8). The phenolic hydroxyl group of intermediate (8) is selectively protected with a pivaloyl group and then resolved by chiral column chromatography to obtain intermediate (10). Intermediate (10) undergoes a reductive amination reaction with p-formylphenylacetic acid (11) to obtain intermediate (12). Intermediate (12) is condensed with ethylamine to obtain intermediate (13). Finally, intermediate 13 is reduced to an amine with lithium aluminum hydride, and the pivaloyl protecting group is also reduced and removed, thus yielding the target compound Elacestrant (I). This synthetic route involves 11 chemical reactions, with the target configuration intermediate obtained through chemical resolution in step 8. The synthetic route is complex.

[0006]

[0007] Patent CN 202080011109.9 improved upon the original patent (route 2), converting intermediate 3 into boric acid to 14, and then coupling it with 4-bromo-3-acetaminophen (15) via Suzuki coupling to obtain compound 16. After palladium carbon hydrogenation and deacetylation, compound 16 is obtained. After hydrolysis and deacetylation of compound 17, chiral intermediate 19 is obtained by chemical resolution. Intermediate 19 is reductively amination with N-ethyl-2-(4-formylphenyl)acetamide (20) to obtain compound 22. Finally, sodium borohydride-iodine is used to reduce the amide of compound 22 to an amine to obtain the target compound Elacestrant (I). The main differences compared to the previous patent process are: 1) 4-bromo-3-acetamidoanisole (15) is used instead of 4-bromo-3-nitrobenzyl ether (15) for coupling reaction, which is equivalent to extending the reaction by one step; 2) The exposed phenolic hydroxyl group after debenzylation protection is not reprotected, reducing the reaction by one step; 3) The carboxyl group of intermediate 11 is first subjected to amidation reaction with ethylamine to obtain N-ethyl-2-(4-formylphenyl)acetamide (20), and then reduced amination and hydrogenation are performed; 4) In the final step, the sodium borohydride-iodine system is used instead of lithium aluminum hydride to reduce the amide bond, which is safer in reaction operation and has lower reagent costs. However, due to the presence of tetrahydronaphthol fragments in the molecule that are prone to halogenation, the final reduction step using the sodium borohydride-iodine system has problems such as serious side reactions, difficult product purification, and low yield. In addition, the synthesis of intermediate 20 (route 3, CN117049977 A) also has many problems. This intermediate is prepared from p-tolueneacetic acid via a five-step reaction involving NBS bromination, hydrolysis, esterification, amino-ester exchange, and oxidation. However, it suffers from low yield, uncontrollable side reactions, and significant challenges in product quality control. For example: 1) In step 20-2, the methyl group of compound 20-1 is brominated via NBS, resulting in side reactions such as the methyl group being replaced by dibromide and the methylene group of the phenylacetamide moiety being more easily brominated; 2) In step 20, the oxidation of benzyl alcohol intermediate 20-5 to aldehyde intermediate 20 results in low yield and the intermediate is prone to over-oxidation into an acid.

[0008]

[0009] The disclosed methods for synthesizing elacestrant all have certain shortcomings that hinder industrial production. It is necessary to develop new preparation methods that are simple to operate, low in cost, high in purity, and high in yield. Summary of the Invention

[0010] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies in the preparation of elastoline, such as complex processes, low purity, and low yield. Through our research, we have proposed a method for synthesizing tetrahydronaphthalene derivatives and their intermediates. This invention features good reaction selectivity, mild and easily controllable reaction conditions, high reaction yield, and good product purity. Furthermore, the materials used in this invention are readily available, and the reaction operation is simple, demonstrating promising application prospects and value.

[0011] The present invention provides a method for synthesizing compound I, which includes the following steps: in a solvent, in the presence of an acid and a palladium catalyst, compound II undergoes a hydroxyl reduction reaction under reducing agent conditions to obtain compound I;

[0012]

[0013] Wherein, R is hydrogen, triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), p-methoxybenzyl (PMB), or methoxymethylene (MOM).

[0014] In one particular scheme, R stands for methoxymethylene.

[0015] In one embodiment, compound II is

[0016] In one embodiment, the solvent is an organic solvent, preferably an alcohol solvent, an ether solvent, a benzene solvent, or a haloalkane solvent; the alcohol solvent may be methanol, ethanol, n-propanol, n-butanol, or isopropanol; the ether solvent may be diethyl ether, tetrahydrofuran, isopropyl ether, or methyl tert-butyl ether, preferably tetrahydrofuran; the benzene solvent may be toluene, xylene, or N,N-dimethylaniline; the haloalkane solvent may be dichloromethane or 1,2-dichloroethane; preferably, the organic solvent is an ether solvent.

[0017] In one embodiment, the reducing agent is hydrogen.

[0018] In one embodiment, the acid is hydrochloric acid; preferably, it is 2M dilute hydrochloric acid.

[0019] In one embodiment, the palladium catalyst is divalent palladium, preferably palladium chloride.

[0020] The molar ratio of compound II to the palladium catalyst is a conventional molar ratio for such reactions in the art, preferably 1:(0.01-0.1), more preferably 1:0.05.

[0021] The mass-to-volume ratio of compound II to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05 g / mL to 0.15 g / mL, more preferably 0.11 g / mL.

[0022] The reaction time for the hydroxyl reduction reaction is the conventional reaction time for such reactions in the art, preferably 2-8 hours; more preferably 5 hours.

[0023] The reaction temperature for the hydroxyl reduction reaction is the conventional reaction temperature for such reactions in the art, preferably 10°C-45°C; more preferably room temperature.

[0024] In one embodiment, the hydroxyl reduction reaction further includes the following post-processing steps: filtration, concentration (e.g., vacuum concentration), and silica gel chromatography purification to obtain compound I.

[0025] In one embodiment, the reactants for the hydroxyl reduction reaction are the solvent, the palladium catalyst, the reducing agent, and compound II.

[0026] In one embodiment, the method for synthesizing compound I further includes a method for synthesizing compound II, wherein the synthesis of compound II comprises the following steps: in a solvent, compound III undergoes a ring-opening reaction with compound a to obtain compound II;

[0027]

[0028] Wherein, R is as described in any embodiment of the present invention; compound a is ethylamine hydrochloride or ethylamine organic solution; the ethylamine organic solution may be ethylamine methanol solution, ethylamine ethanol solution or ethylamine tetrahydrofuran solution, preferably ethylamine ethanol solution, more preferably 30% wt (wt is mass fraction, 30% wt means 100g of mixture contains 30g of ethylamine) ethylamine ethanol solution.

[0029] In one embodiment, compound III is

[0030] In one embodiment, compound II is

[0031] In one embodiment, in the ring-opening reaction, the solvent is an alcohol solvent, an ether solvent, or a sulfur-containing organic solvent; the alcohol solvent may be ethanol, n-butanol, or methanol, preferably ethanol; the ether solvent may be tetrahydrofuran or dimethyl sulfoxide; more preferably, the solvent is an alcohol solvent.

[0032] In the ring-opening reaction, the molar ratio of compound III to compound a is a conventional molar ratio for such reactions in the art, preferably 1:2 to 1:5, and more preferably 1:3.

[0033] In the ring-opening reaction, the mass-to-volume ratio of compound III to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.08 g / mL to 0.12 g / mL, and more preferably 0.1 g / mL.

[0034] The reaction time for the ring-opening reaction is the conventional reaction time for such reactions in the art, preferably 2-5 hours, and more preferably 3 hours.

[0035] The reaction temperature of the ring-opening reaction is the conventional reaction temperature for such reactions in the art, preferably 10℃-45℃; more preferably room temperature.

[0036] In one embodiment, the ring-opening reaction further includes the following post-processing steps: concentration and silica gel chromatography purification to obtain target compound II.

[0037] In one embodiment, the reactants for the ring-opening reaction are the solvent, compound III, and compound a.

[0038] In one embodiment, the method for synthesizing compound II further includes a method for synthesizing compound III, wherein the method for synthesizing compound III comprises the following steps: in a solvent and in the presence of a base, a methylene transfer reagent undergoes a cyclization reaction with compound IV to obtain compound III;

[0039]

[0040] Wherein, R is defined as described in any embodiment of the present invention.

[0041] In one embodiment, compound IV is...

[0042] In one embodiment, compound III is

[0043] In one embodiment, the base in the cyclization reaction is an organic base, preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium bis(trimethylsilylamino)amine, sodium bis(trimethylsilylamino)amine, potassium bis(trimethylsilylamino)amine, lithium diisopropylamino, sodium hydride, or potassium hydride, preferably potassium tert-butoxide.

[0044] In one embodiment, during the cyclization reaction, the solvent is an organic solvent, preferably an ether solvent or a sulfur-containing organic solvent. The ether solvent may be tetrahydrofuran or dioxane; the sulfur-containing organic solvent may be dimethyl sulfoxide, preferably anhydrous dimethyl sulfoxide; more preferably, the organic solvent is a sulfur-containing organic solvent.

[0045] In one embodiment, the methylene transfer reagent in the cyclization reaction is an iodomethyl-containing methylene reagent; preferably, trimethylstrontium iodide.

[0046] In the cyclization reaction, the molar ratio of compound IV to the base is a conventional molar ratio for such reactions in the art, preferably 1:(1.1-1.6); more preferably 1:1.2.

[0047] In the cyclization reaction, the mass-to-volume ratio of compound IV to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05-0.1 g / mL; more preferably 0.06 g / mL.

[0048] In one embodiment, the molar ratio of compound IV to the methylene transfer reagent in the cyclization reaction is a conventional molar ratio for such reactions in the art, preferably 1:(1-1.6); more preferably 1:1.1.

[0049] The reaction time for the cyclization reaction is the conventional reaction time for such reactions in the art, preferably 2-6 hours, and more preferably 4 hours.

[0050] The cyclization reaction is carried out at a temperature that is conventional for such reactions in the art, preferably 0-60°C, and more preferably 50°C.

[0051] In one embodiment, the cyclization reaction further includes the following post-processing steps: cooling, quenching (e.g., aqueous solution), extraction (e.g., ethyl acetate), combining organic phases, drying with anhydrous sodium sulfate, concentration (e.g., vacuum concentration), and purification by silica gel chromatography to obtain compound III.

[0052] In one embodiment, the reactants for the cyclization reaction are the solvent, the base, the methylene transfer reagent, and compound IV.

[0053] In one embodiment, the method for synthesizing compound III further includes a method for synthesizing compound IV, wherein the method for synthesizing compound IV comprises the following steps: in a solvent and in the presence of a base, compound V and 4-bromomethylbenzaldehyde undergo an alkylation reaction to obtain compound IV;

[0054]

[0055] Wherein, R is defined as described in any embodiment of the present invention.

[0056] In one embodiment, compound V is...

[0057] In one embodiment, compound IV is...

[0058] In one embodiment, during the alkylation reaction, the base is an inorganic or organic base. The inorganic base may be potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide, preferably potassium carbonate. The organic base may be sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium bis(trimethylsilylamino), sodium bis(trimethylsilylamino), potassium bis(trimethylsilylamino), lithium diisopropylamino, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, or triethylenediamine. Preferably, the base is an inorganic base.

[0059] In one embodiment, during the alkylation reaction, the solvent is an organic solvent, which may be a halogenated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent, a sulfur-containing organic solvent, or a benzene solvent; the halogenated hydrocarbon solvent may be dichloromethane; the nitrile solvent may be acetonitrile; the ether solvent may be tetrahydrofuran or dioxane; the amide solvent may be N,N-dimethylformamide; the sulfur-containing organic solvent may be dimethyl sulfoxide; and the benzene solvent may be toluene; preferably, the organic solvent is a nitrile solvent.

[0060] In the alkylation reaction, the molar ratio of compound V to 4-bromomethylbenzaldehyde is a conventional molar ratio for such reactions in the art, preferably 1:(0.8-1:2), and more preferably 1:1.

[0061] In the alkylation reaction, the molar ratio of compound V to the base is a conventional molar ratio for such reactions in the art, preferably 1:(1.5-2.5), and more preferably 1:2.

[0062] In the alkylation reaction, the mass-to-volume ratio of compound V to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05 g / ml to 0.15 g / ml, and more preferably 0.085 g / ml.

[0063] In the alkylation reaction, the reaction time is the conventional reaction time for such reactions in the art, preferably 12h-36h, and more preferably 24h.

[0064] In the alkylation reaction, the reaction temperature is the conventional reaction temperature for such reactions in the art, preferably 10°C-45°C, and more preferably room temperature.

[0065] In one embodiment, the alkylation reaction comprises the following post-processing steps: evaporation (e.g., evaporation under vacuum), dissolution (e.g., dissolution with dichloromethane), washing (e.g., washing with water and saturated brine), drying (e.g., drying with anhydrous sodium sulfate), filtration, removal of solvent under vacuum, and purification by silica gel chromatography to obtain compound IV.

[0066] In one embodiment, the reactants for the alkylation reaction are the solvent, the base, compound V, and 4-bromomethylbenzaldehyde.

[0067] In one embodiment, the method for synthesizing compound IV further includes a method for synthesizing compound V, wherein the synthesis of compound V includes the following steps: in a solvent, in the presence of an acid and a reducing agent, compound V-5 undergoes a condensation reaction with acetaldehyde to obtain compound V;

[0068]

[0069] Wherein, R is defined as described in any embodiment of the present invention.

[0070] In one embodiment, compound V-5 is...

[0071] In one embodiment, compound V is...

[0072] In one embodiment, the acid in the condensation reaction is an organic acid; preferably acetic acid.

[0073] In one embodiment, the solvent in the condensation reaction is an organic solvent; preferably an ether solvent; more preferably tetrahydrofuran.

[0074] In one embodiment, the reducing agent in the condensation reaction is sodium borohydride triacetate.

[0075] In the condensation reaction, the molar ratio of compound V-5 to acetaldehyde is a conventional molar ratio for such reactions in the art; preferably 1:(0.8-1.2); more preferably 1:1.

[0076] In the condensation reaction, the molar ratio of compound V-5 to the acid is a conventional molar ratio for such reactions in the art; preferably 1:(0.8-1.2); more preferably 1:1.

[0077] In the condensation reaction, the mass-to-volume ratio of compound V-5 to the solvent is a conventional mass-to-volume ratio for such reactions in the art; preferably 0.03 g / ml to 0.08 g / ml; more preferably 0.05 g / ml.

[0078] In the condensation reaction, the molar ratio of compound V-5 to the reducing agent is a conventional molar ratio for such reactions in the art; preferably 1:(1.5-2.5); more preferably 1:2.

[0079] In the condensation reaction, the reaction time is the conventional reaction time for such reactions in the art; preferably 4h-8h; more preferably 6h.

[0080] In the condensation reaction, the reaction temperature is the conventional reaction temperature for such reactions in the art; preferably 10℃-45℃; more preferably room temperature.

[0081] In one embodiment, the condensation reaction further comprises the following post-processing steps: quenching (e.g., quenching with a saturated sodium bicarbonate solution), extraction (e.g., extraction with ethyl acetate), drying (e.g., drying with anhydrous magnesium sulfate), filtration, concentration (e.g., vacuum concentration), and silica gel chromatography purification to obtain compound V.

[0082] In one embodiment, the reactants for the condensation reaction are the solvent, the acid, the reducing agent, the compound V-5, and the acetaldehyde.

[0083] In one embodiment, the method for synthesizing compound V further includes a method for synthesizing compound V-5, wherein the synthesis of compound V-5 includes the following steps: in a solvent, in the presence of a catalyst and a reducing agent, compound V-4 undergoes a reduction reaction to obtain compound V-5;

[0084]

[0085] Wherein, R is defined as described in any embodiment of the present invention.

[0086] In one embodiment, compound V-4 is...

[0087] In one embodiment, compound V-5 is...

[0088] In one embodiment, the catalyst used in the synthesis of compound V-5 is a supported catalyst; preferably a palladium-on-carbon catalyst, more preferably 10% wt palladium-on-carbon.

[0089] In one embodiment, the solvent used in the synthesis of compound V-5 is an organic solvent; preferably an alcohol solvent; more preferably ethanol.

[0090] In one embodiment, the reducing agent in the synthesis of compound V-5 is hydrogen.

[0091] In the synthesis method of compound V-5, the molar ratio of compound V-4 to the catalyst is a conventional molar ratio for such reactions in the art; preferably 1:(0.02-0.06); more preferably 1:0.05.

[0092] In the synthesis method of compound V-5, the mass-to-volume ratio of compound V-4 to the solvent is a conventional mass-to-volume ratio for such reactions in the art; preferably 0.05 g / ml to 0.08 g / ml; more preferably 0.075 g / ml.

[0093] In the method for synthesizing compound V-5, the reaction time is the conventional reaction time for such reactions in the art; preferably 4h-8h; more preferably 5h.

[0094] In the synthesis method of compound V-5, the reaction temperature is the conventional reaction temperature for such reactions in the art; preferably 10℃-45℃; more preferably 25℃.

[0095] In one embodiment, the synthesis of compound V-5 further includes the following post-processing steps: filtration (e.g., diatomaceous earth filtration) and concentration (e.g., vacuum concentration) to obtain compound V-5.

[0096] In one embodiment, the reaction materials for the synthesis of compound V-5 are the solvent, the catalyst, the reducing agent, and compound V-4.

[0097] In one embodiment, the method for synthesizing compound V-5 further includes a method for synthesizing compound V-4, wherein the synthesis of compound V-4 includes the following steps: under the conditions of solvent, ligand, catalyst and base, compound V-3 undergoes a coupling reaction with 1-bromo-4-methoxy-2-nitrobenzene to obtain compound V-4.

[0098]

[0099] Wherein, R is defined as described in any embodiment of the present invention.

[0100] In one embodiment, compound V-3 is...

[0101] In one embodiment, compound V-4 is...

[0102] In one embodiment, the base in the coupling reaction is an inorganic base; preferably potassium carbonate.

[0103] In one embodiment, the ligand in the coupling reaction is a monophosphine ligand; preferably tricyclohexylphosphine.

[0104] In one embodiment, the catalyst in the coupling reaction is a palladium catalyst; preferably divalent palladium; more preferably palladium acetate.

[0105] In one embodiment, the solvent in the coupling reaction is a mixture of an organic solvent and water; the organic solvent may be an ether solvent; preferably dioxane.

[0106] In the coupling reaction, the molar ratio of compound V-3 to 1-bromo-4-methoxy-2-nitrobenzene is a conventional molar ratio for such reactions in the art; preferably 1:(0.8-1.2); more preferably 1:1.

[0107] In the coupling reaction, the molar ratio of compound V-3 to the base is a conventional molar ratio for such reactions in the art; preferably 1:(1-3); more preferably 1:2.

[0108] In the coupling reaction, the molar ratio of compound V-3 to the monophosphine ligand is a conventional molar ratio for such reactions in the art; preferably 1:(0.05-0.2); more preferably 1:0.1.

[0109] In the coupling reaction, the molar ratio of compound V-3 to the catalyst is a conventional molar ratio for such reactions in the art; preferably 1:(0.02-0.01); more preferably 1:0.05.

[0110] In the coupling reaction, the mass-to-volume ratio of compound V-3 to the solvent is a conventional mass-to-volume ratio for such reactions in the art; preferably 0.05 g / ml to 0.1 g / ml; more preferably 0.09 g / ml.

[0111] In the coupling reaction, the reaction time is the conventional reaction time for such reactions in the art; preferably 1h-3h; more preferably 1.5h.

[0112] In the coupling reaction, the reaction temperature is the conventional reaction temperature for such reactions in the art, preferably 80℃-120℃; more preferably 100℃.

[0113] In one embodiment, the coupling reaction comprises the following post-processing steps: cooling, dilution (e.g., dilution with a saturated sodium bicarbonate solution), extraction (e.g., extraction with ethyl acetate), drying (e.g., drying with anhydrous sodium sulfate), concentration (e.g., concentration under reduced pressure), and silica gel chromatography purification to obtain compound V-4.

[0114] In one embodiment, the reaction raw materials for the coupling reaction are the solvent, the ligand, the catalyst, the base, the compound V-3, and the 1-bromo-4-methoxy-2-nitrobenzene.

[0115] In one embodiment, the synthesis method of compound V-4 further includes a method for synthesizing compound V-3, wherein the method for synthesizing compound V-3 comprises the following steps: in the presence of a catalyst, a ligand, a base, and a solvent, compound V-2 reacts with B2Pin2 to obtain compound V-3.

[0116]

[0117] Wherein, R is defined as described in any embodiment of the present invention.

[0118] In one embodiment, compound V-2 is...

[0119] In one embodiment, compound V-3 is...

[0120] In one embodiment, the catalyst used in the synthesis of compound V-3 is a transition metal catalyst, preferably a transition metal halide, which may be cuprous chloride and / or cobalt bromide.

[0121] In one embodiment, the ligand in the synthesis of compound V-3 is a phosphine ligand; preferably (S,S)-Ph-BPE, (S,S)-Meferrocelane, (S,S)-Et-ferrocelane, (R,R)-Me-Duphos, or (R,R)-QuinoxP**, for example, (S,S)-Ph-BPE or (R,R)-QuinoxP**.

[0122] In one embodiment, the base used in the synthesis of compound V-3 is an organic or inorganic base; the organic base is preferably potassium methoxide; and the inorganic base is preferably cesium carbonate.

[0123] In one embodiment, the solvent used in the synthesis of compound V-3 is an organic solvent; preferably an ether solvent or an alcohol solvent; the ether solvent may be tetrahydrofuran; and the alcohol solvent may be methanol or tert-butanol.

[0124] In the synthesis method of compound V-3, the molar ratio of compound V-2 to the catalyst is a conventional molar ratio for such reactions in the art; preferably 1:(0.01-0.15); more preferably 1:0.05 or 1:0.1.

[0125] In the synthesis method of compound V-3, the molar ratio of compound V-2 to the ligand is a conventional molar ratio for such reactions in the art; preferably 1:(0.01-0.15); more preferably 1:0.05 or 1:0.1.

[0126] In the method for synthesizing compound V-3, the molar ratio of compound V-2 to the base is a conventional molar ratio for such reactions in the art; preferably 1:(0.1-1.2); more preferably 1:0.2 or 1:1.

[0127] In the synthesis method of compound V-3, the mass-to-volume ratio of compound V-2 to the solvent is a conventional mass-to-volume ratio for such reactions in the art; preferably 0.05-0.12 g / mL; more preferably 0.06 g / mL or 0.11 g / mL.

[0128] In the synthesis method of compound V-3, the volume ratio of the ether solvent to the alcohol solvent is the conventional volume ratio for such reactions in the art; preferably (6-40):1; more preferably 8:1 or 37.6:1.

[0129] In the synthesis method of compound V-3, the reaction time is the conventional reaction time for such reactions in the art; preferably 2-60 h; more preferably 4 h or 48 h.

[0130] In the synthesis method of compound V-3, the reaction temperature is the conventional reaction temperature for such reactions in the art; preferably 0-40°C; more preferably 0°C or 20°C.

[0131] In one embodiment, the synthesis of compound V-3 further includes any of the following post-processing steps:

[0132] ① Pour into ice water, extract (e.g., with ethyl acetate), combine the organic phases, wash (e.g., with saturated sodium carbonate aqueous solution, water and saturated brine), dry (e.g., with anhydrous sodium sulfate), and purify the residue by silica gel chromatography to obtain compound V-3;

[0133] ② Filtration (e.g., filtration with a thin silica gel layer), washing (e.g., washing with dichloromethane), concentration, and purification of the residue by silica gel chromatography to obtain compound V-3.

[0134] In one embodiment, the reaction materials for the synthesis of compound V-3 are the catalyst, the ligand, the base, the solvent, compound V-2, and B2Pin2.

[0135] The present invention provides a method for synthesizing compound II, comprising the following steps: in a solvent and in the presence of a base, compound III undergoes a ring-opening reaction to obtain compound II;

[0136] The definition of R is as described in any embodiment of the present invention.

[0137] In one embodiment, the operation and conditions of the synthesis method of compound II, compound III, and compound II are as described in any embodiment of the present invention.

[0138] The present invention provides a method for synthesizing compound III, comprising the following steps: in a solvent and in the presence of a base, trimethylstrontium iodide undergoes a cyclization reaction with compound IV to obtain compound III;

[0139]

[0140] Wherein, R is defined as described in any embodiment of the present invention.

[0141] In one embodiment, the operation and conditions of the synthesis method of compound III, compound IV, and compound III are as described in any embodiment of the present invention.

[0142] The present invention provides a method for synthesizing compound IV, comprising the following steps: in a solvent and in the presence of a base, compound V and 4-bromomethylbenzaldehyde undergo an alkylation reaction to obtain compound IV;

[0143]

[0144] Wherein, R is defined as described in any embodiment of the present invention.

[0145] In one embodiment, the operation and conditions of the synthesis method of compound IV, compound V, and compound IV are as described in any embodiment of the present invention.

[0146] The present invention provides a method for synthesizing compound V, which includes the following steps: in a solvent, in the presence of an acid and a reducing agent, compound V-5 undergoes a condensation reaction with acetaldehyde to obtain compound V;

[0147]

[0148] Wherein, R is defined as described in any embodiment of the present invention.

[0149] In one embodiment, the operation and conditions of the synthesis method of compound V, compound V-5, and compound V are as described in any embodiment of the present invention.

[0150] The present invention provides a method for synthesizing compound V-5, which includes the following steps: in a solvent, in the presence of a catalyst and a reducing agent, compound V-4 undergoes a reduction reaction to obtain compound V-5;

[0151]

[0152] Wherein, R is defined as described in any embodiment of the present invention.

[0153] In one embodiment, the operation and conditions of the synthesis method of compound V-5, compound V-4, and compound V-5 are as described in any embodiment of the present invention.

[0154] The present invention provides a method for synthesizing compound V-4, which includes the following steps: under the conditions of a monophosphine ligand, a catalyst and a base, compound V-3 undergoes a coupling reaction with 1-bromo-4-methoxy-2-nitrobenzene to obtain compound V-4;

[0155]

[0156] Wherein, R is defined as described in any embodiment of the present invention.

[0157] In one embodiment, the operation and conditions of the synthesis method of compound V-4, compound V-3, and compound V-4 are as described in any embodiment of the present invention.

[0158] This invention provides a method for synthesizing compound I, which includes the following steps:

[0159] Compound V undergoes an alkylation reaction with 4-bromomethylbenzaldehyde to prepare compound IV;

[0160] The methylene transfer reagent undergoes a cyclization reaction with compound IV to prepare compound III; compound III undergoes a ring-opening reaction to prepare compound II;

[0161] Compound II undergoes a hydroxyl reduction reaction to yield compound I;

[0162]

[0163] Wherein, R is defined as described in any embodiment of the present invention; for example...

[0164]

[0165] In one embodiment, the operation and conditions of the synthetic methods for alkylation, cyclization, ring-opening, and hydroxyl reduction are as described in any embodiment of the present invention.

[0166] In one embodiment, the synthesis of compound I further includes the synthesis of compound V.

[0167] Compound V-3 was coupled with 1-bromo-4-methoxy-2-nitrobenzene to prepare compound V-4;

[0168] Compound V-4 underwent a reduction reaction to prepare compound V-5;

[0169] Compound V-5 undergoes a condensation reaction with acetaldehyde to prepare compound V;

[0170]

[0171] Wherein, R is defined as described in any embodiment of the present invention; for example...

[0172]

[0173] In one embodiment, the operation and conditions of the synthesis methods for the coupling reaction, reduction reaction, and condensation reaction are as described in any embodiment of the present invention.

[0174] This invention provides a compound having any of the following structures:

[0175]

[0176] Wherein, R is triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), p-methoxybenzyl (PMB) or methoxymethylene (MOM); preferably methoxymethylene;

[0177] Better place,

[0178]

[0179] The compound is

[0180] The room temperature described in this invention is 25-35℃.

[0181] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0182] The reagents and raw materials used in this invention are all commercially available.

[0183] The positive and progressive effects of this invention are as follows: This invention provides a method for synthesizing compound I. The preparation method of this invention has one or more of the following advantages: (1) good reaction selectivity, (2) mild and easy-to-control reaction, (3) high reaction yield, (4) good product purity, and (5) the materials of this invention are easy to obtain, the reaction operation is simple, and it has good application prospects and value. Detailed Implementation

[0184] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0185] Example 1: Synthesis of 2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (V-3)

[0186] Step 1: 7,8-Dihydronaphth-2-ol (V-1)

[0187] 100.0 g (616.57 mmol) of 6-hydroxy-3,43-dihydronaphthyl-1(2H)-one was dissolved in 800 mL of methanol and cooled to 0 °C. Sodium borohydride (NaBH4, 46.65 g, 1.23 mol) was added in portions, and the mixture was stirred at 0 °C for 2 hours until complete. The reaction was quenched with water, concentrated to dryness under reduced pressure, and the residue was redissolved in toluene (850 mL). 5.31 g (30.83 mmol) of p-toluenesulfonic acid was added, and the mixture was refluxed under nitrogen protection for about 1 hour. The mixture was cooled to room temperature, and the reaction mixture was washed with saturated sodium bicarbonate (NaHCO3) solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate (Na2SO4). The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound V-1 (79.63 g, yield 87.1%, purity 98.6%). MS(ESI,m / z):147[M+H] + .

[0188] Step 2: 7-(methoxymethoxy)-1,2-dihydronaphthalene (V-2)

[0189] Under nitrogen protection, compound V-1 (60.0 g, 410.43 mmol) and diisopropylethylamine (106.1 g, 820.86 mmol) were dissolved in N,N-dimethylformamide (500 mL) solution, followed by dropwise addition of a tetrahydrofuran (100 mL) solution of bromo(methoxy)methane (MOMBr, 56.42 g, 451.47 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was poured into ice water (800 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium carbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound V-2 (75.38 g, yield 95.9%, purity 99.3%). MS (ESI, m / z): 191 [M+H] + .1H NMR(400MHz,DMSO-d6)δ6.96(d,1H),6.79(d,2H),6.42(dt,1H),5.90(dt,1H),5.16(s,2H),3.37(s,3H),2.69(t,2H),2.21(tdd,2H).

[0190] Step 3: (R)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (V-3)

[0191] In a dry round-bottom flask, cuprous chloride (CuCl, 390 mg, 3.94 mmol), cobalt bromide (CoBr2, 862 mg, 3.94 mmol), and 1,2-bis(2S,5S-2,5-diphenylphosphono)ethane ((S,S)-Ph-BPE, 3.99 g, 7.88 mmol) were dissolved in THF (120 mL), purged three times with nitrogen, and stirred for 30 minutes. Then, cesium carbonate (Cs2C) was added. O3 (25.69 g, 78.85 mmol), 4,4,4',4',5,5,5',5'-octylmethyl-2,2'-bi(1,3,2-dioxaborhexane) (B2Pin2, 30.0 g, 118.27 mmol), compound V-2 (15.0 g, 78.85 mmol), and tert-butanol (15.0 mL, 157.69 mmol) were reacted at 20 °C under nitrogen protection for 48 hours with stirring. After the reaction was complete, the solution was filtered through a thin silica gel layer by TLC monitoring. The mixture was washed with dichloromethane (100 mL x 2). The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography to give the target compound V-3 (23.57 g, yield 91.7%, purity 97.6%). MS (ESI, m / z): 319 (M+H) + .1H NMR(400MHz,DMSO-d6)δ6.94(d,1H),6.74-6.65(m,2H),5.10(s,2H),3.34(s ,3H),2.74-2.52(m,4H),1.90-1.81(m,1H),1.57-1.45(m,1H),1.18(d,13H).

[0192] Example 2: Synthesis of (R)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (V-3)

[0193]

[0194] Cuprous chloride (130 mg, 1.31 mmol), potassium methoxide (368 mg, 5.26 mmol), and (R,R)-(-)-2,3-bis(T-tert-butylmethylphosphine)quinoxaline ((R,R)-QuinoxP**, 439 mg, 1.31 mmol) were dissolved in tetrahydrofuran (80 mL). Then, 4,4,4',4',5,5,5',5'-octylmethyl-2,2'-biphenylbis(1,3,2-dioxaborhecylbutane) (8.1 g, 31.54 mmol) was added at 0 °C, and the reaction mixture was stirred for 15 minutes under a nitrogen atmosphere. Compound V-2 (5.0 g, 26.28 mmol) was then added in portions to the mixture, and the reaction was carried out at 0 °C for 2 hours. Methanol (1.68 g, 2.13 mL, 52.56 mmol) was then added dropwise at 0 °C, and the reaction was carried out for 2 hours. Thin-layer chromatography (TLC) showed complete consumption of the starting material. The reaction mixture was added to water and extracted with dichloromethane. The combined organic phases were washed with water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target compound V-3 (7.68 g, yield 90.2%, purity 98.62%). MS (ESI, m / z): 319 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ6.96(d,1H),6.76-6.67(m,2H),5.11(s,2H),3.35(s ,3H),2.74-2.52(m,4H),1.92-1.83(m,1H),1.59-1.48(m,1H),1.14(d,13H).

[0195] Example 3: Synthesis of (R)-N-ethyl-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (V)

[0196] Step 1: (R)-2-(4-methoxy-2-nitrophenyl)-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalene (V-4)

[0197] Compound V-3 (20.0 g, 62.85 mmol), 1-bromo-4-methoxy-2-nitrobenzene (14.6 g, 62.85 mmol), palladium acetate (706 mg, 3.14 mmol), tricyclohexylphosphine (1.8 g, 6.28 mmol), and potassium carbonate (17.4 g, 125.70 mmol) were added to a mixture of dioxane (200 mL) and water (20 mL). The mixture was stirred under nitrogen protection for 5 minutes, and then stirred at 100 °C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate (EtOAc). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound V-4 (18.62 g, yield 83.9%, purity 97.2%). MS (ESI, m / z): 344 (M+H) + .

[0198] Step 2: (R)-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (V-5)

[0199] Compound V-4 (15.0 g, 43.68 mmol) and palladium on carbon (2.32 g, 2.18 mmol, 10% wt) were added to ethanol (200 mL). The mixture was stirred at 25 °C for 5 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound V-5 (13.35 g, yield 96.3%, purity 98.8%). MS (ESI, m / z): 314 (M+H) + .

[0200] Step 3: (R)-N-ethyl-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (V)

[0201] A tetrahydrofuran solution of acetaldehyde (16 mL, 31.91 mmol, 2 M), compound V-5 (10.0 g, 31.91 mmol), and acetic acid (1.92 g, 31.91 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 13.5 g, 63.82 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (300 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound V (9.63 g, yield 86.7%, purity 98.1%). MS (ESI, m / z): 342 (M+H)+ ; 1 H NMR(400MHz,Chloroform-d)δ7.03(dd,2H),6.83(dd,2H),6.30-6.23(m,2H),5.16(s,2H),3.80(s,3H),3.64(d,1 H),3.49(s,3H),3.17(qd,2H),3.04-2.92(m,3H),2.76(s,2H),2.13-2.03(m,1H),2.03-1.87(m,1H),1.27(t,3H).

[0202] Example 4: Synthesis of 4-((ethyl(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)benzaldehyde (IV)

[0203]

[0204] Compound V (8.5 g, 24.89 mmol) was dissolved in acetonitrile (75 mL), and potassium carbonate (6.88 g, 49.79 mmol) was added. The mixture was stirred for 10 minutes. 4-Bromomethylbenzaldehyde (4.96 g, 24.89 mmol) was dissolved in acetonitrile (25 mL) and added to the reaction mixture in one step. The mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under vacuum, and the residue was dissolved in dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography to give compound IV (10.83 g, yield 93.2%, purity 98.5%). MS (ESI, m / z): 460 (M+H) + ; 1 H NMR(400MHz,Chloroform-d)δ9.96(s,1H),7.79-7.72(m,2H),7.43(d 2H),7.15(d,1H),6.96(d,1H),6.83(d,2H),6.78(d,1H),6.70(dd,1H),5.17(s,2H),4.11(s,2H),3.79( s,3H),3.71-3.61(m,1H),3.50(s,3H),2.98-2.87(m,4H),2.72(d,2H),1.82-1.71(m,2H),0.98(t,3H).

[0205] Example 5: Synthesis of 1-(4-((ethyl(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenyl)-2-(ethylamino)ethyl-1-ol(II))

[0206]

[0207] Step 1: N-Ethyl-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)-N-(4-(epoxypropane-2-yl)benzyl)aniline(III)

[0208] Trimethylsulphur iodide (6.1 g, 29.92 mmol) and potassium tert-butoxide (4.0 g, 35.36 mmol) were dissolved in anhydrous dimethyl sulfoxide (100 mL) and stirred at room temperature for 30 minutes. Then, compound IV (12.5 g, 27.20 mmol) was added, and the reaction was carried out at 50 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give target compound III (11.53 g, yield 87.1%, purity 97.3%). MS (ESI, m / z): 474 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ7.23(dd,2H),7.17-7.11(m,3H),6.97(d,1H),6.82(d,2H),6.78(d,1H),6.69(dd,1H),5.17(s,2H),4.01(s,2H),3. 82(dd,1H),3.79(s,3H),3.72-3.62(m,1H),3.50(s,3H),3.13(dd,1H),2 .95-2.86(m,4H),2.79(ddd,1H),2.72(d,2H),1.76(td,2H),0.94(t,3H).

[0209] Step 2: 1-(4-((ethyl(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenyl)-2-(ethylamino)ethyl-1-ol(II)

[0210] Compound III (10.0 g, 21.11 mmol) was dissolved in ethanol (100 mL), and an ethanol solution of ethylamine (9.5 g, 63.34 mmol, 30% wt) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give title compound II (9.91 g, yield 88.3%, purity 97.6%). MS (ESI, m / z): 519 [M+H] + ;

[0211] Example 6: 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0212]

[0213] Compound II (8.5 g, 16.39 mmol) was dissolved in tetrahydrofuran (80 mL) and 2 M dilute hydrochloric acid (12 mL). Palladium chloride (145 mg, 819.36 μmol) was added, and the mixture was hydrogenated under normal pressure at room temperature with stirring for 5 hours. Sodium bicarbonate was added for neutralization, and the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give target compound I (5.62 g, yield 73.4%, purity 98.2%), MS (ESI, m / z): 459 (M+H). + .

[0214] Preparation of dihydrochloride of compound I: Compound I (5.62 g, 12.25 mmol) was dissolved in ethanol and ethyl acetate, ethanol hydrochloride solution was added, stirred for 1 hour, diluted with ethyl acetate, filtered, and dried to obtain dihydrochloride of compound I (6.5 g, yield 99.0%, purity 99.2%). 1 H NMR(400MHz,Methanol-d4,2HCl)δ8.55(s,1H),7.23(d,2H),7.12(dd,3H),6.83-6.76(m,2H),6.67(dd,1H),6.54(dd,2H),4.00(s,2H),3.75( s,3H),3.63(dtd,1H),3.15(dd,2H),3.03(q,2H),2.92(td,4H),2.82- 2.73(m,2H),2.60(d,2H),1.79-1.57(m,2H),1.28(t,3H),0.94(t,3H).

Claims

1. A process for the synthesis of Compound I, characterized in that, comprising the step of subjecting compound II to a hydroxyl reduction reaction in the presence of an acid and a palladium catalyst in a solvent under the condition of a reducing agent to produce compound I; wherein R is hydrogen, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, p-methoxybenzyl or methoxymethylene.

2. The method of synthesis of Compound I according to claim 1, characterized in that, The method satisfies one or more of the following conditions: (1) R is methoxymethylene; (2) the compound II is (3) the solvent is an organic solvent, preferably an alcohol solvent, an ether solvent, a benzene solvent or a halogenated alkane solvent; the alcohol solvent can be methanol, ethanol, n-propanol, n-butanol or isopropanol; the ether solvent can be diethyl ether, tetrahydrofuran, isopropyl ether or methyl tert-butyl ether, preferably tetrahydrofuran; the benzene solvent can be toluene, xylene or N,N-dimethylaniline; the halogenated alkane solvent can be dichloromethane or 1,2-dichloroethane; preferably, the organic solvent is an ether solvent; (4) the reducing agent is hydrogen; (5) the acid is hydrochloric acid; preferably 2M dilute hydrochloric acid; (6) the palladium catalyst is divalent palladium, preferably palladium chloride; (7) the molar ratio of compound II to the palladium catalyst is 1:(0.01-0.1), preferably 1:0.05; (8) the mass-volume ratio of compound II to the solvent is 0.05 g / mL-0.15 g / mL, preferably 0.11 g / mL; (9) the reaction time of the hydroxyl reduction reaction is 2-8h; preferably 5h; (10) the reaction temperature of the hydroxyl reduction reaction is 10℃-45℃; preferably room temperature; (11) the hydroxyl reduction reaction comprises the following post-treatment steps: filtration, concentration (e.g. concentration under reduced pressure), silica gel chromatography to obtain compound I; and (12) the reaction material of the hydroxyl reduction reaction is the solvent, the palladium catalyst, the reducing agent and the compound II.

3. The method of synthesis of Compound I according to claim 1, characterized in that, The synthesis method of compound I further comprises a synthesis method of compound II, which comprises the step of subjecting compound III to an opening ring reaction with compound a in a solvent to produce compound II; wherein R is as defined in claim 1 or 2; compound a is ethylamine hydrochloride or an ethylamine organic solution; the ethylamine organic solution can be an ethylamine methanol solution, an ethylamine ethanol solution or an ethylamine tetrahydrofuran solution, preferably an ethylamine ethanol solution, more preferably a 30%wt ethylamine ethanol solution; Preferably, the synthesis method of compound II satisfies one or more of the following conditions: (3) in the opening ring reaction, the solvent is an alcohol solvent, an ether solvent or a sulfur-containing organic solvent; the alcohol solvent can be ethanol, n-butanol or methanol, preferably ethanol; the ether solvent can be tetrahydrofuran or dimethyl sulfoxide; preferably, the solvent is an alcohol solvent; (1) the compound III is (2) the compound II is (4) in the opening ring reaction, the molar ratio of compound III to compound a is 1:2-1:5, preferably 1:3; (5) in the opening ring reaction, the mass-volume ratio of compound III to the solvent is 0.08 g / mL-0.12 g / mL, preferably 0.1 g / mL; ​ (6) the reaction time of the ring-opening reaction is 2-5 h, preferably 3 h; (7) the reaction temperature of the ring-opening reaction is 10-45 °C, preferably room temperature; (8) in the ring-opening reaction, the reaction further comprises the following post-treatment steps: concentration, silica gel chromatography purification to obtain the target compound II; and (9) the reaction material of the ring-opening reaction is the solvent, the compound III and the compound a.

4. The method of synthesis of Compound I according to claim 3, characterized in that, The synthesis method of the compound II further comprises a synthesis method of the compound III, which comprises the following steps: in a solvent, in the presence of a base, a methylene transfer reagent is subjected to a cyclization reaction with a compound IV to prepare the compound III; wherein, the R is as described in claim 1 or 2; Preferably, the synthesis method of the compound III satisfies one or more of the following conditions: (1) the compound IV is (2) said compound III is (3) in the cyclization reaction, the base is an organic base, preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydride or potassium hydride, preferably potassium tert-butoxide; (4) in the cyclization reaction, the solvent is an organic solvent, preferably an ether solvent or a sulfur-containing organic solvent, the ether solvent can be tetrahydrofuran or dioxane; the sulfur-containing organic solvent can be dimethyl sulfoxide, preferably anhydrous dimethyl sulfoxide; preferably, the organic solvent is a sulfur-containing organic solvent; (5) in the cyclization reaction, the methylene transfer reagent is an iodine-containing methylene reagent; preferably trimethylsilyl iodide; (6) the molar ratio of the compound IV to the base is 1:(1.1-1.6); further preferably 1:1.2; (7) the mass-volume ratio of the compound IV to the solvent is 0.05-0.1 g / mL; preferably 0.06 g / mL (8) in the cyclization reaction, the molar ratio of the compound IV to the methylene transfer reagent is 1:(1-1.6); preferably 1:1.1; (9) the reaction time of the cyclization reaction is 2-6 h; preferably 4 h; (10) the reaction temperature of the cyclization reaction is 0-60 °C, further preferably 50 °C; (11) the cyclization reaction further comprises the following post-treatment steps: cooling, quenching, for example, aqueous solution, extraction, for example, ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentration, for example, concentration under reduced pressure, purification by silica gel chromatography to obtain the compound III; and (12) the reaction material of the cyclization reaction is the solvent, the base, the methylene transfer reagent and the compound IV.

5. The method of synthesis of Compound I according to claim 4, characterized in that, The synthesis method of the compound III further comprises a synthesis method of the compound IV, which comprises the following steps: in a solvent, in the presence of a base, an alkylating reaction of a compound V and 4-bromomethylbenzaldehyde to prepare the compound IV; wherein, the R is as described in claim 1 or 2; Preferably, the synthesis method of the compound IV satisfies one or more of the following conditions: (1) the compound V is (2) the compound IV is (3) in the alkylation reaction, the base is an inorganic base or an organic base, the inorganic base can be potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, preferably potassium carbonate; the organic base can be sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene or triethylenediamine; preferably, the base is an inorganic base; (4) in the alkylation reaction, the solvent is an organic solvent, which can be a halogenated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent, a sulfur-containing organic solvent or a benzene solvent; the halogenated hydrocarbon solvent can be dichloromethane; the nitrile solvent can be acetonitrile; the ether solvent can be tetrahydrofuran or dioxane; the amide solvent can be N,N-dimethylformamide; the sulfur-containing organic solvent can be dimethyl sulfoxide; the benzene solvent can be toluene; preferably, the organic solvent is a nitrile solvent; (5) the molar ratio of the compound V to the 4-bromomethylbenzaldehyde is 1:(0.8-1:2); preferably 1:1; (6) the molar ratio of the compound V to the base is 1:(1.5-2.5); preferably 1:2; (7) the mass-volume ratio of the compound V to the solvent is 0.05 g / ml-0.15 g / ml, further preferably 0.085 g / ml; (8) the reaction time of the alkylation reaction is 12 h-36 h, preferably 24 h; (9) the reaction temperature of the alkylation reaction is 10℃-45℃, preferably room temperature; (10) the alkylation reaction comprises the following work-up steps: evaporation, for example, evaporation under vacuum, dissolution, for example, dissolution with dichloromethane, washing, for example, washing with water and saturated brine, drying, for example, drying with anhydrous sodium sulfate, filtration, removal of the solvent under vacuum, and silica gel chromatography to obtain the compound IV; and (11) the raw materials for the alkylation reaction are the solvent, the base, the compound V and the 4-bromomethylbenzaldehyde.

6. The method of synthesis of Compound I according to claim 5, wherein, The synthesis method of the compound IV further comprises a synthesis method of the compound V, which comprises the following steps: in the presence of an acid and a reducing agent, compound V-5 is subjected to a condensation reaction with acetaldehyde in a solvent to prepare the compound V; wherein R is as defined in claim 1 or 2; Preferably, the synthesis method of the compound V satisfies one or more of the following conditions: (1) the compound V-5 is (2) the compound V is (3) in the condensation reaction, the acid is an organic acid; preferably acetic acid; (4) in the condensation reaction, the solvent is an organic solvent; preferably an ether solvent; further preferably tetrahydrofuran; (5) in the condensation reaction, the reducing agent is sodium borohydride triacetate; (6) the molar ratio of the compound V-5 to the acetaldehyde is 1:(0.8-1.2); preferably 1:1; (7) in the condensation reaction, the molar ratio of the compound V-5 to the acid is 1: (0.8-1.2); preferably 1:1; (8) in the condensation reaction, the mass-volume ratio of the compound V-5 to the solvent is 0.03 g / ml-0.08 g / ml; preferably 0.05 g / ml; (9) in the condensation reaction, the molar ratio of the compound V-5 to the reducing agent is 1: (1.5-2.5); preferably 1:2; (10) in the condensation reaction, the reaction time of the reaction is 4h-8h; preferably 6h; (11) in the condensation reaction, the reaction temperature of the reaction is 10℃-45℃; preferably room temperature; (12) in the condensation reaction, the reaction further comprises the following post-processing steps: quenching, for example, with saturated sodium bicarbonate solution, extraction, for example, with ethyl acetate, drying, for example, with anhydrous magnesium sulfate, filtration, concentration, for example, vacuum concentration, silica gel chromatography to obtain compound V; and (13) the reaction raw materials of the condensation reaction are the solvent, the acid, the reducing agent, the compound V-5 and the acetaldehyde.

7. The synthesis method of the compound I according to claim 6, characterized in that, the synthesis method of the compound V further comprises the synthesis method of the compound V-5, and the synthesis of the compound V-5 comprises the following steps: in the presence of a catalyst and a reducing agent, the compound V-4 undergoes a reduction reaction in a solvent to prepare the compound V-5; wherein, the R is as described in claim 1 or 2; Preferably, the synthesis method of the compound V-5 meets one or more of the following conditions: (1) the compound V-4 is (2) the compound V-5 is (3) in the synthesis method of the compound V-5, the catalyst is a supported catalyst; preferably, it is a palladium-carbon catalyst; further preferably, it is 10%wt palladium-carbon; (4) in the synthesis method of the compound V-5, the solvent is an organic solvent; preferably, it is an alcohol solvent; further preferably, it is ethanol; (5) in the synthesis method of the compound V-5, the reducing agent is hydrogen; (6) in the synthesis method of the compound V-5, the molar ratio of the compound V-4 to the catalyst is 1: (0.02-0.06); preferably 1:0.05; (7) in the synthesis method of the compound V-5, the mass-volume ratio of the compound V-4 to the solvent is 0.05 g / ml-0.08 g / ml; preferably 0.075 g / ml; (8) in the synthesis method of the compound V-5, the reaction time of the reaction is 4h-8h; preferably 5h; (9) in the synthesis method of the compound V-5, the reaction temperature of the reaction is 10℃-45℃; preferably 25℃; (10) in the synthesis method of the compound V-5, the reaction further comprises the following post-processing steps: filtration, for example, diatomite filtration, concentration, for example, concentration under reduced pressure, to obtain the compound V-5; and (11) in the synthesis method of the compound V-5, the reaction raw materials are the solvent, the catalyst, the reducing agent and the compound V-4; The synthesis method of the compound V-5 can further comprise a synthesis method of the compound V-4, and the synthesis of the compound V-4 comprises the following steps: coupling reaction of the compound V-3 with 1-bromo-4-methoxy-2-nitrobenzene in a solvent under the condition of a ligand, a catalyst and a base to prepare the compound V-4; wherein, the R is as defined in claim 1 or 2; Preferably, the synthesis method of the compound V-4 satisfies one or more of the following conditions: (1) the compound V-3 is (2) the compound V-4 is (3) In the coupling reaction, the base is an inorganic base; preferably, potassium carbonate; (4) In the coupling reaction, the ligand is a monophosphine ligand; preferably, tricyclohexylphosphine; (5) In the coupling reaction, the catalyst is a palladium catalyst; preferably, divalent palladium; further preferably, palladium acetate; (6) In the coupling reaction, the solvent is a mixed solvent of an organic solvent and water, and the organic solvent can be an ether solvent; preferably, dioxane; (7) In the coupling reaction, the molar ratio of the compound V-3 to the 1-bromo-4-methoxy-2-nitrobenzene is 1:(0.8-1.2); preferably, 1:1; (8) In the coupling reaction, the molar ratio of the compound V-3 to the base is 1:(1-3); further preferably, 1:2; (9) In the coupling reaction, the molar ratio of the compound V-3 to the monophosphine ligand is 1:(0.05-0.2); preferably, 1:0.1; (10) In the coupling reaction, the molar ratio of the compound V-3 to the catalyst is 1:(0.02-0.01); preferably, 1:0.05; (11) In the coupling reaction, the mass-volume ratio of the compound V-3 to the solvent is 0.05g / ml-0.1g / ml; preferably, 0.09g / ml; (12) In the coupling reaction, the reaction time of the coupling reaction is 1h-3h; preferably, 1.5h; (13) In the coupling reaction, the reaction temperature of the coupling reaction is 80℃-120; preferably, 100℃; (14) The coupling reaction comprises the following post-treatment steps: cooling, dilution, for example, dilution with saturated sodium bicarbonate solution, extraction, for example, extraction with ethyl acetate, drying, for example, drying with anhydrous sodium sulfate, concentration, for example, concentration under reduced pressure, and silica gel chromatography to obtain the compound V-4; and (15) The reaction raw materials of the coupling reaction are the solvent, the ligand, the catalyst, the base, the compound V-3 and the 1-bromo-4-methoxy-2-nitrobenzene; The synthesis method of the compound V-4 can further comprise a synthesis method of the compound V-3, and the synthesis method of the compound V-3 comprises the following steps: reaction of the compound V-2 with B2Pin2 in the presence of a catalyst, a ligand, a base and a solvent to prepare the compound V-3, wherein, the R is as defined in claim 1 or 2; Preferably, the synthesis method of the compound V-3 satisfies one or more of the following conditions: (3) In the coupling reaction, the base is an inorganic base; preferably, potassium carbonate; (4) In the coupling reaction, the ligand is a monophosphine ligand; preferably, tricyclohexylphosphine; (5) In the coupling reaction, the catalyst is a palladium catalyst; preferably, divalent palladium; further preferably, palladium acetate; (6) In the coupling reaction, the solvent is a mixed solvent of an organic solvent and water, and the organic solvent can be an ether solvent; preferably, dioxane; (7) In the coupling reaction, the molar ratio of the compound V-3 to the 1-bromo-4-methoxy-2-nitrobenzene is 1:(0.8-1.2); preferably, 1:1; (8) In the coupling reaction, the molar ratio of the compound V-3 to the base is 1:(1-3); further preferably, 1:2; (9) In the coupling reaction, the molar ratio of the compound V-3 to the monophosphine ligand is 1:(0.05-0.2); preferably, 1:0.1; (10) In the coupling reaction, the molar ratio of the compound V-3 to the catalyst is 1:(0.02-0.01); preferably, 1:0.05; (11) In the coupling reaction, the mass-volume ratio of the compound V-3 to the solvent is 0.05g / ml-0.1g / ml; preferably, 0.09g / ml; (12) In the coupling reaction, the reaction time of the coupling reaction is 1h-3h; preferably, 1.5h; (13) In the coupling reaction, the reaction temperature of the coupling reaction is 80℃-120; preferably, 100℃; (14) The coupling reaction comprises the following post-treatment steps: cooling, dilution, for example, dilution with saturated sodium bicarbonate solution, extraction, for example, extraction with ethyl acetate, drying, for example, drying with anhydrous sodium sulfate, concentration, for example, concentration under reduced pressure, and silica gel chromatography to obtain the compound V-4; and (15) The reaction raw materials of the coupling reaction are the solvent, the ligand, the catalyst, the base, the compound V-3 and the 1-bromo-4-methoxy-2-nitrobenzene; (1) the compound V-2 is (2) the compound V-3 is (3) In the synthesis method of the compound V-3, the catalyst is a transition metal catalyst, preferably a transition metal halide, which can be cuprous chloride and / or cobalt bromide; (4) In the synthesis method of the compound V-3, the ligand is a phosphine ligand; preferably (S,S)-Ph-BPE, (S,S)-Meferrocelane, (S,S)-Et-ferrocelane, (R,R)-Me-Duphos or (R,R)-QuinoxP**, for example, (S,S)-Ph-BPE or (R,R)-QuinoxP**; (5) In the synthesis method of the compound V-3, the base is an organic base or an inorganic base; the organic base is preferably potassium methoxide; the inorganic base is preferably cesium carbonate; (6) In the synthesis method of the compound V-3, the solvent is an organic solvent; preferably an ether solvent and an alcohol solvent; the volume ratio of the ether solvent and the alcohol solvent can be (6-40):1, for example, 8:1 or 37.6:1; the ether solvent can be tetrahydrofuran; the alcohol solvent can be methanol or tert-butanol; (7) In the synthesis method of the compound V-3, the molar ratio of the compound V-2 to the catalyst is 1:(0.01-0.15); preferably 1:0.05 or 1:0.1; (8) In the synthesis method of the compound V-3, the molar ratio of the compound V-2 to the ligand is 1:(0.01-0.15); preferably 1:0.05 or 1:0.1; (9) In the synthesis method of the compound V-3, the molar ratio of the compound V-2 to the base is 1:(0.1-1.2); preferably 1:0.2 or 1:1; (10) In the synthesis method of the compound V-3, the mass-volume ratio of the compound V-2 to the solvent is 0.05-0.12 g / mL; preferably 0.06 g / mL or 0.11 g / mL; (11) In the synthesis method of the compound V-3, the reaction time of the reaction is 2-60 h; preferably 4 h or 48 h; (12) In the synthesis method of the compound V-3, the reaction temperature of the reaction is 0-40℃; preferably 0℃ or 20℃; (13) The synthesis method of the compound V-3 further comprises any one of the following work-up steps: ① Pour into ice water, extract, for example, extract with ethyl acetate, combine the organic phases, wash, for example, with saturated aqueous sodium carbonate, water and saturated brine, dry, for example, with anhydrous sodium sulfate, and purify the residue by silica gel chromatography to obtain the compound V-3; ② Filter, for example, filter with a thin layer of silica gel, wash, for example, with dichloromethane, concentrate, and purify the residue by silica gel chromatography to obtain the compound V-3 and; (14) In the synthesis method of the compound V-3, the reaction material of the reaction is the catalyst, the ligand, the base, the solvent, the compound V-2 and the B2Pin2.

8. A method for synthesizing a compound II, a compound III, a compound IV, a compound V, a compound V-5 and a compound V-4, characterized in that, the method for synthesizing the compound II comprises the following step: ring-opening reaction of the compound III in a solvent in the presence of a base to prepare the compound II; wherein, the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound II, the compound III and the compound II are as described in claim 3; the method for synthesizing the compound III comprises the following step: cyclization reaction of trimethylsilyl iodide and the compound IV in a solvent in the presence of a base to prepare the compound III; the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound III, the compound IV and the compound III are as described in claim 4; the method for synthesizing the compound IV comprises the following step: alkylation reaction of the compound V and 4-bromomethylbenzaldehyde in a solvent in the presence of a base to prepare the compound IV; the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound IV, the compound V and the compound IV are as described in claim 5; the method for synthesizing the compound V comprises the following step: condensation reaction of the compound V-5 and acetaldehyde in a solvent in the presence of an acid and a reducing agent to prepare the compound V; the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound V, the compound V-5 and the compound V are as described in claim 6; the method for synthesizing the compound V-5 comprises the following step: reduction reaction of the compound V-4 in a solvent in the presence of a catalyst and a reducing agent to prepare the compound V-5; the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound V-5, the compound V-4 and the compound V-5 are as described in claim 7; the method for synthesizing the compound V-4 comprises the following step: coupling reaction of the compound V-3 and 1-bromo-4-methoxy-2-nitrobenzene under the conditions of a monophosphine ligand, a catalyst and a base to prepare the compound V-4; the definition of R is as described in claim 1 or 2; preferably, the operation and conditions of the method for synthesizing the compound V-4, the compound V-3 and the compound V-4 are as described in claim 7.

9. A method of synthesis of Compound I, characterized in that, which comprises the following steps, alkylation reaction of the compound V and 4-bromomethylbenzaldehyde to prepare the compound IV; cyclization reaction of a methylene transfer reagent and the compound IV to prepare the compound III; ring-opening reaction of the compound III to prepare the compound II; hydroxyl reduction reaction of the compound II to prepare the compound I; wherein R is as defined in claim 1 or 2; for example, preferably, the alkylation reaction is as described in claim 5; the cyclization reaction is as described in claim 4; the ring-opening reaction is as described in claim 3; the hydroxyl reduction reaction is as described in claim 1 or 2. Preferably, the synthesis of the compound I further comprises the synthesis of the compound V, The compound V-3 is subjected to a coupling reaction with 1-bromo-4-methoxy-2-nitrobenzene to produce the compound V-4; The compound V-4 is subjected to a reduction reaction to produce the compound V-5; The compound V-5 is subjected to a condensation reaction with acetaldehyde to produce the compound V; wherein R is as defined in claim 1 or 2; for example, The definitions of the coupling reaction and the reduction reaction can be as defined in claim 7; the definition of the condensation reaction can be as defined in claim 6.

10. A compound, characterized in that, which is any one of the following structures, wherein R is triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, p-methoxybenzyl or methoxymethylene, preferably methoxymethylene, Preferably, The compound is

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