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 a reducing agent, carrying out a reduction reaction on a compound II 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] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to the synthesis of a tetrahydronaphthalene derivative and its intermediates. Background Art

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

[0003]

[0004] The patent WO2004058682A1 of Eisai Co., Ltd. first disclosed the following synthesis method of Elacestrant (Route 1). Starting from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1), after demethoxylation and benzyl protection, it reacts with bromine to be converted into an alkenyl bromide intermediate (3). Under the co-catalysis of triphenylphosphine palladium chloride and copper, intermediate (3) undergoes a coupling reaction with 4-bromo-3-nitroanisole (4) to obtain intermediate (5). Under the condition of palladium-carbon hydrogenation, the nitro group and double bond of intermediate (5) are reduced while the benzyl protection is removed to obtain intermediate (6). After the amino group of intermediate (6) is acetylated, it is then reduced with lithium aluminum hydride to obtain intermediate (8). The phenolic hydroxyl group of intermediate (8) is selectively protected with pivaloyl and then resolved by chiral column chromatography to obtain intermediate (10). Intermediate (10) undergoes a reductive amination reaction with 4-formylphenylacetic acid (11) to obtain intermediate (12). Intermediate (12) is condensed with ethylamine to obtain intermediate (13). Finally, lithium aluminum hydride reduces the amide of intermediate 13 to an amine while the pivaloyl protecting group is also reduced and removed, thereby obtaining the target compound Elacestrant (I). This synthesis route involves a total of 11 chemical reactions, and the intermediate with the target configuration is obtained by chemical resolution in the 8th step. The synthesis route is complex.

[0005]

[0006] Route 1

[0007] Rudius' patent CN202080011109.9 is an improvement on Eisai's patent, as shown in route 2 below. Intermediate 3 is converted into boric acid to 14, and then Suzuki coupling is performed with 4-bromo-3-acetaminophen (15) 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, the amide of compound 22 is reduced to amine with sodium borohydride-iodine 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 (4) 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 cost. 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] Route 2

[0010]

[0011] Route 3

[0012] 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. Therefore, developing methods with high yield, high purity, short synthesis steps, readily available starting materials, low cost, and environmental friendliness is of great significance. Summary of the Invention

[0013] The technical problem to be solved by this invention is to overcome the defects of the existing technology in the preparation of Elacestrant, such as complex process operation, low purity and low yield. Through our research, we have proposed a synthesis method for tetrahydronaphthalene derivatives and their intermediates. 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 and the reaction operation is simple, which has good application prospects and value.

[0014] The present invention provides a method for synthesizing compound I, which includes the following steps: in a solvent and in the presence of a reducing agent, compound II undergoes a reduction reaction to prepare compound I;

[0015]

[0016] In one embodiment, the reducing agent is Raney nickel, sodium hypophosphite, zinc powder, or lithium aluminum hydride; Raney nickel is preferred.

[0017] In one embodiment, when the reducing agent is sodium hypophosphite, the reduction reaction further includes a catalyst; the catalyst may be a nickel-zinc alloy.

[0018] In one embodiment, when the reducing agent is zinc powder, the reduction reaction also includes an acid, which may be hydrochloric acid; for example, concentrated hydrochloric acid.

[0019] In one embodiment, the solvent is an organic solvent, preferably one or more of an ether solvent, an alcohol solvent, or water. The ether solvent may be tetrahydrofuran or 1,4-dioxane, the tetrahydrofuran may be anhydrous tetrahydrofuran, and the alcohol solvent may be ethanol, for example, anhydrous ethanol. Preferably, the solvent is an ether solvent.

[0020] In one embodiment, the solvent is a mixture of an ether solvent and water, for example, 1,4-dioxane and water; preferably, the volume ratio of the ether solvent to the water is 7:3.

[0021] The molar ratio of compound II to the catalyst is a conventional molar ratio for such reactions in the art, preferably 1:(0.10-0.30), more preferably 1:0.20.

[0022] The molar ratio of compound II to the acid is a conventional molar ratio for such reactions in the art, preferably 1:(12-15), more preferably 1:14.7.

[0023] The molar ratio of compound II to the reducing agent is a conventional molar ratio for such reactions in the art, preferably 1:(1-6), more preferably 1:1.5, 1:2.5 or 1:5.0; and even more preferably 1:1.5.

[0024] 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 0.2 g / mL, more preferably 0.1 g / mL or 0.14 g / mL.

[0025] The reaction time of the reduction reaction is the conventional reaction time for such reactions in the art, preferably 1h-6h, more preferably 3h, 4h, 10h or 6h; and even more preferably 3h.

[0026] The reaction temperature of the reduction reaction is the conventional reaction temperature for such reactions in the art, preferably 10℃-45℃, and more preferably room temperature.

[0027] In one embodiment, the reduction reaction includes the following post-processing steps: filtration (e.g., filtration with diatomaceous earth), washing, removing solvent under reduced pressure, and silica gel chromatography purification to obtain target compound I; the filtration may also include a pre-filtration neutralization reaction solution (e.g., sodium carbonate neutralization) or a quenching reaction solution (e.g., sodium sulfate decahydrate quenching).

[0028] In one embodiment, the reaction raw materials for the synthesis of compound I are compound II, the solvent, and the reducing agent.

[0029] In one embodiment, the synthesis method of compound I further includes a synthesis method of compound II, wherein the synthesis of compound II is any of the following embodiments.

[0030] Scheme 1: In a solvent and in the presence of a reducing agent, compound VI and compound III undergo a reducing amination reaction 1 to prepare compound II;

[0031]

[0032] Scheme 2: In a solvent and in the presence of a reducing agent, compound IV undergoes a reducing amination reaction 2 with acetaldehyde to prepare compound II;

[0033]

[0034] In one embodiment, in embodiment 1, the solvent is an organic solvent, preferably an ether solvent, and more preferably tetrahydrofuran.

[0035] In one embodiment, in embodiment 1, the reducing agent is a borohydride reagent; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, or sodium tricyanoborohydride, with sodium triacetoxyborohydride being the most preferred.

[0036] In Scheme 1, the molar ratio of compound VI to compound III is a conventional molar ratio for such reactions in the art, preferably 1:(1-2), and more preferably 1:1.

[0037] In Scheme 1, the molar ratio of compound VI to the reducing agent is a conventional molar ratio for such reactions in the art, preferably 1:(1.5-3), and more preferably 1:2.2.

[0038] In Scheme 1, the mass-to-volume ratio of compound VI to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05 g / mL to 0.2 g / mL, and more preferably 0.1 g / mL.

[0039] In Scheme 1, the reaction time of the reductive amination reaction is the conventional reaction time for such reactions in the art, preferably 4h-20h, more preferably 8h.

[0040] In Scheme 1, the reaction temperature of the reductive amination reaction is the conventional reaction temperature for such reactions in the art, preferably 30℃-80℃, and more preferably 65℃.

[0041] In one embodiment, in embodiment 1, the reductive amination reaction comprises the following post-processing steps: dilution (e.g., dilution with water), extraction (e.g., extraction with ethyl acetate), concentration (e.g., concentration under reduced pressure), and purification by silica gel column chromatography to obtain compound II.

[0042] In one embodiment, in embodiment 1, the reaction raw materials are the solvent, the reducing agent, compound VI, and compound III.

[0043] In one embodiment, in embodiment 2, the acetaldehyde is an acetaldehyde tetrahydrofuran solution; preferably, it is a 2M acetaldehyde tetrahydrofuran solution (1L of tetrahydrofuran solution contains 2mol of acetaldehyde).

[0044] In one embodiment, in embodiment 2, the solvent is an organic solvent, preferably an ether solvent, and more preferably tetrahydrofuran.

[0045] In one embodiment, in embodiment 2, the reducing agent is a borohydride; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, or sodium tricyanoborohydride, with sodium triacetoxyborohydride being the most preferred.

[0046] In Scheme 2, the molar ratio of compound IV to acetaldehyde is a conventional molar ratio for such reactions in the art, preferably 1:(1-2), and more preferably 1:1.1.

[0047] In Scheme 2, the molar ratio of compound IV to the reducing agent is a conventional molar ratio for such reactions in the art, preferably 1:(1.5-3), and more preferably 1:2.

[0048] In Scheme 2, 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 g / mL to 0.2 g / mL, and more preferably 0.16 g / mL.

[0049] In Scheme 2, the reaction time of the reductive amination reaction is the conventional reaction time for such reactions in the art, preferably 4h-20h, more preferably 16h.

[0050] In Scheme 2, the reaction temperature of the reductive amination reaction is the conventional reaction temperature for such reactions in the art, preferably 20℃-60℃, and more preferably 40℃.

[0051] In one embodiment, embodiment 2, the reductive amination reaction comprises the following post-processing steps: dilution (e.g., dilution with water), extraction (e.g., extraction with ethyl acetate), concentration (e.g., concentration under reduced pressure), and purification by silica gel column chromatography to obtain compound II.

[0052] In one embodiment, in embodiment 2, the reaction raw materials are the solvent, the reducing agent, compound IV, and acetaldehyde.

[0053] In one embodiment, the method for synthesizing compound II 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 reducing agent, compound (R)-V undergoes a reductive amination reaction with compound III to prepare compound IV;

[0054]

[0055] In one embodiment, the solvent used in the synthesis of compound IV is an organic solvent, preferably an ether solvent, and more preferably tetrahydrofuran.

[0056] In one embodiment, the reducing agent in the synthesis of compound IV is a borohydride reagent; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, or sodium tricyanoborohydride, with sodium triacetoxyborohydride being the most preferred.

[0057] In the method for synthesizing compound IV, the molar ratio of compound IV to compound III is a conventional molar ratio for such reactions in the art, preferably 1:(1-2), and more preferably 1:1.

[0058] In the method for synthesizing compound IV, the molar ratio of compound IV to the reducing agent is a conventional molar ratio for such reactions in the art, preferably 1:(1.5-3), more preferably 1:2.5.

[0059] In the synthesis method of compound IV, the mass-to-volume ratio of compound VI to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05 g / mL to 0.2 g / mL, more preferably 0.15 g / mL.

[0060] In the synthesis method of compound IV, the reaction time of the reductive amination reaction is the conventional reaction time for such reactions in the art, preferably 4h-20h, more preferably 8h.

[0061] In the synthesis method of compound IV, the reaction temperature of the reductive amination reaction is the conventional reaction temperature for such reactions in the art, preferably 30℃-80℃, more preferably 65℃.

[0062] In one embodiment, the reductive amination reaction of compound IV comprises the following post-processing steps: dilution (e.g., dilution with water), extraction (e.g., extraction with ethyl acetate), concentration (e.g., concentration under reduced pressure), and purification by silica gel column chromatography to obtain compound IV.

[0063] In one embodiment, the reaction raw materials for the synthesis of compound IV are the solvent, the reducing agent, compound (R)-V, and compound III.

[0064] 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, in the presence of a catalyst, compound III-2 undergoes a deprotection reaction to obtain compound III;

[0065]

[0066] In one embodiment, the catalyst in the deprotection reaction is an acid catalyst, preferably p-toluenesulfonic acid.

[0067] In one embodiment, during the deprotection reaction, the solvent is a mixture of an organic solvent and water; the organic solvent is preferably an ether solvent; more preferably tetrahydrofuran; preferably, the volume ratio of the organic solvent to the water is (8-12):1; more preferably 10:1.

[0068] In the deprotection reaction, the molar ratio of compound III-2 to the catalyst is a conventional molar ratio for such reactions in the art, preferably 1:(0.05-0.2), more preferably 1:0.1.

[0069] In the deprotection reaction, the mass-to-volume ratio of compound III-2 to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.15 g / mL to 0.2 g / mL, more preferably 0.18 g / mL.

[0070] The reaction time for the deprotection reaction is the conventional reaction time for such reactions in the art, preferably 0.5h-6h, more preferably 1h.

[0071] The deprotection reaction is carried out at a temperature that is conventional for such reactions in the art, preferably 10°C-45°C, and more preferably at room temperature.

[0072] In one embodiment, the deprotection reaction comprises the following post-processing steps: pouring the reaction solution into water, extracting (e.g., with ethyl acetate), drying, concentrating, and purifying by silica gel column chromatography to obtain compound III.

[0073] In one embodiment, the reactants for the deprotection reaction are the solvent, the catalyst, and compound III-2.

[0074] In one embodiment, the method for synthesizing compound III further includes a method for synthesizing compound III-2, which comprises the following steps: in a solvent and in the presence of a base, compound III-1 undergoes a Willgerodt-Kindler reaction with compound a and sulfur to prepare compound III-2.

[0075]

[0076] The compound a is ethylamine or N-formylethylamine; preferably N-formylethylamine.

[0077] In one embodiment, in the Willgerodt-Kindler reaction, the solvent is a mixture of an organic solvent and water; the organic solvent can be an aromatic solvent, an amide solvent, an alcohol solvent, or an ether solvent; the aromatic solvent can be pyridine, quinoline, or N,N-dimethylaniline, preferably quinoline; the amide solvent can be N,N-dimethylformamide or N-methylpyrrolidone; the alcohol solvent can be ethanol or n-butanol; the ether solvent can be dioxane; preferably, the organic solvent is an aromatic solvent or an ether solvent; more preferably, the organic solvent is an ether solvent; the volume ratio of the organic solvent to water can be (3-6):1, preferably 5:1.

[0078] In one embodiment, in the Willgerodt-Kindler reaction, the base is an organic base and / or an inorganic base; the organic base may be triethylamine; the inorganic base may be sodium carbonate; preferably, the base is both an organic base and an inorganic base.

[0079] In the Willgerodt-Kindler reaction, the molar ratio of compound III-1 to sulfur is a conventional molar ratio for such reactions in the art, preferably 1:(1.5-2.5), more preferably 1:2.

[0080] In the Willgerodt-Kindler reaction, the molar ratio of compound III-1 to compound a is a conventional molar ratio for such reactions in the art, preferably 1:(1-12), more preferably 1:2.

[0081] In the Willgerodt-Kindler reaction, the molar ratio of compound III-1 to the organic base is a conventional molar ratio for such reactions in the art, preferably 1:(2-8), more preferably 1:3 or 1:6.

[0082] In the Willgerodt-Kindler reaction, the molar ratio of compound III-1 to the inorganic base is a conventional molar ratio for such reactions in the art, preferably 1:(2-4), more preferably 1:3 or 1:6.

[0083] In the Willgerodt-Kindler reaction, the mass-to-volume ratio of compound III-1 to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.05 g / mL to 0.2 g / mL, and more preferably 0.125 g / mL.

[0084] The reaction time of the Willgerodt-Kindler reaction is the conventional reaction time for such reactions in the art, preferably 6h-15h, more preferably 12h.

[0085] The reaction temperature of the Willgerodt-Kindler reaction is the conventional reaction temperature for such reactions in the art, preferably 100°C-145°C, and more preferably 120°C.

[0086] In one embodiment, the Willgerodt-Kindler reaction comprises the following post-processing steps: cooling, dilution (e.g., dilution with water), extraction (with ethyl acetate), washing (e.g., washing with water and saturated brine, respectively), drying, solvent removal (e.g., removal under vacuum), and purification by silica gel column chromatography to obtain compound III-2.

[0087] In one embodiment, the reactants for the Willgerodt-Kindler reaction are the solvent, the base, compound III-1, compound a, and sulfur.

[0088] In one embodiment, the method for synthesizing compound III-2 further includes a method for synthesizing compound III-1, wherein the method for synthesizing compound III-1 comprises the following steps: in a solvent, in the presence of a dehydrating agent, selectively protecting the aldehyde group of 4-acetylbenzaldehyde with ethylene glycol to react and obtain the corresponding acetal compound III-1.

[0089]

[0090] In one embodiment, the solvent used in the synthesis of compound III-1 is an organic solvent, preferably an ether solvent; more preferably ethyl acetate.

[0091] In one embodiment, the dehydrating agent in the synthesis of compound III-1 is an acid dehydrating agent; preferably propane phosphoric anhydride, and more preferably a 50% ethyl acetate solution of propane phosphoric anhydride.

[0092] In the synthesis method of compound III-1, the molar ratio of compound III-1 to ethylene glycol is a conventional molar ratio for such reactions in the art, preferably 1:(1-2), more preferably 1:1.2.

[0093] In the synthesis method of compound III-1, the molar ratio of compound III-1 to the dehydrating agent is a conventional molar ratio for such reactions in the art, preferably 1:(0.05-0.2), more preferably 1:0.1.

[0094] In the synthesis method of compound III-1, the mass-to-volume ratio of compound III-1 to the solvent is a conventional mass-to-volume ratio for such reactions in the art, preferably 0.1 g / mL to 0.2 g / mL, more preferably 0.14 g / mL.

[0095] In the synthesis method of compound III-1, the reaction time is the conventional reaction time for such reactions in the art, preferably 2h-8h, more preferably 5h.

[0096] In the synthesis method of compound III-1, the reaction temperature is the conventional reaction temperature for such reactions in the art, preferably 10℃-45℃, and more preferably room temperature.

[0097] In one embodiment, the synthesis of compound III-1 includes the following post-processing steps: cooling, dilution (e.g., dilution with ethyl acetate), washing (e.g., washing with saturated sodium bicarbonate), drying (e.g., drying with anhydrous sodium sulfate), filtration and concentration to obtain compound III-1.

[0098] In one embodiment, the reaction raw materials for the synthesis of compound III-1 are the solvent, the dehydrating agent, the 4-acetylbenzaldehyde, and the ethylene glycol.

[0099] This invention provides a method for synthesizing compound I, which is scheme a or scheme b.

[0100] Option a includes the following steps:

[0101] Compound VI and compound III undergo a reductive amination reaction 1 to prepare compound II; compound II undergoes a reduction reaction to prepare compound I.

[0102]

[0103] Option b includes the following steps:

[0104] Compound IV undergoes a reducing amination reaction 2 with acetaldehyde to prepare compound II; compound II undergoes a reduction reaction to prepare compound I.

[0105]

[0106] In one embodiment, the operation and conditions of the synthesis methods of compound II and compound I are as described in any embodiment of the present invention.

[0107] In one embodiment, the synthesis of compound I further includes the synthesis of compound III.

[0108] Compound III-1 reacts with compound a and sulfur in a Willgerodt-Kindler reaction to prepare compound III-2; compound III-2 undergoes a deprotection reaction to prepare compound III.

[0109]

[0110] The compound a is ethylamine or N-formylethylamine; preferably N-formylethylamine.

[0111] In one embodiment, the operation and conditions of the synthesis methods of compound III-2 and compound III are as described in any embodiment of the present invention.

[0112] In one embodiment, the method for synthesizing compound I further includes the synthesis of compound IV.

[0113] Compound (R)-V reacts with compound III via a reductive amination reaction to prepare compound IV;

[0114]

[0115] In one embodiment, the operation and conditions of the synthesis method of compound IV are as described in any embodiment of the present invention.

[0116] This invention provides a method for synthesizing compound II, wherein the synthesis of compound II is carried out according to any of the following schemes:

[0117] Scheme 1: In a solvent and in the presence of a reducing agent, compound VI and compound III undergo a reduction amination 1 reaction to prepare compound II;

[0118]

[0119] Scheme 2: In a solvent and in the presence of a reducing agent, compound IV undergoes a reducing amination reaction 2 with acetaldehyde to prepare compound II;

[0120]

[0121] In one embodiment, the operation and conditions of the synthesis method of compound II are as described in any embodiment of the present invention.

[0122] The present invention provides a method for synthesizing compound IV, the method comprising the following steps: in a solvent and in the presence of a reducing agent, compound (R)-V undergoes a reductive amination reaction with compound III to prepare compound IV;

[0123]

[0124] In one embodiment, the operation and conditions of the synthesis method of compound IV are as described in any embodiment of the present invention.

[0125] The present invention provides a method for synthesizing compound III, the method comprising the following steps: in a solvent and in the presence of a catalyst, compound III-2 undergoes a deprotection reaction to obtain compound III;

[0126]

[0127] In one embodiment, the operation and conditions of the synthesis method of compound III are as described in any embodiment of the present invention.

[0128] The present invention provides a method for synthesizing compound III-2, the method comprising the following steps: in a solvent and in the presence of a base, compound III-1 undergoes a Willgerodt-Kindler reaction with compound a and sulfur to prepare compound III-2;

[0129]

[0130] The compound a is ethylamine or N-formylethylamine; preferably N-formylethylamine.

[0131] In one embodiment, the operation and conditions of the synthesis method of compound III-2 are as described in any embodiment of the present invention.

[0132] The present invention provides a method for synthesizing compound III-1, the method comprising the following steps: in a solvent, in the presence of a dehydrating agent, selectively protecting the aldehyde group of 4-acetylbenzaldehyde with ethylene glycol to obtain compound III-1.

[0133]

[0134] In one embodiment, the operation and conditions of the synthesis method of compound III-1 are as described in any embodiment of the present invention.

[0135] This invention provides a compound having any of the following structures:

[0136]

[0137]

[0138] The room temperature described in this invention is 25-35℃.

[0139] 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.

[0140] The reagents and raw materials used in this invention are all commercially available.

[0141] The positive and progressive effects of this invention are as follows: The technical problem to be solved by this invention is to propose a synthesis of a tetrahydronaphthalene derivative and its intermediates. 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

[0142] 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.

[0143] Example 1: Synthesis of N-ethyl-2-(4-formylphenyl)thioacetamide (III)

[0144]

[0145] Step 1: 1-4-(1,3-dioxacyclopentan-2-yl)phenyl)ethyl ketone (III-1)

[0146] 4-Acetylbenzaldehyde (100 g, 674.94 mmol) was dissolved in ethyl acetate (700 mL), followed by the addition of ethylene glycol (50.3 g, 809.93 mmol) and propane phosphoric anhydride (10%, 50% ethyl acetate solution, 43.0 g, 67.49 mmol). The mixture was stirred at room temperature for 5 hours, diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sulfuric acid, filtered, and concentrated to give compound III-1 (126.8 g, yield 94.2%, purity 96.4%), which was used directly in the next reaction. MS (ESI, m / z): 193 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.00–7.95(m,2H),7.60–7.55(m,2H),5.81(s,1H),4.10–3.92(m,4H),2.59(s,3H).

[0147] Step 2: 2-(4-(1,3-dioxolane-2-yl)phenyl)-N-ethylthioformamide (III-2)

[0148] Compound III-1 (50.0 g, 260.13 mmol) obtained in the previous step was dissolved in dioxane and water (V / V = 5:1, 400 mL). Sulfur (16.7 g, 520.25 mmol), triethylamine (79.0 g, 780.38 mmol), sodium carbonate (82.7 g, 780.38 mmol), and N-formylethylamine (38.0 g, 520.25 mmol) were added. The mixture was sealed and heated to 120 °C with stirring for 12 hours. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and then dried. The solvent was removed under vacuum. The residue was purified by silica gel chromatography to give compound III-2 (54.3 g, yield 80.1%, purity 96.5%). MS (ESI, m / z): 252 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),7.36-7.31(m,4H),5.68(s,1H),4.28–3.78(m,6H),1.13(t,3H).

[0149] Step 3: N-Ethyl-2-(4-formylphenyl)thioacetamide (III)

[0150] Compound III-2 (45 g, 179.04 mmol) was dissolved in a tetrahydrofuran / water mixture (250 mL, V / V = 10 / 1), and p-toluenesulfonic acid (3.1 g, 17.90 mmol) was added. The mixture was stirred at room temperature (20℃–35℃) for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound III (36.5 g, yield 96.7%, purity 98.3%). MS (ESI, m / z): 208 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.97(s,1H),7.81–7.88(m,2H),7.53(d,2H),3.98(s,2H),3.50(qd,2H),1.15(t,3H).

[0151] Example 2: Synthesis of (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)thioacetamide (II)

[0152]

[0153] Step 1: (R)-N-ethyl-2-(4-(((2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)thioacetamide (IV)

[0154] Compound (R)-V (30.0 g, 111.38 mmol), compound III (23.1 g, 111.38 mmol), and sodium triacetoxyborohydride (59.0 g, 278.45 mmol) were dissolved in tetrahydrofuran (200 mL). The mixture was heated to 65 °C and reacted for 8 hours. After the reaction was monitored for completeness, the mixture was diluted with water, extracted with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound IV (47.3 g, yield 89.1%, purity 97.3%). LC-MS (ESI, m / z) 461 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ10.16(s,1H),9.00(s,1H),7.29–7.22(m,4H),6.90( dd,2H),6.52(d,2H),6.10(dd,1H),5.96(t,1H),5.90(d,1H),4.26(d,2H),3. 82(s,2H),3.55(s,3H),3.47(q,2H),3.02(t,1H),2.95–2.86(m,2H),2.80–2 .70(m,1H),2.57-2.52(m,2H),1.96–1.88(m,1H),1.78(qd,1H),1.13(t,3H).

[0155] Step 2: (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)thioacetamide(II)

[0156] Compound IV (40.0 g, 86.84 mmol), acetaldehyde tetrahydrofuran solution (2 M, 47.8 mL, 95.6 mmol), and sodium triacetoxyborohydride (36.8 g, 173.67 mmol) were dissolved in tetrahydrofuran (250 mL). The mixture was heated to 40 °C and reacted for 16 hours. After the reaction was monitored for completeness, the solution was diluted with water, extracted with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound II (38.8 g, yield 90.2%, purity 98.6%). LC-MS (ESI, m / z) 489 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ10.14(s,1H),9.01(s,1H),7.20–7.11(m,5H),6.84–6.78(m,2H),6.66(dd,1H),6.50(d,2H),4.03–3.93(m,2H),3.79(s ,2H),3.71(s,3H),3.56–3.41(m,3H),2.87(q,2H),2.77-2.72(d,2H),2 .63–2.52(m,2H),1.69(qd,1H),1.57(d,1H),1.12(t,3H),0.88(t,3H).

[0157] Example 3: Synthesis of (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)thioacetamide (II)

[0158]

[0159] Step 1: (R)-N-ethyl-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (VI)

[0160] A tetrahydrofuran solution of acetaldehyde (55.7 mL, 111.38 mmol, 2 M), compound (R)-V (30.0 g, 111.38 mmol), and acetic acid (3.3 g, 55.69 mmol) were dissolved in anhydrous tetrahydrofuran (300 mL) and stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (51.9 g, 245.04 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. The reaction mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound VI (29.2 g, yield 86.6%, purity 98.2%). LC-MS (ESI, m / z) 298 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.03(dd,2H),6.83(dd,1H),6.30-6.23(m,2H),3.80(s,3H),3.1 7(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).

[0161] Step 2: (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)thioacetamide(II)

[0162] Compound VI (25.0 g, 84.06 mmol), compound III (17.4 g, 84.06 mmol), and sodium triacetoxyborohydride (39.2 g, 184.94 mmol) were dissolved in tetrahydrofuran (250 mL). The mixture was heated to 65 °C and reacted for 8 hours. After the reaction was monitored for completeness, the mixture was diluted with water, extracted with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound II (34.8 g, yield 83.0%, purity 98.0%). LC-MS (ESI, m / z) 489 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ10.14(s,1H),9.01(s,1H),7.20–7.11(m,5H),6.84–6.78(m,2H),6.66(dd,1H),6.50(d,2H),4.03–3.93(m,2H),3.79(s ,2H),3.71(s,3H),3.56–3.41(m,3H),2.87(q,2H),2.77-2.72(d,2H),2 .63–2.52(m,2H),1.69(qd,1H),1.57(d,1H),1.12(t,3H),0.88(t,3H).

[0163] Example 4: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0164]

[0165] Under nitrogen protection, compound II (25.0 g, 51.16 mmol) was dissolved in tetrahydrofuran (250 mL) solution, and Raney nickel (3.5 g, 76.74 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After complete consumption of compound II was detected, the reaction solution was filtered through diatomaceous earth and washed. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography to obtain target compound I (22.4 g, yield 94.7%, purity 99.2%). LC-MS (ESI, m / z) 459 [M+H] + ; 1H NMR(400MHz, Methanol-d4)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).

[0166] Example 5: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0167]

[0168] Under nitrogen protection, compound II (25.0 g, 51.16 mmol) was dissolved in anhydrous ethanol (250 mL), and Raney nickel (3.5 g, 76.74 mmol) was added. The mixture was stirred at room temperature for 3 hours. After complete consumption of compound II was detected, the reaction solution was filtered through diatomaceous earth and washed. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography to obtain target compound I (22.8 g, yield 96.6%, purity 99.4%). LC-MS (ESI, m / z) 459 [M+H] + . 1 H NMR(400MHz, Methanol-d4)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).

[0169] Example 6: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0170]

[0171] Under nitrogen protection, compound II (10.0 g, 20.46 mmol) was dissolved in a mixed solvent of 1,4-dioxane (70 mL) and water (30 mL). Nickel-zinc alloy (705 mg, 4.09 mmol) and sodium hypophosphite (4.5 g, 51.16 mmol) were added, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC until complete. The reaction solution was filtered through diatomaceous earth and washed. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography to obtain target compound I (7.23 g, yield 76.2%, purity 98.9%). LC-MS (ESI, m / z) 459 [M+H] + . 1 H NMR(400MHz, Methanol-d4)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).

[0172] Example 7: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0173]

[0174] Under nitrogen protection, compound II (10.0 g, 20.46 mmol) was dissolved in a mixed solvent of anhydrous ethanol (70 mL) and concentrated hydrochloric acid (25 mL, 300 mmol), and zinc powder (6.7 g, 102.31 mmol) was added. The mixture was stirred at 70 °C for 10 hours. The reaction was monitored by TLC until complete. The reaction solution was neutralized with sodium carbonate, filtered through diatomaceous earth, and washed. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography to obtain target compound I (6.38 g, yield 67.0%, purity 98.5%). LC-MS (ESI, m / z) 459 [M+H] + . 1H NMR(400MHz, Methanol-d4)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).

[0175] Example 8: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I, i.e., Elacestrant)

[0176]

[0177] Under nitrogen protection, compound II (10.0 g, 20.46 mmol) was dissolved in anhydrous tetrahydrofuran (70 mL), and lithium aluminum hydride (1.2 g, 30.69 mmol) was added. The mixture was stirred at 60 °C for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and washed. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography to give target compound I (7.88 g, yield 83.1%, purity 99.0%). LC-MS (ESI, m / z) 459 [M+H] + . 1 H NMR(400MHz, Methanol-d4)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 method for synthesizing compound I, comprising the following steps: reducing compound II in the presence of a reducing agent in a solvent to prepare compound I; 2. The process for the synthesis of compound I according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) the reducing agent is Raney nickel, sodium hypophosphite, zinc powder or lithium aluminum hydride; (2) in the reducing reaction, when the reducing agent is sodium hypophosphite, the reaction further comprises a catalyst, which can be a nickel-zinc alloy; (3) in the reducing reaction, when the reducing agent is zinc powder, the reaction further comprises an acid, which can be hydrochloric acid; (4) the solvent is one or more of an organic solvent, preferably an ether solvent, an alcohol solvent or water, the ether solvent can be tetrahydrofuran or 1,4-dioxane, the tetrahydrofuran can be anhydrous tetrahydrofuran, and the alcohol solvent can be ethanol, for example, anhydrous ethanol; (5) the solvent is a mixed solvent of the ether solvent and water, for example, 1,4-dioxane and water, and preferably the volume ratio of the ether solvent to water is 7:3; (6) the molar ratio of compound II to the catalyst is 1:(0.10-0.30), preferably 1:0.20; (7) the molar ratio of compound II to the acid is 1:(12-15), more preferably 1:14.7; (8) the molar ratio of compound II to the reducing agent is 1:(1-6), preferably 1:1.5, 1:2.5 or 1:5.0, and further preferably 1:1.5; (9) the mass-volume ratio of compound II to the solvent is 0.05g / mL-0.2g / mL, preferably 0.1g / mL or 0.14g / mL; (10) the reaction time of the reducing reaction is 1h-6h, preferably 3h, 4h, 10h or 6h, and further preferably 3h; (11) the reaction temperature of the reducing reaction is 10℃-45℃, preferably room temperature; (12) the reducing reaction comprises the following post-treatment steps: filtration, for example, filtration with diatomite, washing, removal of the solvent under reduced pressure, and silica gel chromatography to obtain the target compound I, wherein the filtration can further comprise neutralization of the reaction solution before filtration, for example, sodium carbonate neutralization, or quenching of the reaction solution, for example, sodium sulfate quenching;and (13) in the method for synthesizing compound I, the reaction raw materials are compound II, the solvent and the reducing agent.

3. The process for the synthesis of compound I according to claim 1, characterized in that, The method for synthesizing compound I further comprises a method for synthesizing compound II, which is any one of the following schemes, Scheme 1: reducing compound VI and compound III in the presence of a reducing agent in a solvent to prepare compound II; Scheme 2: reducing compound IV and acetaldehyde in the presence of a reducing agent in a solvent to prepare compound II; Preferably, the method for synthesizing compound II satisfies one or more of the following conditions: (1) in the scheme 1, the solvent is an organic solvent, preferably an ether solvent, and further preferably tetrahydrofuran; (2) In the scheme 1, the reducing agent is a borohydride reagent; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium tricyano borohydride, preferably sodium triacetoxyborohydride; (3) In the scheme 1, the molar ratio of the compound VI to the compound III is 1: (1-2), preferably 1:1; (4) In the scheme 1, the molar ratio of the compound VI to the reducing agent is 1: (1.5-3), preferably 1:2.2; (5) In the scheme 1, the mass-volume ratio of the compound VI to the solvent is 0.05 g / mL-0.2 g / mL, preferably 0.1 g / mL; (6) In the scheme 1, the reaction time of the reductive amination reaction is 4h-20h, preferably 8h; (7) In the scheme 1, the reaction temperature of the reductive amination reaction is 30℃-80℃, preferably 65℃; (8) In the scheme 1, the reductive amination reaction comprises the following post-treatment steps: dilution, for example, dilution with water, extraction, for example, extraction with ethyl acetate, concentration, for example, concentration under reduced pressure, purification by silica gel column chromatography to obtain the compound II; (9) In the scheme 1, the reaction raw materials are the solvent, the reducing agent, the compound VI and the compound III; (10) In the scheme 2, the acetaldehyde is acetaldehyde tetrahydrofuran solution; preferably 2M acetaldehyde tetrahydrofuran solution; (11) In the scheme 2, the solvent is an organic solvent, preferably an ether solvent, further preferably tetrahydrofuran; (12) In the scheme 2, the reducing agent is a borohydride reagent; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium tricyano borohydride, preferably sodium triacetoxyborohydride; (13) In the scheme 2, the molar ratio of the compound IV to the acetaldehyde is 1: (1-2), preferably 1:1.1; (14) In the scheme 2, the molar ratio of the compound IV to the reducing agent is 1: (1.5-3), preferably 1:2; (15) In the scheme 2, the mass-volume ratio of the compound IV to the solvent is 0.05 g / mL-0.2 g / mL, preferably 0.16 g / mL; (16) In the scheme 2, the reaction time of the reductive amination reaction is 4h-20h, preferably 16h; (17) In the scheme 2, the reaction temperature of the reductive amination reaction is 20℃-60℃, preferably 40℃; (18) In the scheme 2, the reductive amination reaction comprises the following post-treatment steps: dilution, for example, dilution with water, extraction, for example, extraction with ethyl acetate, concentration, for example, concentration under reduced pressure, purification by silica gel column chromatography to obtain the compound II; and (19) In the scheme 2, the reaction raw materials are the solvent, the reducing agent, the compound IV and the acetaldehyde.

4. The process for the 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 IV, which comprises the following step: a reductive amination reaction of the compound (R)-V with the compound III in a solvent in the presence of a reducing agent to prepare the compound IV; Preferably, the synthesis method of the compound IV satisfies one or more of the following conditions: (1) In the synthesis method of the compound IV, the solvent is an organic solvent, preferably an ether solvent, and further preferably tetrahydrofuran; (2) In the synthesis method of the compound IV, the reducing agent is a borohydride reagent; preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium tricyano borohydride, preferably sodium triacetoxyborohydride; (3) In the synthesis method of the compound IV, the molar ratio of the compound IV to the compound III is 1:(1-2), preferably 1:1; (4) In the synthesis method of the compound IV, the molar ratio of the compound IV to the reducing agent is 1:(1.5-3), preferably 1:2.5; (5) In the synthesis method of the compound IV, the mass-volume ratio of the compound VI to the solvent is 0.05 g / mL-0.2 g / mL, preferably 0.15 g / mL; (6) In the synthesis method of the compound IV, the reaction time of the reductive amination reaction is 4 h-20 h, more preferably 8 h; (7) In the synthesis method of the compound IV, the reaction temperature of the reductive amination reaction is 30°C-80°C, more preferably 65°C; (9) In the synthesis method of the compound IV, the reductive amination reaction comprises the following post-treatment steps: dilution, for example, dilution with water, extraction, for example, extraction with ethyl acetate, concentration, for example, concentration under reduced pressure, and purification of the compound IV by silica gel column chromatography; and (10) In the synthesis method of the compound IV, the reaction raw materials are the solvent, the reducing agent, the compound (R)-V and the compound III.

5. The process for the synthesis of compound I according to claim 3 or 4, characterized in that, The synthesis method of the compound II further comprises a synthesis method of the compound III, which comprises the following step: a deprotection reaction of the compound III-2 in a solvent in the presence of a catalyst to prepare the compound III; Preferably, the synthesis method of the compound III satisfies one or more of the following conditions: (1) In the deprotection reaction, the catalyst is an acid catalyst, preferably p-toluenesulfonic acid; (2) In the deprotection reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is preferably an ether solvent; further preferably tetrahydrofuran; preferably, the volume ratio of the organic solvent to the water is (8-12):1; preferably 10:1; (3) In the deprotection reaction, the molar ratio of the compound III-2 to the catalyst is 1:(0.05-0.2), preferably 1:0.1; (4) the mass-volume ratio of the compound III-2 to the solvent in the deprotection reaction is 0.15 g / mL-0.2 g / mL, preferably 0.18 g / mL; (5) the reaction time of the deprotection reaction is 0.5 h-6 h, preferably 1 h; (6) the reaction temperature of the deprotection reaction is 10°C-45°C, preferably room temperature; (7) the deprotection reaction comprises the following post-treatment steps: pouring the reaction solution into water, extraction, for example, extraction with ethyl acetate, drying, concentration, purification by silica gel column chromatography to obtain the compound III; and (8) the reaction raw materials of the deprotection reaction are the solvent, the catalyst and the compound III-2.

6. The method for synthesizing compound I according to claim 5, characterized in that, The synthesis method of the compound III further comprises a synthesis method of the compound III-2, which comprises the following steps: in a solvent, in the presence of a base, Willgerodt-Kindler reaction of the compound III-1 with a compound a and sulfur to prepare the compound III-2; The compound a is ethylamine or N-formyl ethylamine; preferably N-formyl ethylamine; Preferably, the synthesis method of the compound III-2 meets one or more of the following conditions: (1) in the Willgerodt-Kindler reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent can be an aromatic solvent, an amide solvent, an alcohol solvent or an ether solvent; the aromatic solvent can be pyridine, quinoline or N,N-dimethyl aniline, preferably quinoline; the amide solvent can be N,N-dimethylformamide or N-methyl pyrrolidone; the alcohol solvent can be ethanol or n-butanol; the ether solvent can be dioxane; preferably, the organic solvent is an aromatic solvent or an ether solvent; more preferably, the organic solvent is an ether solvent; the volume ratio of the organic solvent to water can be (3-6):1, preferably 5:1; (2) in the Willgerodt-Kindler reaction, the base is an organic base and / or an inorganic base; the organic base can be triethylamine; the inorganic base can be sodium carbonate; preferably, the base is an organic base and an inorganic base; (3) in the Willgerodt-Kindler reaction, the molar ratio of the compound III-1 to the sulfur is 1:(1.5-2.5), preferably 1:2; (4) in the Willgerodt-Kindler reaction, the molar ratio of the compound III-1 to the compound a is 1:(1-12), preferably 1:2; (5) in the Willgerodt-Kindler reaction, the molar ratio of the compound III-1 to the organic base is 1:(2-8), preferably 1:3 or 1:6; (6) in the Willgerodt-Kindler reaction, the molar ratio of the compound III-1 to the inorganic base is 1:(2-4), preferably 1:3 or 1:6; (7) In the Willgerodt-Kindler reaction, the mass-volume ratio of the compound III-1 to the solvent is 0.05 g / mL-0.2 g / mL, preferably 0.125 g / mL; (8) The reaction time of the Willgerodt-Kindler reaction is 6 h-15 h, preferably 12 h; (9) The reaction temperature of the Willgerodt-Kindler reaction is 100℃-145℃, preferably 120℃; (10) The Willgerodt-Kindler reaction comprises the following post-treatment steps: cooling, dilution, for example, dilution with water, extraction, extraction with ethyl acetate, washing, for example, washing with water and saturated brine respectively, drying, removal of the solvent, for example, removal under vacuum, purification of the compound III-2 by silica gel column chromatography; and (11) The reaction raw materials of the Willgerodt-Kindler reaction are the solvent, the base, the compound III-1, the compound a and the sulfur.

7. The method of claim 6 for the synthesis of compound I, wherein, The synthesis method of the compound III-2 further comprises a synthesis method of the compound III-1, which comprises the following steps: selectively protecting the aldehyde group of 4-acetylbenzaldehyde with ethylene glycol in a solvent in the presence of a dehydrating agent, to obtain the corresponding acetal compound III-1 by reaction; Preferably, the synthesis method of the compound III-1 meets one or more of the following conditions: (1) In the synthesis method of the compound III-1, the solvent is an organic solvent, preferably an ether solvent; further preferably ethyl acetate; (2) In the synthesis method of the compound III-1, the dehydrating agent is an acid dehydrating agent; preferably propane phosphonic anhydride, further preferably 50% ethyl acetate solution of propane phosphonic anhydride; (3) In the synthesis method of the compound III-1, the molar ratio of the compound III-1 to the ethylene glycol is 1:(1-2), preferably 1:1.2; (4) In the synthesis method of the compound III-1, the molar ratio of the compound III-1 to the dehydrating agent is 1:(0.05-0.2), more preferably 1:0.1; (5) In the synthesis method of the compound III-1, the mass-volume ratio of the compound III-1 to the solvent is 0.1 g / mL-0.2 g / mL, more preferably 0.14 g / mL; (6) In the synthesis method of the compound III-1, the reaction time is 2 h-8 h, preferably 5 h; (7) In the synthesis method of the compound III-1, the reaction temperature is 10℃-45℃, preferably room temperature; (8) In the synthesis method of the compound III-1, the reaction comprises the following post-treatment steps: cooling, dilution, for example, dilution with ethyl acetate, washing, for example, washing with saturated sodium bicarbonate, drying, for example, drying with anhydrous sodium sulfate, and filtering and concentrating to obtain the compound III-1; and (9) In the synthesis method of the compound III-1, the reaction raw material of the reaction is the solvent, the dehydrating agent, the 4-acetylbenzaldehyde and the ethylene glycol.

8. A synthesis method of a compound I, which is scheme a or scheme b Scheme a comprises the following steps, The compound VI and the compound III undergo a reductive amination reaction 1 to prepare the compound II; the compound II undergoes a reduction reaction to prepare the compound I; Scheme b comprises the following steps, The compound IV and acetaldehyde undergo a reductive amination reaction 2 to prepare the compound II; the compound II undergoes a reduction reaction to prepare the compound I; The operation and condition of the synthesis method of the compound II can be as described in claim 3; The operation and condition of the synthesis method of the compound I can be as described in claim 1 or 2; Preferably, the synthesis of the compound I further comprises any of the following schemes: Scheme 3, the synthesis of the compound I further comprises the synthesis of the compound III, The compound III-1 and the compound a, sulfur undergo a Willgerodt-Kindler reaction to prepare the compound III-2; the compound III-2 undergoes a deprotection reaction to prepare the compound III; The compound a is ethylamine or N-formyl ethylamine; preferably, N-formyl ethylamine; The operation and condition of the synthesis method of the compound III-2 can be as described in claim 6; The operation and condition of the synthesis method of the compound III can be as described in claim 5; Scheme 4, The synthesis method of the compound I further comprises the synthesis of the compound IV, The compound (R)-V and the compound III undergo a reductive amination reaction to prepare the compound IV; The operation and condition of the synthesis method of the compound IV can be as described in claim 4.

9. A synthesis method of a compound II, a compound IV, a compound III, a compound III-2 or a compound III-1, characterized in that, The synthesis of the compound II is any of the following schemes, Scheme 1, in a solvent, in the presence of a reducing agent, a reductive amination 1 reaction of the compound VI and the compound III to prepare the compound II; Scheme 2, in a solvent, in the presence of a reducing agent, a reductive amination reaction 2 of the compound IV and acetaldehyde to prepare the compound II; Preferably, the operation and condition of the synthesis method of the compound II are as described in claim 3; The synthesis method of the compound IV comprises the following steps, in a solvent, in the presence of a reducing agent, a reductive amination reaction of the compound (R)-V and the compound III to prepare the compound IV; Preferably, the operation and condition of the synthesis method of the compound IV are as described in claim 4; The synthesis method of the compound III comprises the following steps, in a solvent, in the presence of a catalyst, a deprotection reaction of the compound III-2 to prepare the compound III; Preferably, the operation and condition of the synthesis method of the compound III are as described in claim 5; The synthesis method of the compound III-2 comprises the following steps: in the presence of a base, a Willgerodt-Kindler reaction of compound III-1 with compound a and sulfur in a solvent to prepare compound III-2; The compound a is ethylamine or N-formyl ethylamine; preferably, the compound a is N-formyl ethylamine; Preferably, the operation and conditions of the synthesis method of the compound III-2 are as described in claim 6. The synthesis method of the compound III-1 comprises the following steps: in the presence of a dehydrating agent, an aldehyde group of 4-acetylbenzaldehyde is selectively protected by ethylene glycol in a solvent to obtain compound III-1; Preferably, the operation and conditions of the synthesis method of the compound III-1 are as described in claim 7.

10. A compound, which is any one of the following structures,

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