A method for synthesizing doxepin hydrochloride using benzofuranone as raw material

Abstract

A method for synthesizing doxepin hydrochloride using 3-benzofuranone as a raw material belongs to the technical field of chemical synthesis. The method uses cheap 3-benzofuranone as a raw material, and prepares doxepin hydrochloride through triflate, Suzuki coupling reaction, C-O bond activation dearomatization, Mitsunobu reaction and Heck reaction. The present invention simplifies the synthesis steps, has mild reaction conditions, is simple to operate, and has a high product yield, providing a new approach for the synthesis of doxepin hydrochloride compounds. Compared with the existing method, concentrated acid, organic lithium or Grignard reagent is not required, the reaction conditions are mild, the reaction steps are simplified, and the reaction efficiency is improved.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of doxepin hydrochloride, and in particular to a new method for fully synthesizing doxepin hydrochloride by taking 3-benzofuranone as a raw material. Background Art

[0002] Doxepin hydrochloride is also known as doxepin. Its chemical name is N,N-dimethyl-3-dibenzo[b,e]-oxepin-11(6H)ylidene-1-propylamine hydrochloride. It is a mixture of cis and trans isomers with a structural formula of

[0003]

[0004] Doxepin hydrochloride is a drug used to treat major depression, anxiety, chronic urticaria and sleep difficulties. This product is used as an external ointment to treat itching caused by atopic dermatitis or chronic simple lichen. This product also has a certain effect on resisting amine H1 and H2 receptors and can be used to treat allergic skin diseases. It is well absorbed orally, with a bioavailability of 13% to 45% and a half-life (t 1 / 2 ) is 8 to 12 hours, and the apparent volume of distribution (V d )9~33L / kg. It is mainly metabolized in the liver, and the active metabolite is a demethylated product, which is excreted from the kidneys. There are some patent reports on the total synthesis of doxepin hydrochloride (such as patents US20100179215, US20100179214, US20100305326, CN105061386A, CN105330638A, CN11279809A, CN102924424B). These synthetic methods use one or more steps to synthesize 6,11-dihydrodibenzo[b,e]oxepin-11-one intermediates, nucleophilic addition with Grignard reagents to obtain hydroxyl compounds, and then successively undergo elimination reaction under concentrated sulfuric acid conditions, halogenation reaction and dimethylamine substitution reaction, and finally salify with hydrochloric acid to obtain doxepin hydrochloride. Since these synthetic routes use very unstable Grignard reagents, highly corrosive concentrated sulfuric acid and hydrohalic acid, the experimental manipulation and synthetic conditions are required to be high, and the highly acidic waste liquid in the synthetic process brings high processing costs and environmental pollution. Therefore, the present invention adopts a new synthetic route system, using cheap benzofuranone as a raw material, and obtaining a diphenylethylene structural unit through CO bond activation dearomatization, followed by Mistunobu reaction to form methylene dibenzoxazine, and then through Heck reaction to obtain doxepin. The present invention has few synthetic steps, mild reaction conditions, simple manipulation, and is suitable for industrial preparation of doxepin hydrochloride. Summary of the invention

[0005] The object of the present invention is to provide a novel method for synthesizing doxepin hydrochloride by using benzofuranone as a raw material, with fewer synthesis steps and mild reaction conditions.

[0006] The present invention adopts the following technical route:

[0007] (1) 3-Benzofuranone is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to obtain 3-benzofuran trifluoromethanesulfonate compound 1.

[0008] (2) Compound 1 is reacted with a phenylboronic acid compound under the catalysis of metal palladium to undergo a Suzuki reaction to obtain compound 2.

[0009] (3) Compound 2 is reacted with a silicon boron reagent under alkaline conditions to prepare compound 3 via CO bond activation dearomatization.

[0010] (4) Compound 3 is subjected to an intramolecular Mistunobu reaction to obtain compound 4.

[0011] (5) Compound 4 was reacted with N,N-dimethyl-2-haloethylamine to prepare doxepin via Heck reaction.

[0012] (6) The obtained doxepin is reacted with hydrochloric acid to form a salt, thereby obtaining doxepin hydrochloride.

[0013] Among them, the preferred step (1) of the present invention is: the trifluoromethanesulfonyl esterification can use trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride as the trifluoromethanesulfonyl source, the equivalent ratio of which is 1 to 2, calculated as 1 based on the equivalent of 3-benzofuranone; the organic base is N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine, the equivalent ratio of which is 1 to 2, calculated as 1 based on the equivalent of 3-benzofuranone; the reaction solvent is dichloromethane, tetrahydrofuran, carbon tetrachloride, 1,2-dichloroethane, toluene, acetonitrile or ethylene glycol dimethyl ether. The reaction temperature is 0 to 30°C, and the reaction time is 6 to 24 hours.

[0014] Step (2) is: the phenylboronic acid compound is 2-hydroxymethylphenylboronic acid, 2-hydroxymethylphenylboronic acid pinacol ester or 2-hydroxymethylphenyl neopentyl glycol ester, and the equivalent ratio is 1 to 2, which is 1 based on the equivalent of compound 1;

[0015] The palladium catalyst is palladium acetate (Pd(OAc)2, palladium dichloride, bistriphenylphosphine palladium dichloride (PdCl2(PPh3)2 or tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), and the equivalent ratio is 0.01 to 0.1, which is 1 based on the equivalent of compound 1;

[0016] The base is potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate or potassium phosphate, and the equivalent ratio is 1 to 5, which is 1 based on the equivalent of compound 1;

[0017] The reaction solvent is a N,N-dimethylformamide / water mixture, 1,4-dioxane or an alcohol / water mixture, the reaction temperature is 60-100° C., and the reaction time is 6-24 hours.

[0018] Step (3) is: the silicon boron reagent is (dimethylphenylsilyl) boric acid pinacol ester (PhMe2SiBpin) or (triethylsilyl) boric acid pinacol ester (Et3SiBpin), and the equivalent ratio is 1 to 2, which is 1 based on the equivalent of compound 2;

[0019] The base is potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, lithium bistrimethylsilylamide or potassium bistrimethylsilylamide, and the equivalent ratio is 1 to 3, which is 1 based on the equivalent of compound 2;

[0020] The reaction solvent is tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether, the reaction temperature is 20-80° C., and the reaction time is 1-24 hours.

[0021] Step (4) is: the Mistunobu reaction uses 1 to 2 equivalents of diethyl azodicarboxylate and 1 to 2 equivalents of triphenylphosphine to react in toluene for 6 to 2 hours to obtain the product.

[0022] Step (5) is: the N,N-dimethyl-2-haloethylamine may be N,N-dimethyl-2-chloroethylamine, N,N-dimethyl-2-bromoethylamine or N,N-dimethyl-2-iodoethylamine;

[0023] The metal catalyst used in the Heck reaction is NiBr2·glyme, Ni(COD)2, NiBr2, [Pd(ally)Cl]2, PdCl2(dppf), Pd(PPh3)4 or Pd(OAc)2, and the equivalent ratio is 0.01 to 0.1, which is 1 based on the equivalent of compound 4;

[0024] The organophosphorus ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine (PPh3) or 1,1'-bis(di-tert-butylphosphino)ferrocene PdCl2 (dtbpf), and the dosage equivalent ratio is 0.01-0.2, which is 1 based on the equivalent of compound 4; the reaction conditions are blue light, the reaction temperature is 20-80°C, and the reaction time is 1-24h;

[0025] The reaction conditions are manganese powder or zinc powder, the base is triethylamine, cesium carbonate or potassium carbonate, the reaction temperature is 20-80°C, and the reaction time is 1-24h;

[0026] The crude product doxepin obtained by the synthesis method can be purified by recrystallization.

[0027] Step (6) is: adding an ethanol solution of anhydrous hydrogen chloride to the neutralization reaction, the content of hydrogen chloride gas in anhydrous ethanol is 20-30% at 0°C. The system is adjusted to pH 1-3, the reaction solvent is anhydrous ethanol, the reaction temperature is 0-10°C, and the reaction time is 2-12h.

[0028] The entire reaction route is shown below:

[0029]

[0030] By adopting the above technical solution, the present invention has the following gain effects:

[0031] 1. The synthesis method is simple and controllable, the reaction route is shortened, and the total yield can reach 52%.

[0032] 2. The present invention uses benzofuranone as a raw material and only needs six steps to complete the synthesis, which shortens the synthesis route compared with the traditional method.

[0033] 3. The present invention does not use Grignard reagent, and the synthesis equipment and operation requirements are simple and economical.

[0034] 4. For the synthesis step 3, a silicon boron reagent was innovatively used to realize the activation and ring-opening dearomatization of the CO bond of benzofuran under non-metallic conditions, with a high yield of up to 87% and few by-products.

[0035] 5. The reaction involved in the present invention does not use highly corrosive reagents such as concentrated acid, is environmentally friendly, meets the requirements of clean and low-carbon production, and is conducive to industrial production. DETAILED DESCRIPTION

[0036] The present invention is further described in detail below by way of examples, but the protection scope of the present invention is not limited to the described contents.

[0037] Embodiment 1: (1)

[0039]

[0040] 3-Benzofuranone (2g, 14.9mmol) was dissolved in a 100mL round-bottom flask filled with dichloromethane (20mL), and N,N-diisopropylethylamine (3.1mL, 17.88mmol) was transferred through a syringe under nitrogen protection. Stirring, trifluoromethanesulfonic anhydride (3.0mL, 17.88mmol) was transferred under -10°C, and the low temperature condition was removed and reacted at room temperature for 20h. After the reaction, 10mL of water was added, the liquid was separated, the aqueous phase was extracted with dichloromethane twice, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a mixture, which was then purified by silica gel column chromatography to obtain 4.76g of compound 1 with a yield of 95%.

[0041] 1H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.52 (d, J = 8.2Hz, 1H), 7.42 (td, J = 7.9, 1.4Hz, 1H), 7.37 (t, J = 7.4Hz, 1H). (2)

[0043]

[0044] Compound 1 (3.0 g, 11.27 mmol) and o-hydroxymethylphenylboronic acid (2.05 g, 13.52 mmol) were transferred to a round-bottom flask, and 20 mL of DMF / H2O (v / v, 4 / 1) mixed solvent was added, stirred, and protected by nitrogen. PdCl2(PPh3)2 (0.39 g, 0.56 mmol) and potassium carbonate (6.23 g, 45.08 mmol) were added, and the mixture was heated to 85°C and reacted for 12 h. After the reaction was completed, the temperature was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with a mixture of petroleum ether and ethyl acetate, the organic phase was dried, concentrated, and the obtained product was purified by silica gel column chromatography to obtain 2.40 g of compound 2 with a yield of 94%.

[0045] 1 H NMR (400MHz, CDCl3) δ7.87–7.80(m,1H),7.50–7.46(m,1H),7.44–7.35(m,5H),7.30–7.24(m,2H),4.89(dd,J=5.7,0.9Hz,2H). (3)

[0047]

[0048] Compound 2 (2.5 g, 11.1 mmol) was transferred into a round-bottom flask containing 20 mL of ethylene glycol dimethyl ether, and Et3SiBpin (4.03 g, 16.65 mmol) and potassium tert-butoxide (2.49 g, 22.2 mmol) were added. The mixture was protected by nitrogen and reacted at room temperature for 12 h. Tetrabutylammonium fluoride (2.90 g, 11.1 mmol) was then added and reacted at room temperature for 2 h. After the reaction was completed, 20 mL of water was added, the mixture was extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 2.18 g of compound 3 with a yield of 87%. 1H NMR (400MHz, CDCl3) δ7.57–7.45(m,2H),7.33–7.27(m,3H),7.10–7.08(m,1H), 7.02–6.87(m,1H),6.89–6.80(m,1H),5.60(d,J=2.2Hz,1H),5.24(d,J=2.2Hz,1H),4.89–4.73(m,2H). (4)

[0050]

[0051] Compound 3 (2.0 g, 8.8 mmol), diethyl azodicarboxylate (1.68 g, 9.68 mmol) and triphenylphosphine (8.8 mmol) were added to a round-bottom flask containing 17 mL of toluene, heated to 60°C, and reacted for 6 h. After the reaction was completed, 10 mL of water was added, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 1.68 g of compound 4 with a yield of 91%.

[0052] 1 H NMR(400MHz, CDCl3)δ7.49(dt,J=7.9,1.2Hz,1H),7.45–7.34(m,4H),7.23(td,J =7.9,1.7Hz,1H),7.01–6.94(m,1H),6.89(d,J=8.1Hz,1H),5.75(s,1H),5.33(d,J=1.1Hz,1H),5.24(s,2H).

[0053] 13 C NMR (101MHz, CDCl3) δ156.12,148.47,144.11,134.41,130.35,129.78,129.25, 128.23,127.63,127.01,125.79,121.39,119.82,117.43,70.96. (5)

[0055]

[0056] Compound 4 (0.5 g, 2.40 mmol) and N,N-dimethylaminoethyl bromide (0.54 g, 3.6 mmol) were added to a round-bottom flask containing 10 mL of tetrahydrofuran, and tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol) and cesium carbonate (1.56 g, 4.8 mmol) were added under nitrogen protection, and 40 W blue LED light was irradiated, and the reaction temperature was controlled at 20–30°C and the reaction was carried out for 12 h. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 0.52 g of compound 5 with a yield of 77%.

[0057] 1 H NMR (400MHz, CDCl3) δ7.40 (dd, J=7.9, 1.6Hz, 1H), 7.30–7.19 (m, 5H), 7.16–7.10 (m, 2H), 6.15–6.10(m,1H),5.16(s,2H),2.77–2.70(m,2H),2.61–2.56(m,2H),2.58–2.20(m,6H). (6)

[0059]

[0060] Compound 5 (0.139 g, 0.5 mmol) was dissolved in anhydrous ethanol. At 0°C, anhydrous hydrogen chloride ethanol solution with a mass concentration of 20-30% was added dropwise to generate a white precipitate. Anhydrous hydrogen chloride ethanol solution was added continuously to adjust the pH to 2-3. A white solid was obtained that no longer dissolved. The filter cake was filtered and air-dried to obtain 0.15 g of compound 6 with a yield of 95%.

[0061] Embodiment 2:

[0062] Compared with Example 1, the difference of this embodiment is:

[0063] Step 1 is:

[0064]

[0065] In this synthesis, the equivalent of 3-benzofuranone is 1. The reagent used for the trifluoromethanesulfonyl esterification of 3-benzofuranone is trifluoromethanesulfonyl chloride, the equivalent ratio is 1.1, and the equivalent ratio of N,N-diisopropylethylamine is 1.5, and the reaction is carried out at room temperature for 6 hours. After the reaction, water is added, the liquid is separated, the aqueous phase is extracted twice with dichloromethane, the organic phase is washed with saturated brine, dried with anhydrous magnesium sulfate, and concentrated to obtain a mixture, which is then purified by silica gel column chromatography with a yield of 94%.

[0066] Step 2 is:

[0067]

[0068] In this synthesis, the equivalent of compound 1 is calculated as 1. The reagents used are 2-hydroxymethylphenylboronic acid pinacol ester, the equivalent ratio is 1.5, the equivalent ratio of PdCl2(PPh3)2 is 0.05, the equivalent ratio of potassium phosphate is 3, and the reaction solvent is a DMF / H2O mixed system. Heat to 85°C and react for 12h. After the reaction is completed, cool to room temperature, add water, extract with a mixture of petroleum ether and ethyl acetate, dry the organic phase, concentrate, and purify the obtained product by silica gel column chromatography with a yield of 80%.

[0069] Step 3 is:

[0070]

[0071] In this synthesis, the equivalent of compound 2 is calculated as 1. The silicon boron reagent used is PhMe2SiBpin, the equivalent ratio is 1.5, potassium tert-butoxide is 2.5 equivalents, tetrahydrofuran is used as solvent, nitrogen protection, reaction at room temperature for 12 hours, and then 1.2 equivalents of tetrabutylammonium fluoride are added, and the reaction is carried out at room temperature for 2 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and then purified by silica gel column chromatography, with a yield of 81%.

[0072] Step 5 is:

[0073] In this synthesis, the equivalent of compound 4 is calculated as 1. The equivalent ratio of PdCl2(PPh3)2 is 0.05, the phosphine ligand Xantphos is 0.06 equivalent, potassium carbonate is 2.5 equivalent, DMA / H2O mixed system is used as solvent, 40W blue light is irradiated, the temperature is controlled at 20-30°C, and the reaction is carried out for 12 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and purified by silica gel column chromatography, with a yield of 80%.

[0074] Embodiment 3:

[0075] Compared with Example 1, the difference of this embodiment is:

[0076] Step 2 is:

[0077] In this synthesis, the equivalent of compound 1 is calculated as 1. The reagent used is 2-hydroxymethylphenylboronic acid, the equivalent ratio is 1.5, the catalyst is Pd(OAc)2, the equivalent ratio is 0.1, the phosphine ligand is Xantphos 0.05 equivalent, the equivalent ratio of cesium carbonate is 2.5, and the reaction solvent is 1,4-dioxane. Heat to 110°C and react for 12 hours. After the reaction is completed, cool to room temperature, add water, extract with a mixture of petroleum ether and ethyl acetate, dry the organic phase, concentrate, and purify the obtained product by silica gel column chromatography with a yield of 84%.

[0078] Step 3 is:

[0079] In this synthesis, the equivalent of compound 2 is calculated as 1. The silicon boron reagent is Et3SiBpin, the equivalent ratio is 1.5, 2.5 equivalents of sodium tert-butoxide, 1,4-dioxane is used as solvent, nitrogen protection, reaction at room temperature for 12 hours, and then 1.2 equivalents of tetrabutylammonium fluoride are added, and the reaction is carried out at room temperature for 2 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and then purified by silica gel column chromatography, with a yield of 84%.

[0080] Step 5 is:

[0081] In this synthesis, the equivalent of compound 4 is calculated as 1. The equivalent ratio of Pd(OAc)2 is 0.1, the phosphine ligand Xantphos is 0.2 equivalents, cesium carbonate is 3.0 equivalents, benzene is used as the reaction solvent, 40W blue light is irradiated, the temperature is controlled at 20-30°C, and the reaction is carried out for 12 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and purified by silica gel column chromatography, with a yield of 67%.

[0082] Embodiment 4:

[0083] Compared with Example 1, the difference of this embodiment is:

[0084] Step 3 is:

[0085] In this synthesis, the equivalent of compound 2 is calculated as 1. The silicon boron reagent is Et3SiBpin, the equivalent ratio is 2.0, potassium tert-butoxide is 2.5 equivalents, ethylene glycol dimethyl ether is used as solvent, nitrogen protection, room temperature reaction for 12 hours, and then tetrabutylammonium fluoride 1.2 equivalents are added, and the reaction is carried out at room temperature for 2 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and then purified by silica gel column chromatography, with a yield of 80%.

[0086] Step 5 is:

[0087] In this synthesis, the equivalent of compound 4 is calculated as 1. The equivalent ratio of tetrakis(triphenylphosphine)palladium is 0.05, potassium carbonate is 2.0 equivalents, DMA is used as the reaction solvent, 40W blue light is irradiated, the temperature is controlled at 20-30°C, and the reaction is carried out for 24 hours. After the reaction is completed, water is added, ethyl acetate is extracted, the organic phase is dried, concentrated, and purified by silica gel column chromatography, and the yield is 90%.

[0088] Embodiment 5:

[0089] Compared with Example 1, the difference of this embodiment is:

[0090] Step 2 is:

[0091]

[0092] Compound 3-bromobenzofuran (1.0 g, 5.07 mmol) and o-hydroxymethylphenylboronic acid (0.92 g, 6.08 mmol) were transferred to a round-bottom flask, 10 mL of DMF / H2O (v / v, 4 / 1) mixed solvent was added, stirred, nitrogen was protected, PdCl2(PPh3)2 (0.177 g, 0.25 mmol) and potassium carbonate (2.10 g, 15.21 mmol) were added, the mixture was heated to 85°C, and the reaction was continued for 12 h. After the reaction was completed, the temperature was lowered to room temperature, 5 mL of water was added, and the mixture was extracted with a mixture of petroleum ether and ethyl acetate, the organic phase was dried, concentrated, and the obtained product was purified by silica gel column chromatography to obtain 0.97 g of compound 2 with a yield of 85%.

[0093] Step 5 is: In this synthesis, the equivalent of compound 4 is calculated as 1. The equivalent ratio of bis(dibenzylideneacetone)palladium (Pd(dba)2) is 0.05, 1,1'-bis(diphenylphosphino)ferrocenecarbonate (dppf) is 0.1 equivalent, lithium iodide is 2.0 equivalent, N-methyldicyclohexylamine is 1.5 equivalent, trifluorotoluene is used as the reaction solvent, the reaction temperature is 110°C, and the reaction is carried out for 24 hours. After the reaction is completed, water is added, extracted with ethyl acetate, the organic phase is dried, concentrated, and purified by silica gel column chromatography to obtain compound 5 with a yield of 71%.

[0094] 1 H NMR (400MHz, CDCl3) δ7.87–7.80(m,1H),7.50–7.46(m,1H),7.44–7.35(m,5H),7.30–7.24(m,2H),4.89(dd,J=5.7,0.9Hz,2H).

[0095] Embodiment 6:

[0096] Compared with Example 1, the difference of this embodiment is:

[0097] Step 2 is:

[0098]

[0099] Compound 3-bromobenzofuran (1.0 g, 5.07 mmol) and o-hydroxymethylphenylboronic acid pinacol ester (1.42 g, 6.08 mmol) were transferred to a round-bottom flask, 10 mL of DMF / H2O (v / v, 4 / 1) mixed solvent was added, stirred, nitrogen was protected, PdCl2(PPh3)2 (0.177 g, 0.25 mmol) and potassium carbonate (2.10 g, 15.21 mmol) were added, and the mixture was heated to 85°C and reacted for 12 h. After the reaction was completed, the temperature was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with a mixture of petroleum ether and ethyl acetate, the organic phase was dried and concentrated, and the obtained product was purified by silica gel column chromatography to obtain 0.92 g of compound 2 with a yield of 81%.

[0100] 1 H NMR (400MHz, CDCl3) δ7.87–7.80(m,1H),7.50–7.46(m,1H),7.44–7.35(m,5H),7.30–7.24(m,2H),4.89(dd,J=5.7,0.9Hz,2H).

[0101] The applicant declares that the present invention illustrates the detailed process flow of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process equipment and process flow to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing doxepin hydrochloride using 3-benzofuranone as a raw material, characterized in that: Includes steps: (1) reacting 3-benzofuranone with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to obtain 3-benzofuran trifluoromethanesulfonate compound 1; the reaction equation is as follows: (2) Compound 1 is reacted with a phenylboronic acid compound under the catalysis of metal palladium by Suzuki reaction to obtain compound 2. The reaction equation is as follows: (3) Compound 2 is reacted with a silicon boron reagent under alkaline conditions to prepare compound 3, and the reaction equation is as follows: The silicon boron reagent is (dimethylphenylsilyl)boric acid pinacol ester or (triethylsilyl)boric acid pinacol ester; (4) Compound 3 is subjected to an intramolecular Mistunobu reaction to obtain compound 4. The reaction equation is as follows: (5) Compound 4 and N,N-dimethyl-2-haloethylamine are reacted to prepare doxepin via Heck reaction. The reaction equation is as follows: (6) reacting the obtained doxepin with hydrochloric acid to obtain doxepin hydrochloride, and the reaction equation is as follows:

2. The synthesis method according to claim 1, characterized in that In the step (1): Using trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride as the trifluoromethanesulfonyl reagent, the equivalent ratio is 1 to 2, based on the equivalent of 3-benzofuranone as 1; Use N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine as an organic base in an equivalent ratio of 1 to 2, based on the equivalent of 3-benzofuranone as 1; The reaction solvent is dichloromethane, tetrahydrofuran, carbon tetrachloride, 1,2-dichloroethane, toluene, acetonitrile or ethylene glycol dimethyl ether; the reaction temperature is 0-30° C., and the reaction time is 6-24 hours.

3. The synthesis method according to claim 1, characterized in that In the step (2): The phenylboronic acid compound is 2-hydroxymethylphenylboronic acid, 2-hydroxymethylphenylboronic acid pinacol ester or 2-hydroxymethylphenyl neopentyl glycol ester, and the equivalent ratio is 1 to 2, with the equivalent of compound 1 being 1; The metal palladium is palladium acetate (Pd(OAc)2), palladium dichloride, bistriphenylphosphine palladium dichloride (PdCl2(PPh3)2) or tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), and the equivalent ratio is 0.01 to 0.1, based on the equivalent of compound 1 being 1; Potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate or potassium phosphate is used as a base in an equivalent ratio of 1 to 5, based on the equivalent of compound 1 being 1; The reaction solvent is a N,N-dimethylformamide / water mixture, 1,4-dioxane or an ethanol / water mixture, the reaction temperature is 60-100° C., and the reaction time is 6-24 hours.

4. The synthesis method according to claim 1, characterized in that In the step (3): The equivalent ratio of the silicon boron reagent is 1 to 2, with the equivalent of compound 2 being 1; Potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, lithium bistrimethylsilylamide or potassium bistrimethylsilylamide is used as a base in an equivalent ratio of 1 to 3, based on the equivalent of compound 2 being 1; The reaction solvent is tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether, the reaction temperature is 20-80° C., and the reaction time is 1-24 hours.

5. The synthesis method according to claim 1, characterized in that In the step (5): The N,N-dimethyl-2-haloethylamine is N,N-dimethyl-2-chloroethylamine, N,N-dimethyl-2-bromoethylamine or N,N-dimethyl-2-iodoethylamine; The Heck reaction uses NiBr2·glyme, Ni(COD)2, NiBr2, [Pd(ally)Cl]2, PdCl2(dppf), Pd(PPh3)4 or Pd(OAc)2 as a metal catalyst, and the equivalent ratio is 0.01 to 0.1, based on the equivalent of compound 4 being 1; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine (PPh3) or 1,1'-bis(di-tert-butylphosphino)ferrocene PdCl2 (dtbpf) is used as an organic phosphorus ligand in an equivalent ratio of 0.01 to 0.2, based on the equivalent of compound 4 being 1; The reaction conditions are blue light, reaction temperature is 20-80°C, and reaction time is 1-24h; The reaction conditions are manganese powder or zinc powder, triethylamine, cesium carbonate or potassium carbonate as a base, a reaction temperature of 20 to 80° C., and a reaction time of 1 to 24 hours.

6. The synthesis method according to claim 1, characterized in that In the step (6): An ethanol solution of anhydrous hydrogen chloride is added to the reaction, and the content of hydrogen chloride gas in anhydrous ethanol is 20-30% at 0°C; the system pH is adjusted to 1-3, the reaction solvent is anhydrous ethanol, the reaction temperature is 0-10°C, and the reaction time is 2-12h.

Images