CN116239562A - Method for synthesizing doxepin hydrochloride by taking benzofuranone as raw material - Google Patents
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Abstract
A method for synthesizing doxepin hydrochloride by taking 3-benzofuranone as a raw material belongs to the technical field of chemical synthesis. The method takes cheap 3-benzofuranone as a raw material, and prepares doxepin hydrochloride through trifluoro methane sulfonic acid esterification, suzuki coupling reaction, C-O bond activation dearomatization, mitsunobu reaction and Heck reaction. The method simplifies the synthesis steps, has mild reaction conditions, simple operation and high product yield, and provides a new way for synthesizing the doxepin hydrochloride compound. Compared with the existing method, concentrated acid, organic lithium or Grignard reagent is not needed, the reaction condition is mild, the reaction steps are simplified, and the reaction efficiency is improved.
Description
Technical Field
The invention relates to the technical field of doxepin hydrochloride synthesis, in particular to a novel method for fully synthesizing doxepin hydrochloride by taking 3-benzofuranone as a raw material.
Background
Doxepin hydrochloride is also known as doxepin, has the chemical name of N, N-dimethyl-3-dibenzo [ b, e ] -oxepin-11 (6H) subunit-1-propylamine hydrochloride, is a mixture of cis and trans isomers, and has the structural formula
Doxepin hydrochloride is a medicine for treating major depression, anxiety, chronic urticaria and sleep difficulties, and the topical ointment is used for treating atopic dermatitis or pruritus caused by chronic simple moss. The product also has certain effects of resisting amine H1 and H2 receptor, and can be used for treating allergic dermatoses. Has good oral absorption, 13-45 percent of bioavailability and half-life (t) 1/2 ) For 8 to 12 hours, apparent distribution volume (V d ) 9-33L/kg. Mainly in liver metabolism, the active metabolite is a demethylate, and the metabolite is excreted from the kidneys. There are some patent reports on the total synthesis of doxepin hydrochloride (e.g. patent US20100179215, US20100179214, US20100305326, CN105061386a, CN105330638a, CN112798 09a, CN102924424 b). These synthetic methods employ one or more steps for the synthesis of 6, 11-dihydrodibenzo [ b, e]The oxaheptin-11-one intermediate is nucleophilic added with Grignard reagent to obtain hydroxyl compound, and then the hydroxyl compound is subjected to elimination reaction, halogenation reaction and dimethylamine substitution reaction under the condition of concentrated sulfuric acid in sequence, and finally is salified with hydrochloric acid to obtain doxepin hydrochloride. Because the synthetic routes adopt very unstable Grignard reagents, strong corrosive concentrated sulfuric acid and halogen acid, the requirements on experimental control and synthetic conditions are high, and the strong acid waste liquid in the synthetic process brings high treatment cost and environmental pollution. Therefore, the invention adopts a brand new synthetic route system, takes cheap benzofuranone as a raw material, obtains a stilbene structural unit through C-O bond activation dearomatization, then forms methylene dibenzoxazepine through Mistunbu reaction, and finally obtains doxepin through Heck reaction. The method has the advantages of few synthesis steps, mild reaction conditions and simple control, and is suitable for industrially preparing doxepin hydrochloride.
Disclosure of Invention
The invention aims to provide a method for synthesizing doxepin hydrochloride by taking benzofuranone as a raw material, which has few synthesis steps and mild and novel reaction conditions.
The invention adopts the following technical route:
(1) 3-benzofuranone is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to give 3-benzofurantriflate compound 1.
(2) And (3) carrying out a Suzuki reaction on the compound 1 and the phenylboronic acid compound under the catalysis of metal palladium to obtain a compound 2.
(3) Compound 2 and a silicon-boron reagent are activated and dearomatized through a C-O bond under the condition of alkali to prepare compound 3.
(4) Compound 3 was subjected to intramolecular mistenobu reaction to give compound 4.
(5) Compound 4 and N, N-dimethyl-2-halogenated ethylamine are subjected to Heck reaction to prepare doxepin.
(6) Salifying the doxepin with hydrochloric acid to obtain doxepin hydrochloride
Wherein, the step (1) is preferably: the trifluoro methanesulfonic acid esterification can use trifluoro methanesulfonic anhydride or trifluoro methanesulfonyl chloride as a trifluoro methanesulfonyl source, the using amount equivalent ratio is 1-2, and the equivalent ratio of 3-benzofuranone is 1; n, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethyl ethylenediamine is used as an organic base, the dosage equivalent ratio is 1-2, and the equivalent ratio of 3-benzofuranone is 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 ℃ and the reaction time is 6-24 h.
The step (2) is as follows: the phenylboronic acid compound is 2-hydroxymethylphenylboronic acid, 2-hydroxymethylphenylboronic acid pinacol ester or 2-hydroxymethylphenylneopentyl glycol ester, the using amount equivalent ratio is 1-2, and the equivalent weight of the compound 1 is 1;
the palladium catalyst is palladium acetate (Pd (OAc) 2 Palladium dichloride, ditriphenylphosphine palladium dichloride (PdCl) 2 (PPh 3 ) 2 Or tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) The equivalent ratio of the dosage is 0.01 to 0.1, and the equivalent of the compound 1 is 1;
the alkali is potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate or potassium phosphate, the dosage equivalent ratio is 1-5, and the equivalent of the compound 1 is 1;
the reaction solvent is N, N-dimethylformamide/water mixed solution, 1, 4-dioxane or alcohol/water mixed solution, the reaction temperature is 60-100 ℃, and the reaction time is 6-24 h.
The step (3) is as follows: the silicon-boron reagent is (dimethylbenzenyl) boric acid pinacol ester (PhMe) 2 SiBpin) or pinacol (triethylsilyl) borate (Et) 3 SiBpin), the equivalent ratio of the dosage is 1-2, and the equivalent of the compound 2 is 1;
the alkali is potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide, and the dosage equivalent ratio is 1-3, and the equivalent of the compound 2 is 1;
the reaction solvent is tetrahydrofuran, 1, 4-dioxane or ethylene glycol dimethyl ether, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 h.
The step (4) is as follows: the Mistunbu reaction is carried out by adopting 1-2 equivalents of diethyl azodicarboxylate and 1-2 equivalents of triphenylphosphine, and reacting in toluene for 6-2 hours.
The step (5) is as follows: the N, N-dimethyl-2-halogenated ethylamine can be N, N-dimethyl-2-chloroethylamine, N-dimethyl-2-bromoethylamine or N, N-dimethyl-2-iodoethylamine;
the metal catalyst used in the Heck reaction is NiBr 2 ·glyme、Ni(COD) 2 、NiBr 2 、[Pd(ally)Cl] 2 、 PdCl 2 (dppf)、Pd(PPh 3 ) 4 Or Pd (OAc) 2 The equivalent ratio of the dosage is 0.01 to 0.1, and the equivalent of the compound 4 is 1;
the organophosphorus ligand is 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (Xantphos), triphenylphosphine (PPh) 3 ) Or 1,1' -bis (di-tert-butylphosphine) ferrocene PdCl 2 (dtbpf) in an amount equivalent ratio of 0.01 to 0.2, 1 in terms of equivalent of compound 4; the reaction condition is blue light, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 hours;
the reaction condition is manganese powder or zinc powder, wherein the alkali is triethylamine, cesium carbonate or potassium carbonate, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 hours;
the crude product doxepin obtained by the synthesis method can be purified by adopting a recrystallization method.
The step (6) is as follows: the neutralization reaction is carried out by adding ethanol solution of anhydrous hydrogen chloride, and the content of hydrogen chloride gas in the absolute ethanol is 20-30% at 0 ℃. The pH value of the system is regulated to be 1-3, the reaction solvent is absolute ethyl alcohol, the reaction temperature is 0-10 ℃, and the reaction time is 2-12h.
The entire reaction scheme is shown below:
by adopting the technical scheme, the invention has the following gain effects:
1. the synthesis method is simple and controllable, the reaction route is shortened, and the total yield can reach 52%.
2. The invention adopts benzofuranone as raw material, only six steps are needed to complete the synthesis, and compared with the traditional method, the synthesis route is shortened.
3. The invention does not use Grignard reagent, and has simple and economical synthesis equipment and operation requirements.
4. For the synthetic step 3, a silicon-boron reagent is innovatively adopted, the benzofuran C-O bond activation ring opening dearomatization is realized under a nonmetallic condition, the yield is high and can reach 87%, and the byproducts are few.
5. The reaction related by the invention does not use strong corrosive reagents such as concentrated acid, is environment-friendly, meets the requirement of clean low-carbon production, and is favorable for industrial production.
Detailed Description
The present invention will be described in further detail by way of examples, but the scope of the present invention is not limited to the above.
Example 1:
(1)
3-benzofuranone (2 g,14.9 mmol) was dissolved in a 100mL round bottom flask containing dichloromethane (20 mL), nitrogen purged, transferred by syringe to N, N-diisopropylethylamine (3.1 mL,17.88 mmol), stirred, transferred to trifluoromethanesulfonic anhydride (3.0 mL,17.88 mmol) at-10℃and removed from the low temperature and reacted at room temperature for 20h. After the completion of the reaction, 10mL of water was added, the mixture was separated, the aqueous phase was extracted twice with methylene chloride, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a mixture, which was purified by silica gel column chromatography to give 4.76g of Compound 1 in 95% yield.
1 H NMR(400MHz,CDCl 3 )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)
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 20mL DMF/H was added 2 O (v/v, 4/1) mixed solvent, stirring, nitrogen protection, adding PdCl 2 (PPh 3 ) 2 (0.39 g, 0.56 mmol) and potassium carbonate (6.23 g,45.08 mmol), and the mixture was heated to 85℃and reacted for 12h. After the reaction was completed, the reaction mixture was cooled to room temperature, 20mL of water was added, the mixture was extracted with 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 2.40g of Compound 2 in 94% yield.
1 H NMR(400MHz,CDCl 3 )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)
Compound 2 (2.5 g,11.1 mmol) was transferred to a round bottom flask containing 20mL of glyme and Et was added 3 SiBpin (4.03 g,16.65 mmol) and potassium tert-butoxide (2.49 g,22.2 mmol), under nitrogen, were reacted at room temperature for 12h, tetrabutylammonium fluoride (2.90 g,11.1 mmol) was added thereto, and reacted at room temperature for 2h. After the completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate, the organic phase was dried, concentrated, and further purified by silica gel column chromatography to obtain 2.18g of Compound 3 in 87% yield. 1 H NMR(400MHz,CDCl 3 )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)
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 17mL toluene and heated to 60℃for 6h. After the completion of the reaction, 10. 10mL water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to give 1.68g of compound 4 in 91% yield.
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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)
Compound 4 (0.5 g,2.40 mmol) and N, N-dimethylaminobromoethane (0.54 g,3.6 mmol) were added to a round-bottomed flask containing 10mL tetrahydrofuran, nitrogen-blanketed, tetra (triphenylphosphine) palladium (0.28 g,0.24 mmol) and cesium carbonate (1.56 g,4.8 mmol) were added, and a 40W blue LED lamp was illuminated, and the reaction temperature was controlled at 20-30℃for 12h. After the completion of the reaction, 10mL of water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to give 0.52g of compound 5 in 77% yield.
1 H NMR(400MHz,CDCl 3 )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)
Compound 5 (0.139 g,0.5 mmol) was dissolved in absolute ethanol, and an absolute hydrogen chloride ethanol solution having a mass concentration of 20 to 30% was added dropwise at 0℃to give a white precipitate. Continuously adding anhydrous hydrogen chloride ethanol solution, and regulating the pH to 2-3 to obtain white solid which is not dissolved. Filtration gave a filter cake, which was air-dried to give 0.15g of Compound 6 in 95% yield.
Example 2:
compared with embodiment 1, this embodiment differs in that:
the step 1 is as follows:
in the present synthesis, the equivalent weight of 3-benzofuranone is 1. The reagent used for 3-benzofuranone triflate is triflyl chloride, the equivalent ratio of the dosage is 1.1, the equivalent ratio of the dosage of N, N-diisopropylethylamine is 1.5, and the reaction is carried out for 6 hours at room temperature. After the completion of the reaction, water was added, the mixture was separated, the aqueous phase was extracted twice with methylene chloride, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a mixture, which was purified by silica gel column chromatography in 94% yield.
The step 2 is as follows:
in this synthesis, the equivalent of compound 1 is 1. The reagent is 2-hydroxymethylphenylboronic acid pinacol ester with the dosage equivalent ratio of 1.5 and PdCl 2 (PPh 3 ) 2 The equivalent ratio of the dosage is 0.05, the equivalent ratio of the dosage of the potassium phosphate is 3, and the reaction solvent is DMF/H 2 And (3) an O mixed system. Heated to 85 ℃ and reacted for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, the mixture was extracted with petroleum ether and ethyl acetate, the organic phase was dried, and concentrated, and the obtained product was purified by silica gel column chromatography in 80% yield.
The step 3 is as follows:
in this synthesis, 1 is calculated as an equivalent of compound 2. Adopts silicon boron reagent as PhMe 2 SiBpin with the dosage equivalent ratio of 1.5, 2.5 equivalents of potassium tert-butoxide, tetrahydrofuran as solvent, nitrogen protection, reaction for 12 hours at room temperature, and further adding 1.2 equivalents of tetrabutylammonium fluoride for reaction for 2 hours at room temperature. After the reaction was completed, water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography, with a yield of 81%.
The step 5 is as follows:
in this synthesis, the equivalent of compound 4 is 1. By PdCl 2 (PPh 3 ) 2 The equivalent ratio of the amount of the phosphine ligand Xantphos is 0.06 equivalent, the potassium carbonate is 2.5 equivalent, and the DMA/H is 0.05 2 The O mixed system is used as a solvent, 40W of blue light is irradiated, the temperature is controlled to be 20-30 ℃, and the reaction is carried out for 12 hours. After the reaction was completed, water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography in 80% yield.
Example 3:
compared with embodiment 1, this embodiment differs in that:
the step 2 is as follows:
in this synthesis, the equivalent of compound 1 is 1. The reagent is 2-hydroxymethylphenylboronic acid, the dosage equivalent ratio is 1.5, and the catalyst is Pd (OA)c) 2 The equivalent ratio of the dosage is 0.1, the phosphine ligand is Xantphos 0.05 equivalent, the equivalent ratio of the dosage of cesium carbonate is 2.5, and the reaction solvent is 1, 4-dioxane. Heated to 110 ℃ and reacted for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, the mixture was extracted with petroleum ether and ethyl acetate, the organic phase was dried, and concentrated, and the obtained product was purified by silica gel column chromatography in a yield of 84%.
The step 3 is as follows:
in this synthesis, 1 is calculated as an equivalent of compound 2. Et using a silico-boron reagent 3 SiBpin with the dosage equivalent ratio of 1.5, 2.5 equivalents of sodium tert-butoxide and 1, 4-dioxane as a solvent, nitrogen protection, and reacting for 12 hours at room temperature, adding 1.2 equivalents of tetrabutylammonium fluoride, and reacting for 2 hours at room temperature. After the reaction was completed, water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography, with a yield of 84%.
The step 5 is as follows:
in this synthesis, the equivalent of compound 4 is 1. Pd (OAc) 2 The equivalent ratio of the dosage is 0.1, the phosphine ligand Xantphos is 0.2 equivalent, cesium carbonate is 3.0 equivalent, benzene is used as a reaction solvent, 40W blue light is irradiated, the temperature is controlled to be 20-30 ℃, and the reaction is carried out at 12-h. After the reaction was completed, water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography in 67% yield.
Example 4:
compared with embodiment 1, this embodiment differs in that:
the step 3 is as follows:
in this synthesis, 1 is calculated as an equivalent of compound 2. Et using a silico-boron reagent 3 SiBpin with the dosage equivalent ratio of 2.0 and potassium tert-butoxide of 2.5 equivalent, ethylene glycol dimethyl ether as solvent, nitrogen protection, reaction at room temperature for 12h, and further adding tetrabutylammonium fluoride of 1.2 equivalent, and reaction at room temperature for 2h. After the reaction was completed, water was added, extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography, with a yield of 80%.
The step 5 is as follows:
in this synthesis, the equivalent of compound 4 is 1. The method adopts tetrakis (triphenylphosphine) palladium with the equivalent ratio of 0.05 and 2.0 equivalents of potassium carbonate and DMA as reaction solvent, and comprises the steps of irradiating with 40W blue light, controlling the temperature to be 20-30 ℃ and reacting for 24 hours. After the reaction was completed, water was added, extraction was performed with ethyl acetate, the organic phase was dried, concentrated, and purified by silica gel column chromatography, with a yield of 90%.
Example 5:
compared with embodiment 1, this embodiment differs in that:
the step 2 is as follows:
the compound 3-bromobenzofuran (1.0 g,5.07 mmol) and o-hydroxymethylphenylboronic acid (0.92 g,6.08 mmol) were transferred into a round-bottomed flask and 10mL DMF/H was added 2 O (v/v, 4/1) mixed solvent, stirring, nitrogen protection, adding PdCl 2 (PPh 3 ) 2 (0.177 g,0.25 mmol) and potassium carbonate (2.10 g,15.21 mmol), and the mixture was heated to 85℃and reacted for 12h. After completion of the reaction, the reaction mixture was cooled to room temperature, 5mL of water was added, the mixture was extracted with petroleum ether and ethyl acetate, the organic phase was dried, and concentrated, and the resultant was purified by silica gel column chromatography to give 0.97g of Compound 2 in 85% yield.
The step 5 is as follows: in this synthesis, the equivalent of compound 4 is 1. Palladium (Pd (dba) using bis (dibenzylideneacetone) 2 ) The dosage equivalent ratio is 0.05,1,1' -bis (diphenylphosphine) ferrocenecarbonate (dppf) 0.1 equivalent, lithium iodide 2.0 equivalent, N-methyl dicyclohexylamine 1.5 equivalent, benzotrifluoride as a reaction solvent, and the reaction temperature is 110 ℃ for 24 hours. After the reaction was completed, water was added, extraction was performed with ethyl acetate, the organic phase was dried, concentrated, and purified by silica gel column chromatography to give compound 5 in 71% yield.
1 H NMR(400MHz,CDCl 3 )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).
Example 6:
compared with embodiment 1, this embodiment differs in that:
the step 2 is as follows:
the compound 3-bromobenzofuran (1.0 g,5.07 mmol) and pinacol o-hydroxymethylphenylborate (1.42 g,6.08 mmol) were transferred into a round-bottomed flask and 10mL DMF/H was added 2 O (v/v, 4/1) mixed solvent, stirring, nitrogen protection, adding PdCl 2 (PPh 3 ) 2 (0.177 g,0.25 mmol) and potassium carbonate (2.10 g,15.21 mmol), and the mixture was heated to 85℃and reacted for 12h. After completion of the reaction, the reaction mixture was cooled to room temperature, 5mL of water was added, the mixture was extracted with petroleum ether and ethyl acetate, the organic phase was dried, and concentrated, and the resultant was purified by silica gel column chromatography to give 0.92g of Compound 2 in a yield of 81%.
1 H NMR(400MHz,CDCl 3 )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).
The applicant states that the detailed process flow of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed process flow, i.e. it does not mean that the present invention must be implemented by means of the detailed process equipment and process flow described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (6)
1. The synthesis method for synthesizing doxepin hydrochloride by taking 3-benzofuranone as a raw material is characterized by comprising the following steps:
(1) 3-benzofuranone is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to give 3-benzofurantriflate compound 1. The reaction equation is as follows:
(2) The compound 1 and phenylboronic acid compound are subjected to Suzuki reaction under the catalysis of metallic palladium to obtain a compound X, and the reaction equation is as follows:
(3) Compound 2 and a silicon-boron reagent react under the condition of alkali to prepare compound 3, and the reaction equation is as follows:
(4) Intramolecular Mistunbu reaction of compound 3 gave compound 4, which was reacted as follows:
(5) The compound 4 and N, N-dimethyl-2-halogenated ethylamine are subjected to Heck reaction to prepare doxepin, and the reaction equation is as follows:
(6) And (3) salifying the doxepin to obtain doxepin hydrochloride, wherein the reaction equation is as follows:
2. the method of synthesis according to claim 1, wherein in step (1):
the trifluoro methanesulfonic acid esterification reaction can use trifluoro methanesulfonic anhydride or trifluoro methanesulfonyl chloride as trifluoro methanesulfonyl reagent, the dosage equivalent ratio is 1-2, and the equivalent ratio of 3-benzofuranone is 1;
n, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethyl ethylenediamine is used as an organic base, the dosage equivalent ratio is 1-2, and the equivalent ratio of 3-benzofuranone is 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 ℃ and the reaction time is 6-24 h.
3. The synthesis method according to claim 1, wherein in the step (2):
the phenylboronic acid compound is 2-hydroxymethylphenylboronic acid, 2-hydroxymethylphenylboronic acid pinacol ester or 2-hydroxymethylphenylneopentyl glycol ester, the using amount equivalent ratio is 1-2, and the equivalent weight of the compound X is 1;
the palladium catalyst is palladium acetate (Pd (OAc) 2 Palladium dichloride, ditriphenylphosphine palladium dichloride (PdCl) 2 (PPh 3 ) 2 ) Or tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) The equivalent ratio of the dosage is 0.01 to 0.1, and the equivalent of the compound 1 is 1;
the alkali is potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate or potassium phosphate, the dosage equivalent ratio is 1-5, and the equivalent of the compound 1 is 1;
the reaction solvent is N, N-dimethylformamide/water mixed solution, 1, 4-dioxane or ethanol/water mixed solution, the reaction temperature is 60-100 ℃, and the reaction time is 6-24 h.
4. The method of synthesis according to claim 1, wherein in step (3):
the silicon-boron reagent is (dimethylbenzenyl) boric acid pinacol ester (PhMe) 2 SiBpin) or pinacol (triethylsilyl) borate (Et) 3 SiBpin), the equivalent ratio of the dosage is 1-2, and the equivalent of the compound 2 is 1;
the alkali is potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide, and the dosage equivalent ratio is 1-3, and the equivalent of the compound 2 is 1;
the reaction solvent is tetrahydrofuran, 1, 4-dioxane or ethylene glycol dimethyl ether, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 h.
5. The synthesis method according to claim 1, wherein in the step (5):
the N, N-dimethyl-2-halogenated ethylamine can be N, N-dimethyl-2-chloroethylamine, N-dimethyl-2-bromoethylamine or N, N-dimethyl-2-iodoethylamine;
the metal catalyst used in the Heck reaction is NiBr 2 ·glyme、Ni(COD) 2 、NiBr 2 、[Pd(ally)Cl] 2 、PdCl 2 (dppf)、Pd(PPh 3 ) 4 Or Pd (OAc) 2 The equivalent ratio of the dosage is 0.01 to 0.1, and the equivalent of the compound 4 is 1;
the organophosphorus ligand is 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (Xantphos), triphenylphosphine (PPh) 3 ) Or 1,1' -bis (di-tert-butylphosphine) ferrocene PdCl 2 (dtbpf) in an amount equivalent ratio of 0.01 to 0.2, 1 in terms of equivalent of compound 4;
the reaction condition is blue light, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 hours;
the reaction condition is manganese powder or zinc powder, the alkali is triethylamine, cesium carbonate or potassium carbonate, the reaction temperature is 20-80 ℃, and the reaction time is 1-24 h.
6. The synthesis method according to claim 1, wherein in the step (6):
the neutralization reaction is carried out by adding ethanol solution of anhydrous hydrogen chloride, and the content of hydrogen chloride gas in the absolute ethanol is 20-30% at 0 ℃. The pH value of the system is regulated to be 1-3, the reaction solvent is absolute ethyl alcohol, the reaction temperature is 0-10 ℃, and the reaction time is 2-12h.
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