阅读说明：本技术 一种盐酸多塞平的合成方法 (Synthesis method of doxepin hydrochloride ) 是由 黄金文 刘福力 吴范宏 倪壮 薛康燕 唐慧 朱冉冉 许超 张兰玲 于 2021-08-26 设计创作，主要内容包括：本发明涉及一种盐酸多塞平的合成方法。该方法包括以下合成步骤：(1)亚磷酸酯与3-氯-1-(N,N-二甲基)丙胺进行艾伯佐夫反应,经蒸馏纯化得到3-(N,N-二甲基)丙基磷酸酯,或其与盐酸成盐结晶得到3-(N,N-二甲基)丙基磷酸酯盐酸盐；(2)将3-(N,N-二甲基)丙基磷酸酯或其盐酸盐与6,11-二氢二苯并[b,e]噁庚英-11-酮在强碱条件下进行Wittig反应得到多塞平；(3)将多塞平与盐酸进行成盐反应,制得盐酸多塞平。本发明于第一步反应步骤中,采用艾伯佐夫反应制得的烷基磷酸酯产物收率较高,由此保证了终产物盐酸多塞平的收率和纯度。与现有技术相比,本发明具有工艺简单,生产成本低,工艺步骤少等优点。(The invention relates to a synthesis method of doxepin hydrochloride. The method comprises the following synthetic steps: (1) carrying out an Ebazochralski reaction on phosphite ester and 3-chloro-1- (N, N-dimethyl) propylamine, and distilling and purifying to obtain 3- (N, N-dimethyl) propyl phosphate, or salifying and crystallizing the phosphate and hydrochloric acid to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride; (2) carrying out Wittig reaction on 3- (N, N-dimethyl) propyl phosphate or hydrochloride thereof and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone under a strong alkali condition to obtain doxepin; (3) and carrying out salifying reaction on doxepin and hydrochloric acid to prepare doxepin hydrochloride. In the first step of reaction, the yield of the alkyl phosphate prepared by the Ebefur reaction is high, so that the yield and the purity of the final product doxepin hydrochloride are ensured. Compared with the prior art, the method has the advantages of simple process, low production cost, few process steps and the like.)

1. A synthetic method of doxepin hydrochloride is characterized by comprising the following steps:

(1): taking 3-chloro-1- (N, N-dimethyl) propylamine and phosphite ester to carry out an Ebazomib reaction to obtain 3- (N, N-dimethyl) propyl phosphate;

(2): reacting the obtained 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate obtained by acidifying the 3- (N, N-dimethyl) propyl phosphate with 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one under the action of strong alkali to obtain a Wittig reaction product;

(3): and (3) reacting the Wittig reaction product with HCl to obtain the target product.

2. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the phosphite is trimethyl phosphite, triethyl phosphite, triisopropyl phosphite or tribenzyl phosphite.

3. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the molar ratio of 3-chloro-1- (N, N-dimethyl) propylamine to phosphite ester is 1 (1.1-3).

4. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the temperature of the Ebezomib reaction is 140-150 ℃, and the reaction time is 6-8 h.

5. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the process for preparing the hydrochloride of 3- (N, N-dimethyl) propyl phosphate by acidifying 3- (N, N-dimethyl) propyl phosphate specifically comprises the following steps:

dissolving 3- (N, N-dimethyl) propyl phosphate in ethyl acetate, introducing hydrogen chloride gas or adding hydrochloric acid, stirring and crystallizing to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride;

when hydrochloric acid was added, the pH of the ethyl acetate solution of 3- (N, N-dimethyl) propyl phosphate was adjusted to 1-2 by dropwise addition of hydrochloric acid.

6. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the molar ratio of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride is 1 (1.1-1.5).

7. The method according to claim 1, wherein in the step (2), the strong base is potassium tert-butoxide, sodium hydride, sodium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, or butyllithium.

8. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with 3- (N, N-dimethyl) propyl phosphate, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (1.1-1.5);

when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with 3- (N, N-dimethyl) propyl phosphate hydrochloride, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (2.1-2.5).

9. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the reaction temperature is-78-25 ℃ and the reaction time is 10-12 h.

10. The method for synthesizing doxepin hydrochloride according to claim 1, wherein HCl reacted with the Wittig reaction product is added in the form of hydrochloric acid or hydrogen chloride gas in the step (3), and the molar ratio of the Wittig reaction product to HCl is 1 (1.5-3);

in the step (3), the reaction temperature is 135-150 ℃, and the reaction time is 18-22 h.

Technical Field

The invention belongs to the technical field of drug synthesis, and relates to a synthesis method of doxepin hydrochloride.

Background

Doxepin Hydrochloride (Doxepin Hydrochloride) is a mixture of cis and trans isomers of the subunit-1-alaninate, chemically known as N, N-dimethyl-3-dibenzo (b, e) -oxepin-11 (6H). The CAS number is 1229-29-4, and the chemical structural formula is as follows:

doxepin hydrochloride is a common tricyclic antidepressant and is used for treating depression and anxiety neurosis. Doxepin hydrochloride is a non-selective monoamine uptake inhibitor, and the action mechanism of the doxepin hydrochloride is that the doxepin hydrochloride can play an antidepressant role by inhibiting reuptake of Norepinephrine (NE) and 5-hydroxytryptamine (5-HT) to increase the concentration of synaptic cleft, and also has anxiolytic and sedative effects. The doxepin hydrochloride has good oral absorption, the bioavailability is 13-45%, the half-life (t1/2) is 8-12 hours, and the apparent distribution volume (Vd) is 9-33L/kg. Mainly metabolized in the liver, and the active metabolite is demethylated. Metabolites are excreted from the kidney, and the metabolic and excretory abilities of the product are reduced in elderly patients.

So far, there are many reports about the synthesis of doxepin hydrochloride, wherein most of the reaction conditions are harsh and involve the reaction of noble metals, so that the method has the disadvantages of high cost, environmental friendliness and the like, such as foreign reports about the synthesis of doxepin hydrochloride (such as patents US20100179214 and US 20100305326); however, domestic reports on doxepin hydrochloride exist, for example, patent CN102924424A discloses a preparation method of doxepin hydrochloride. The process involves a C-N coupling reaction, i.e. using Ni (OAc)₂/PPh₃The system is catalyzed. Although the catalyst is cheap and easy to obtain, the yield of the reaction in the step is low, and the purity of the product is low. Domestic patent reports about doxepin hydrochloride, such as patent CN112079809A) and CN105085465A, both relate to the Grignard reaction,the reaction has higher requirements on the moisture of a solvent and raw materials, the reaction environment and the like, and the Grignard reaction usually involves the heating of diethyl ether or tetrahydrofuran, so that certain potential safety hazards exist in the production.

Disclosure of Invention

The invention aims to provide a method for synthesizing doxepin hydrochloride, which solves the problems of harsh synthesis conditions, complex process and the like in the prior art.

The purpose of the invention can be realized by the following technical scheme:

the invention provides a method for synthesizing doxepin hydrochloride, which comprises the following steps:

(1) taking 3-chloro-1- (N, N-dimethyl) propylamine and phosphite ester to carry out an Ebazomib reaction to obtain 3- (N, N-dimethyl) propyl phosphate;

(2) reacting the obtained 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate obtained by acidifying the 3- (N, N-dimethyl) propyl phosphate with 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one under the action of strong alkali to obtain a Wittig reaction product;

(3) and (3) reacting the Wittig reaction product with HCl to obtain the target product.

Further, in the step (1), the phosphite ester is trimethyl phosphite, triethyl phosphite, triisopropyl phosphite or tribenzyl phosphite, and may be triethyl phosphite.

Furthermore, in the step (1), the molar ratio of the 3-chloro-1- (N, N-dimethyl) propylamine to the phosphite ester is 1 (1.1-3).

Further, in the step (1), the temperature of the Ebefur reaction is 140-150 ℃, and the reaction time is 6-8 h.

Further, in the step (1) and the step (2), the process for preparing the 3- (N, N-dimethyl) propyl phosphate hydrochloride by acidifying the 3- (N, N-dimethyl) propyl phosphate specifically comprises the following steps:

dissolving 3- (N, N-dimethyl) propyl phosphate in ethyl acetate, introducing hydrogen chloride gas or adding hydrochloric acid, stirring and crystallizing to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride;

further, when hydrochloric acid was added, the pH of the ethyl acetate solution of 3- (N, N-dimethyl) propyl phosphate was adjusted to 1-2 by dropwise addition of hydrochloric acid.

Further, when hydrochloric acid was added, the concentration of hydrochloric acid was 12N.

Further, in the step (2), the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate is 1 (1.1-1.5).

Further, in the step (2), the strong base is potassium tert-butoxide, sodium hydride, sodium tert-butoxide, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (LHMDS), potassium bis (trimethylsilyl) amide (KHMDS) or butyllithium, and may be potassium tert-butoxide or sodium hydride. Specifically, the strong base is added to convert 3- (N, N-dimethyl) propyl phosphate or hydrochloride thereof into carbanion intermediate, and the carbanion intermediate can resonate to generate the Wittig-Horner reagent. The strength and choice of base used depends primarily on the acidity of the hydrogen atom on the α -carbon of the phosphate ester.

Further, in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with the 3- (N, N-dimethyl) propyl phosphate, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (1.1-1.5).

Further, in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with the 3- (N, N-dimethyl) propyl phosphate hydrochloride, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (2.1-2.5).

Further, in the step (2), the solvent for the reaction is tetrahydrofuran.

Further, in the step (2), the reaction temperature is-78-25 ℃, and the reaction time is 10-12 hours.

Furthermore, in the step (3), HCl reacted with the Wittig reaction product is added in the form of hydrochloric acid or hydrogen chloride gas, and the molar ratio of the Wittig reaction product to the HCl is 1 (1.5-3).

Further, when hydrochloric acid was added, the concentration of hydrochloric acid was 12N.

Further, in the step (3), the reaction temperature is 135-150 ℃, and the reaction time is 18-22 h.

Further, in the step (3), the reaction solvent is ethyl acetate or ethanol.

According to the invention, 3-chloro-1- (N, N-dimethyl) propylamine (compound 1) and phosphite ester (compound 2) are used as raw materials in the step (1) to prepare 3- (N, N-dimethyl) propyl phosphate (compound 3) by an Ebazomib reaction, the added phosphite ester is not only used as a reactant, but also used as a reaction solvent, and excessive phosphite ester can ensure complete reaction of the 3-chloro-1- (N, N-dimethyl) propylamine; in the step (2), 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride (compound 4) obtained by acidifying 3- (N, N-dimethyl) propyl phosphate and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone (compound 5) are subjected to Wittig reaction under a strong alkali condition to obtain a doxepin intermediate product (compound 6), wherein the excessive 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride can improve the reaction yield in the reaction process; and then carrying out salification reaction on the doxepin intermediate product and hydrochloric acid to obtain the target product doxepin hydrochloride. The yield of the alkyl phosphate product prepared in the step (1) is higher, so that the yield and the purity of the final product doxepin hydrochloride are ensured.

The reaction process of the step (1) is as follows:

wherein R in the compound 2, the compound 3 and the compound 4 is-CH₃、—CH₂CH₃、—CH(CH₃)CH₃or-CH₂Ph。

The reaction process of the step (2) is as follows:

wherein, R in the compound 3 and the compound 4 is methyl, ethyl, isopropyl or benzyl.

The reaction process of the step (3) is as follows:

compared with the prior art, the invention has the following advantages:

(1) the doxepin hydrochloride can be synthesized through three steps of an Eberkoff reaction, a Wittig reaction and a salt forming reaction.

(2) The invention adopts triethyl phosphite with lower price as the raw material, thereby greatly reducing the cost. The wittig-horner reaction is used for replacing the Grignard reaction to construct the double bond, so that the reaction is simpler, the requirements on reaction conditions such as the moisture of a reaction solvent and raw materials, equipment and the like are lower, and the repetition rate is higher.

(3) The invention does not relate to the Grignard reaction, so the heating of the diethyl ether or the tetrahydrofuran is not related, and the production is safer.

Detailed Description

The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.

In the following examples, the starting materials and treatment steps used are, unless otherwise specified, indicated by the conventional commercial products or conventional techniques.

Example 1

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in an amount of 97.5g and a yield of 88.5%.

¹H NMR(400MHz,D₂O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 2

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.

Dissolving the crude product with ethyl acetate, introducing hydrogen chloride, stirring at room temperature for crystallization for 5 hours, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 110.8g and the yield of 86.47%.

¹H NMR(400MHz,D₂O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 3

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.

Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust pH to 1-2, stirring at room temperature for 5 hours for crystallization, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with an amount of 109.8g and a yield of 85.69%.

¹H NMR(400MHz,D₂O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 4

Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.4g of the compound 6 with the yield of 75.41%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 5

Sodium hydride (11.41g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at-40 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-40 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain the compound 6 with the amount of 91.8g and the yield of 76.57%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 6

Lithium diisopropylamide (51.88g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 87.86g of the compound 6 with the yield of 73.29 percent.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 7

Lithium bis (trimethylsilyl) amide (79.54g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 87.2g of the compound 6 with the yield of 72.74%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 8

Potassium bis (trimethylsilyl) amide (94.83g,475.37mmol) was added portionwise under nitrogen protection to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 87g of the compound 6 with the yield of 72.57%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 9

After dissolving intermediate 6 (i.e., compound 6) (90g,324.43mmol) in ethyl acetate, hydrogen chloride was introduced, heated to 135 ℃, stirred for 22h, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely, the doxepin hydrochloride white solid 91.5g, with the yield of 89.86%.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 10

Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely doxepin hydrochloride white solid 92.1g, with the yield of 90.45%.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 11

Concentrated hydrochloric acid 81ml (12N) (containing 972mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 150 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 92.9g with the yield of 91.23%.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 12

Trimethyl phosphite (67.34g,542.73mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain 3- (N, N-dimethyl) propyldimethyl phosphate (Compound No. 3) in an amount of 85.7g and a yield of 88.98%.

¹H NMR(400MHz,D₂O)δ3.69(s,3H),3.67(s,3H),2.49(t,J＝6.4Hz,2H),2.33(s,6H),2.04(dt,J＝12.0,6.0Hz,2H),1.73(p,J＝6.2Hz,2H).¹³C NMR(125MHz,D₂O)δ57.74,57.66,52.47,52.42,44.78,26.34,25.58,24.20,24.15.

Example 13

Triisopropyl phosphite (113.02g,542.73mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diisopropyl 3- (N, N-dimethyl) propyl phosphate (Compound No. 3) in an amount of 109g in a yield of 87.91%.

¹H NMR(400MHz,D₂O)δ4.67(dhept,J＝8.2,6.2Hz,2H),2.54(t,J＝6.4Hz,2H),2.32(s,6H),2.03(dt,J＝12.0,6.0Hz,2H),1.74(p,J＝6.2Hz,2H),1.31(s,6H),1.30(s,6H).¹³C NMR(125MHz,D₂O)δ71.01,70.96,57.67,57.59,44.73,27.63,26.87,24.14,24.08,23.64,23.59.

Example 14

Triisopropyl phosphite (191.24g,918.37mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the resulting mixture was distilled under reduced pressure to obtain diisopropyl 3- (N, N-dimethyl) propyl phosphate (Compound No. 3) in an amount of 109.1g and a yield of 87.99%.

¹H NMR(400MHz,D₂O)δ4.67(dhept,J＝8.2,6.2Hz,2H),2.54(t,J＝6.4Hz,2H),2.32(s,6H),2.03(dt,J＝12.0,6.0Hz,2H),1.74(p,J＝6.2Hz,2H),1.31(s,6H),1.30(s,6H).¹³C NMR(125MHz,D₂O)δ71.01,70.96,57.67,57.59,44.73,27.63,26.87,24.14,24.08,23.64,23.59.

Example 15

Sodium tert-butoxide (45.68g,475.31mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.29g of the compound 6 with yield of 75.31%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 16

Butyllithium (30.45g, 475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to dissolve and clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 87.5g of the compound 6 with the yield of 72.99%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 17

Triethyl phosphite (163.95g,986.76mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 150 ℃ and stirred for 6 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in an amount of 98.2g and a yield of 89.15%.

¹H NMR(400MHz,D₂O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 18

Triethyl phosphite (245.93g,1480.14mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 145 ℃ and stirred for 7 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain 98.6g of diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in 88.61% yield.

¹H NMR(400MHz,D₂O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 19

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.

Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust the pH value to 1, stirring at room temperature for crystallization for 5 hours, performing suction filtration and drying to obtain the 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 110.1g and the yield of 85.92%.

¹H NMR(400MHz,D₂O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 20

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.

Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust the pH value to 2, stirring at room temperature for crystallization for 5 hours, performing suction filtration and drying to obtain the 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 109.6g and the yield of 85.53%.

¹H NMR(400MHz,D₂O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 21

Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.

Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust pH to 1.5, stirring at room temperature for crystallization for 5 hours, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 109.78g and the yield of 85.67%.

¹H NMR(400MHz,D₂O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).¹³C NMR(125MHz,D₂O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.

Example 22

Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(125.43g,561.80mmol) prepared in example 1 in tetrahydrofuran (320ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.46g of the compound 6 with the yield of 75.46%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 23

Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(144.72g,648.23mmol) prepared in example 1 in tetrahydrofuran (340ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain the compound 6 with the amount of 90.1g and the yield of 75.16%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 24

Potassium tert-butoxide (101.83g,907.52mmol) was added portionwise to a solution of compound 4(123.46g,475.37mmol) prepared in example 2 in tetrahydrofuran (320ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.31g of the compound 6 with yield of 75.33%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 25

Potassium tert-butoxide (111.53g,993.95mmol) was added portionwise to a solution of compound 4(145.91g,561.80mmol) prepared in example 2 in tetrahydrofuran (340ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.6g of the compound 6 with the yield of 75.57%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 26

Potassium tert-butoxide (121.23g,1080.38mmol) was added portionwise to a solution of compound 4(168.36g,648.23mmol) prepared in example 2 in tetrahydrofuran (360ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.62g of the compound 6 with the yield of 75.59 percent.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 27

Potassium tert-butoxide (63.04g,561.80mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.45g of the compound 6 with the yield of 75.45%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 28

Potassium tert-butoxide (72.74g,648.23mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.44g of the compound 6 with yield of 75.44%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 29

Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 25 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition, the reaction was stirred at 25 ℃ for 10 hours and was completed by TLC detection (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 85.7g of the compound 6 with the yield of 71.49%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 30

Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition, the reaction was stirred at 0 ℃ for 11 hours and was completed by TLC detection (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.

Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.38g of the compound 6 with the yield of 75.39%.

¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 31

Concentrated hydrochloric acid 40.5ml (12N) (containing 486mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely, the doxepin hydrochloride white solid 91.6g with the yield of 89.96 percent.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 32

Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 18h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 91.18g with the yield of 89.54%.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

Example 33

Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 20h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 91.2g with the yield of 89.56%.

¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).¹³C NMR(125MHz,CDCl₃)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.