CN102924424B - Method for synthesizing doxepin hydrochloride - Google Patents

Abstract

The invention provides a method for synthesizing doxepin hydrochloride, comprising the following steps: 1. 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3-chloropropyl-tert Addition reaction of butyl ether to obtain alcohol compounds; 2, the alcohol compounds eliminate hydroxyl groups under concentrated hydrochloric acid conditions to obtain olefin compounds; 3, the olefin compounds react with thionyl chloride in the reaction solvent to obtain chlorine 4. The chlorinated compound is coupled with N,N-dimethylmethylamine to obtain doxepin; 5. Doxepin is made into its hydrochloride, to obtain. The present invention creatively uses the Ni(OAc) ₂ /PPh ₃ system in the CN coupling reaction of the fourth step, which has good reaction selectivity, high yield, and is environmentally friendly, and the catalyst can be recycled for many times through simple filtration, greatly reduced production costs. The whole synthesis process is simple to operate, the raw materials are easy to obtain, and the cost is low, which meets the requirements of industrial production and is expected to be applied in industrialization.

Description

A kind of method of synthesizing doxepin hydrochloride

technical field

The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing doxepin hydrochloride. the

Background technique

Doxepin Hydrochloride is a medicine used for the treatment of depression and anxiety neurosis. Its function is to inhibit the reuptake of 5-hydroxytryptamine and norepinephrine in the central nervous system, so that the two in the synaptic cleft It exerts antidepressant effects by increasing the concentration of this neurotransmitter, and also has anti-anxiety and sedative effects. Doxepin hydrochloride is well absorbed orally, with a bioavailability of 13-45%, a half-life (t1/2) of 8-12 hours, and an apparent volume of distribution (Vd) of 9-33L/kg. It is mainly metabolized in the liver, and the active metabolite is demethylation. The metabolites are excreted by the kidneys, and the ability to metabolize and excrete this product decreases in elderly patients. Its chemical name is N,N-dimethyl-3-dibenzo[b,e]-{oxa}heptin-11(6H)ylidene-1-propanamine hydrochloride cis-trans isomer mixture, CAS No.: 1229-29-4. The structural formula of doxepin hydrochloride is as follows:

So far, there are some reports on the total synthesis of doxepin hydrochloride (such as patents US20100179215, US20100179214, US20100305326). Most of the reactions involving the fourth carbon-nitrogen coupling still use some harsh operating conditions or noble metal reagents, such as Pd, Pt, Ru, Rh, etc. This not only involves the disadvantages of high catalyst cost and cumbersome operation, but also involves the recycling of the catalyst and the pollution to the environment. And this step coupling reaction is related to the synthesis of the whole doxepin hydrochloride. Under such conditions, it is particularly important to develop green, low-cost, non-toxic and recyclable catalysts. It is gratifying that the inventor unexpectedly found that the Ni catalyst has a peculiar effect on this step reaction, the reaction yield is high, the by-products are few, the key catalyst is cheap and easy to obtain, and can be recycled. Therefore, the present invention uses Ni(OAc) ₂ /PPh ₃ catalytic system applied to the synthesis of doxepin hydrochloride. At the same time, the overall optimization and improvement of the reaction route was carried out, and an ideal method for synthesizing doxepin hydrochloride was obtained.

Contents of the invention

The object of the present invention is to provide a method for synthesizing doxepin hydrochloride which is simple, environmentally friendly and has a high overall yield. the

To realize the purpose of discovery, the present invention adopts the following technical solutions:

A method for synthesizing doxepin hydrochloride, comprising the following steps:

(1) Addition reaction of 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3-chloropropyl-tert-butyl ether to obtain alcohol compounds;

(2) The alcohol compound is eliminated under the condition of concentrated hydrochloric acid to obtain the olefin compound;

(3) The olefinic compound reacts with thionyl chloride in the reaction solvent to obtain chlorinated compounds;

(4) The chlorinated compound is coupled with N,N-dimethylmethylamine to obtain doxepin;

(5) Make doxepin into its hydrochloride, that is. the

Among them, the preferred step 1 of the present invention is: 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3-chloropropyl with an amount ratio of 1:1-1:1.5 - The addition reaction of tert-butyl ether in anhydrous ether under the action of a catalyst, and the reaction is refluxed to obtain alcohol compounds, and the more preferred dosage ratio is 1:1.2. the

In the description of the present invention, the 6,11-dihydrodibenzo[b,e]oxepin-11-one (CAS: 4504-87-4) is the cyclic ketone described below. the

In addition, in step 1, anhydrous diethyl ether is added dropwise as a solvent, and its volumetric dosage is 5.5-6.3 times the weight of 6,11-dihydrodibenzo[b,e]oxepin-11-one, the The catalyst is magnesium powder, the dosage of the catalyst is 1.8-2.2 times that of 6,11-dihydrodibenzo[b,e]oxepin-11-one, the reaction time is 2-5h, and the temperature is 35-40℃ . the

In this step, the rate of addition of anhydrous ether is 2%-6% per minute of its consumption, and at this rate of addition, 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3-Chloropropyl-tert-butyl ether can achieve a more ideal addition reaction. the

In step 2, the alcohol compound is kept boiling under concentrated hydrochloric acid, and the amount of concentrated hydrochloric acid is 2-10 times that of the reaction substrate; the reaction time is 5-8h. the

In step 3, the reaction solvent is benzene or toluene, the ratio of olefinic compound to thionyl chloride is 1:1-1:1.5, and the reaction is heated under reflux at 110-120°C for 2-4h, preferably olefinic compound and dichloride The dosage ratio of thionyl chloride was 1:1.2, and the reaction was heated to reflux at 115°C for 3h. the

Step 4 uses Ni(OAc) ₂ as the reaction catalyst and triphenylphosphine as the ligand.

The preferred step 4 of the present invention is specifically: under the action of a catalyst, the chloride and N,N-dimethylmethylamine are reacted in DMF at 35-45°C for 4-6h, preferably at 40°C 5h, coupled to get doxepin. the

In this step 4, the consumption ratio of chloride and N,N-dimethylmethylamine is 1:1-1:1.5, the dosage of catalyst is 2-8%, and the consumption ratio of ligand and chloride is 8: 1-12:1, preferably the ratio of chloride to N,N-dimethylmethylamine is 1:1.1, the dosage of catalyst is 5%, and the ratio of ligand to chloride is 10:1. the

In addition, steps 1-4 of the synthesis method described in the present invention also include the operation of recrystallizing the crude product obtained in each step. The specific recrystallization is grasped by those skilled in the art. In the present invention, petroleum ether is preferably used for steps 1-4. 4. The obtained intermediate product is subjected to recrystallization treatment, so that the yield and purity of the whole synthesis method are further guaranteed. the

Preferably described step 5 of the present invention is: doxepin is in concentrated hydrochloric acid, obtains doxepin hydrochloride with 135-145 ℃ of reaction 15-18h, and the consumption ratio of doxepin and concentrated hydrochloric acid is 1:4-1: 6. Preferably, doxepin is reacted in concentrated hydrochloric acid at 140°C for 16 hours to obtain doxepin hydrochloride, and the dosage ratio of doxepin to concentrated hydrochloric acid is 1:5. the

The solvents of the present invention are all processed before use, except that concentrated hydrochloric acid can be used directly, and other solvents are all dried with calcium hydride and then distilled under reduced pressure before use. the

The hydrochloric acid used in the present invention is that volume percent concentration is 35-40%, preferably the concentrated hydrochloric acid of 37%. the

The whole reaction route is shown below:

Adopt above-mentioned technical scheme, the present invention has following beneficial effect:

1. The whole synthesis method is simple and controllable, the reaction path is scientific and reasonable, and the total yield can reach 62%. the

2. For the fourth step coupling reaction in the whole synthesis, the Ni/PPh ₃ catalytic system is creatively used, so that the reaction yield is high, the by-products are few, and the selectivity is good, which can reach more than 99%.

3. Ni is different from other precious metal catalysts. After the reaction, it can continue to be recycled after simple filtration. The most important thing is that it is cheap and easy to get, which greatly saves production costs. the

4. The five-step synthesis involved in the present invention is less corrosive, environmentally friendly, meets the requirements of clean production, is beneficial to industrial production, and meets the low-carbon purpose of a harmonious society. the

Detailed ways

The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. the

Example 1

(1)

Add 0.8 liters of anhydrous tetrahydrofuran and 143 g of magnesium powder, 500 g of cyclic ketone raw materials and 895 g of 3-chloropropyl-tert-butyl ether into a 2-liter reactor, and drop 0.4 liters of anhydrous ether in half an hour Add it to the reactor and keep the system in a slightly boiling state. After the dropwise addition, argon gas is introduced into the system, and the reflux continues for 2 hours. After the reaction was completed, the system was cooled and poured into saturated ammonium chloride solution, extracted three times with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain 698 g of the product, and the HPLC purity analysis was >99%. The yield is 90%. Product molecular formula: C ₂₁ H ₂₆ O ₃ , molecular weight: 326.43. Melting point: 124-126°C, LC-MS: 326.46, elemental analysis: C 77.27%, H 8.03%, O 14.70%.

(2)

In a 2-liter autoclave, add 690 g of the product obtained in the previous step reaction, then add 1500 g of concentrated hydrochloric acid, heat the airtight autoclave to boiling, control the system pressure gauge to 3 MPa, and react for 5 hours. After the reaction was completed and cooled, the excess solvent was distilled off, and the obtained crude product was recrystallized with petroleum ether to obtain 619g of the product. The HPLC purity analysis was >98%, and the yield was 95%. The product molecular formula: C ₂₁ H ₂₄ O ₂ , molecular weight: 308.41. Melting point: 112-114°C, LC-MS: 308.48, elemental analysis: C 81.78%, H 7.84%, O 10.78%.

(3)

Add 615g of the product obtained in the previous reaction and 0.8 liter of benzene into a 2-liter autoclave, dissolve 283 g of thionyl chloride in 0.4 liter of benzene, and add it dropwise to the autoclave in one hour at room temperature After the dropwise addition, the autoclave was sealed and heated to reflux for 2 hours. After the reaction was completed, extract with ethyl acetate three times, dry with anhydrous sodium sulfate for 5 hours, and recrystallize the obtained crude product with petroleum ether to obtain 431g of the product, HPLC purity analysis >99%, yield 80%, product molecular formula: C ₁₇ H ₁₅ ClO ,Molecular weight: 270.75. Melting point: 107-110°C, LC-MS: 270.80, elemental analysis: C 75.41%, H 5.58%, Cl 13.09%, O 5.91%.

(4)

In 2 liters of reactors, add the product 430g that last step reaction obtains and 1.2 liters of DMF as solvent, then add 79g N,N-dimethylmethylamine, two equivalents of salt of wormwood, then add 5% Ni ( OAc) ₂ and 10% PPh ₃ were reacted at 40°C for 5h. After the reaction was completed, ethyl acetate was added to extract three times, and dried with anhydrous sodium sulfate for 5 hours. The obtained crude product was recrystallized with petroleum ether to obtain 435 g of product doxepin. The HPLC purity analysis was >99%, and the yield was 98%. Product molecular formula: C ₁₉ H ₂₁ NO, molecular weight: 279.38. Melting point: 182-184°C, LC-MS: 279.30, elemental analysis: C 81.68%, H 7.58%, N 5.01%, O 5.73%.

(5)

In a 2-liter autoclave, add 430 g of the product obtained by the reaction in the previous step, then add 900 g of concentrated hydrochloric acid, heat the airtight autoclave to 140 ° C, control the system pressure gauge to 3 MPa, and react for 1 to 5 hours. After completion of the reaction, cool to room temperature, filter, and dry to obtain 422 g of the product, with a purity analysis of >98% by HPLC and a yield of 87%. Product molecular formula: C ₁₉ H ₂₂ ClNO, molecular weight: 315.84. LC-MS: 315.80, elemental analysis: C 72.25%, H 7.02%, Cl 11.23%, N 4.43%, O 5.07%.

Example 2

(1)

Add 2 liters of anhydrous tetrahydrofuran and 280g of magnesium powder, 1Kg of cyclic ketone raw material and 1.9Kg of 3-chloropropyl-tert-butyl ether into a 4-liter reactor, and divide 1 liter of anhydrous ether for half an hour Add it dropwise into the reactor, keep the system in a slightly boiling state, after the dropwise addition, feed argon into the system, and continue to reflux for 2h. After the reaction was completed, the system was cooled and poured into a saturated ammonium chloride solution, extracted three times with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain a product of 1.42Kg, HPLC purity analysis >99% , yield 88%. Product molecular formula: C ₂₁ H ₂₆ O ₃ , molecular weight: 326.43. Melting point: 124-126°C, LC-MS: 326.46, elemental analysis: C 77.27%, H 8.03%, O 14.70%.

(2)

Add 1.4Kg of the product obtained in the previous step reaction into a 4-liter autoclave, then add 3Kg of concentrated hydrochloric acid, heat the airtight autoclave to boiling, control the system pressure gauge to 3MPa, and react for 5h. After the reaction was completed and cooled, the excess solvent was distilled off, and the obtained crude product was recrystallized with petroleum ether to obtain 1.21Kg of the product. The HPLC purity analysis was >98%, and the yield was 93%. The product molecular formula: C ₂₁ H ₂₄ O ₂ , molecular weight: 308.41. Melting point: 112-114°C, LC-MS: 308.48, elemental analysis: C 81.78%, H 7.84%, O 10.78%.

(3)

Add 1.2Kg of the product obtained in the previous step reaction and 1.6 liters of benzene into a 4-liter autoclave, dissolve 0.56 Kg of thionyl chloride in 0.8 liters of benzene, and add it dropwise to the pressure-resistant pot in one hour at room temperature. In the kettle, after the dropwise addition, the autoclave was sealed and heated to reflux, and reacted for 2 hours. After the reaction was completed, extract with ethyl acetate three times, dry with anhydrous sodium sulfate for 5 hours, and recrystallize the obtained crude product with petroleum ether to obtain the product 0.86Kg, HPLC purity analysis>99%, yield 79%, product molecular formula: C ₁₇ H ₁₅ ClO, molecular weight: 270.75. Melting point: 107-110°C, LC-MS: 270.80, elemental analysis: C 75.41%, H 5.58%, Cl 13.09%, O 5.91%.

(4)

Add 0.85Kg of the product obtained in the previous step reaction and 2.5 liters of DMF into a 4-liter reactor as a solvent, then add 160g N,N-dimethylmethylamine, two equivalents of potassium carbonate, and then add 5% Ni (OAc) ₂ and 10% PPh ₃ were reacted at 40°C for 5h. After the reaction was completed, ethyl acetate was added to extract three times, and dried with anhydrous sodium sulfate for 5 hours. The obtained crude product was recrystallized with petroleum ether to obtain the product doxepin 0.85Kg. The purity analysis by HPLC was >99%, and the yield was 96%. Product molecular formula: C ₁₉ H ₂₁ NO, molecular weight: 279.38. Melting point: 182-184°C, LC-MS: 279.30, elemental analysis: C 81.68%, H 7.58%, N 5.01%, O 5.73%.

(5)

Add 0.85Kg of the product obtained in the previous step into a 4-liter autoclave, then add 1.8Kg of concentrated hydrochloric acid, heat the closed autoclave to 140°C, control the system pressure gauge to 3MPa, and react for 15 hours. After the reaction was completed, cooled to room temperature, filtered and dried to obtain 0.84Kg of the product, the HPLC purity analysis was >98%, and the yield was 85%. Product molecular formula: C ₁₉ H ₂₂ ClNO, molecular weight: 315.84. LC-MS: 315.80, elemental analysis: C 72.25%, H 7.02%, Cl 11.23%, N 4.43%, O 5.07%.

Example 3

Compared with embodiment 1, the difference of this embodiment only lies in:

Step 1 is: 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3-chloropropyl-tert-butyl ether with a molar ratio of 1:1.2 in the absence of catalyst Addition reaction was carried out in water and ether, and the reaction was refluxed to obtain alcohol compounds. Wherein, anhydrous diethyl ether is added dropwise as a solvent, and its volumetric dosage is 5.8 times the weight of 6,11-dihydrodibenzo[b,e]oxepin-11-one, and its dropping speed is 5% of its dosage per minutes, the catalyst is magnesium powder, the dosage of magnesium powder is twice that of 6,11-dihydrodibenzo[b,e]oxepin-11-one, the reaction time is 3h, and the temperature is 38°C . the

In step 2, the alcohol compound is kept boiling under the condition of concentrated hydrochloric acid, and the amount of concentrated hydrochloric acid is 6 times that of the reaction substrate; the reaction time is 6 hours. the

In step 3, the reaction solvent is benzene, the ratio of olefinic compound to thionyl chloride is 1:1.2, and the reaction is heated to reflux at 115° C. for 3 h. the

Step 4 is specifically: under the action of a catalyst, the chloride and N,N-dimethylmethylamine are reacted in DMF at 40° C. for 5 h, and doxepin is obtained through coupling. Among them, the dosage ratio of chloride and N,N-dimethylmethylamine is 1:1.1, the dosage of catalyst is 5%, and the ratio of ligand to chloride is 10:1. the

Step 5 is: react doxepin in concentrated hydrochloric acid at 140° C. for 16 hours to obtain doxepin hydrochloride, and the dosage ratio of doxepin to concentrated hydrochloric acid is 1:5. the

The purity of doxepin hydrochloride obtained in this example was 98%, and the total yield was 62%. the

Example 4

Compared with Example 1, the difference of this example is only that: Step 1 is: 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3- Chloropropyl-tert-butyl ether undergoes an addition reaction in anhydrous ether under the action of a catalyst, and the reaction is refluxed to obtain alcohol compounds. Among them, the volumetric dosage of anhydrous diethyl ether is 5.5 times the weight of 6,11-dihydrodibenzo[b,e]oxepin-11-one, and its dropping rate is 2% of its dosage per minute. The catalyst is magnesium powder, the dosage of magnesium powder is 1.8 times that of 6,11-dihydrodibenzo[b,e]oxepin-11-one, the reaction time is 2 hours, and the temperature is 35°C. the

In step 2, the alcohol compound is kept boiling under the condition of concentrated hydrochloric acid, and the amount of concentrated hydrochloric acid is twice that of the reaction substrate; the reaction time is 5 hours. the

In step 3, the reaction solvent is toluene, the ratio of olefinic compound to thionyl chloride is 1:1, and the reaction is heated to reflux at 110° C. for 2 h. the

Step 4 is specifically: under the action of a catalyst, the chloride and N,N-dimethylmethylamine are reacted in DMF at 35°C for 4 hours, and doxepin is obtained through coupling. Among them, the dosage ratio of chloride and N,N-dimethylmethylamine is 1:1, the dosage of catalyst is 2%, and the ratio of ligand to chloride is 8:1. the

Step 5 is: react doxepin in concentrated hydrochloric acid at 135° C. for 15 hours to obtain doxepin hydrochloride, and the dosage ratio of doxepin to concentrated hydrochloric acid is 1:4. the

The purity of doxepin hydrochloride obtained in this example was 99%, and the total yield was 60%. the

Example 5

Compared with Example 1, the difference of this example is only that: Step 1 is: 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3- Chloropropyl-tert-butyl ether undergoes an addition reaction in anhydrous ether under the action of a catalyst, and the reaction is refluxed to obtain alcohol compounds. Among them, the volumetric dosage of anhydrous diethyl ether is 6.3 times the weight of 6,11-dihydrodibenzo[b,e]oxepin-11-one, and its dropping rate is 6% of its dosage per minute. The catalyst is magnesium powder, the dosage of magnesium powder is 2.2 times that of 6,11-dihydrodibenzo[b,e]oxepin-11-one, the reaction time is 5 hours, and the temperature is 40°C. the

In step 2, the alcohol compound is kept boiling under the condition of concentrated hydrochloric acid, the amount of concentrated hydrochloric acid is 10 times that of the reaction substrate; the reaction time is 8h. the

In step 3, the reaction solvent is toluene, the ratio of olefinic compound to thionyl chloride is 1:1.5, and the reaction is heated to reflux at 120° C. for 4 h. the

Step 4 is specifically: under the action of a catalyst, the chloride and N,N-dimethylmethylamine are reacted in DMF at 45° C. for 6 hours, and doxepin is obtained through coupling. Among them, the dosage ratio of chloride to N,N-dimethylmethylamine is 1:1.5, the dosage of catalyst is 8%, and the ratio of ligand to chloride is 12:1. the

Step 5 is: react doxepin in concentrated hydrochloric acid at 145° C. for 18 hours to obtain doxepin hydrochloride, and the dosage ratio of doxepin to concentrated hydrochloric acid is 1:6. the

The purity of doxepin hydrochloride obtained in this example was 98%, and the total yield was 62%. the

Example 6

Compared with Example 1, the difference of this example is only that: Step 1 is: 6,11-dihydrodibenzo[b,e]oxepin-11-one and 3- Chloropropyl-tert-butyl ether undergoes an addition reaction in anhydrous ether under the action of a catalyst, and the reaction is refluxed to obtain alcohol compounds. Wherein, its volume consumption of anhydrous diethyl ether is 5.9 times of 6,11-dihydrodibenzo[b,e]oxepin-11-one weight, and described catalyst is magnesium powder, and the dosage of magnesium powder is 6 , 1.9 times that of 11-dihydrodibenzo[b,e]oxepin-11-one, the reaction time is 2-5h, and the temperature is 35-40℃. the

In step 2, the alcohol compound is kept boiling under the condition of concentrated hydrochloric acid, and the amount of concentrated hydrochloric acid is 5 times that of the reaction substrate; the reaction time is 6 hours. the

In step 3, the reaction solvent is benzene, the ratio of olefinic compound to thionyl chloride is 1:1.3, and the reaction is heated to reflux at 115° C. for 3 h. the

Step 4 is specifically: under the action of a catalyst, react the chloride and N,N-dimethylmethylamine in DMF at 42°C for 6 hours, and couple to obtain doxepin. Among them, the dosage ratio of chloride and N,N-dimethylmethylamine is 1:1.3, the dosage of catalyst is 5%, and the ratio of ligand to chloride is 8:1. the

Step 5 is: react doxepin in concentrated hydrochloric acid at 142° C. for 17 hours to obtain doxepin hydrochloride, and the dosage ratio of doxepin to concentrated hydrochloric acid is 1:5. the

The purity of doxepin hydrochloride obtained in this example was 99%, and the total yield was 62%. the

Although, the present invention has been described in detail with general description, specific implementation and test above, but on the basis of the present invention, some modifications or improvements can be made to it, which will be obvious to those skilled in the art . Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention. the

Claims (5)

1. a method for synthetic hydrochloric acid doxepin, is characterized in that: comprise the following steps:

By 6,11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction and obtain alcohol compound;

Described alcohol compound cancellation hydroxyl under concentrated hydrochloric acid condition obtains alkenes compounds;

Described alkenes compounds reacts with thionyl chloride and obtains chloro thing in reaction solvent;

Described chloro thing and N, the coupling of N-dimethyl methylamine obtains doxepin;

Doxepin is made to its hydrochloride, to obtain final product;

Described step 1 is: amount ratio is 1:1.2 6, and 11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether, under the effect of catalyzer, carry out addition reaction in anhydrous diethyl ether, the reaction alcohol compound that refluxes to obtain; Wherein, anhydrous diethyl ether drips as solvent, and its volumetric usage is 6,11-dihydro-dibenzo [b, the 5.5-6.3 of e] Evil English-11-in heptan ketone weight times, the 2%-6% per minute that its rate of addition is its consumption; Described catalyzer is magnesium powder, the injected volume of catalyzer be 6,11-dihydro-dibenzo [b, doubly, the reaction times is 2-5 h to the 1.8-2.2 of e] Evil English-11-in heptan ketone, temperature is 35-40 DEG C;

In described step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, and the 2-10 that the consumption of concentrated hydrochloric acid is reaction substrate doubly; Reaction times is 5-8 h;

In described step 3, reaction solvent is benzene or toluene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1.2, reaction reflux 2-4h at 110-120 DEG C;

Described step 4 is with Ni (OAc) ₂as catalysts, triphenylphosphine is as part.

2. the method for synthetic hydrochloric acid doxepin according to claim 1, is characterized in that: described step 4 is: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 4-6h at DMF under 35-45 DEG C of condition, and coupling obtains doxepin.

3. the method for synthetic hydrochloric acid doxepin according to claim 2, it is characterized in that: chloro thing and N in described step 4, the amount ratio of N-dimethyl methylamine is 1:1-1:1.5, and the injected volume of catalyzer is 2-8%, and the amount ratio of part and chloro thing is 8:1-12:1.

4. according to the method for the synthetic hydrochloric acid doxepin described in claim 1, it is characterized in that: described step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 135-145 DEG C of reaction 15-18 h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:4-1:6.

5. the method for synthetic hydrochloric acid doxepin according to claim 1, is characterized in that: the concentration of volume percent of described concentrated hydrochloric acid is 35-40%.