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A kind of synthetic method of doxepin hydrochloride

A doxepin hydrochloride and synthesis method technology, applied in the field of drug synthesis, can solve the problems of high cost, cumbersome process, low efficiency of nucleophilic addition reaction, etc., and achieve the effect of low cost, simple process and easy operation

Active Publication Date: 2021-07-13
WUHAN AIMIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the method has carried out two substitution reactions, and the efficiency of the nucleophilic addition reaction is low, the product yield is only about 50%, and the process is quite cumbersome, has certain risks, and the cost is high

Method used

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  • A kind of synthetic method of doxepin hydrochloride
  • A kind of synthetic method of doxepin hydrochloride
  • A kind of synthetic method of doxepin hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Step 1: In a 20L glass reaction kettle, add 10 times the mass of toluene and tetrahydrofuran mixed solvent (toluene: tetrahydrofuran mass ratio 4:1) to the magnesium bar, stir and add magnesium bar, 0.001 times the molar number of magnesium bar iodine powder, 0.08 Methyl iodide with multiple moles to the magnesium bar, heated to 55°C, and slowly drop N,N-dimethyl-3-chloropropylamine with an equimolar number to the magnesium bar after the start-up, and react for 1 hour after the dropwise addition is completed, The obtained intermediate 1 was directly used in the next reaction.

[0038]

[0039] In the reaction of preparing intermediate 1, under the activation of iodine powder, methyl iodide and magnesium strips first undergo a Grignard reaction to generate a Grignard reagent, which then triggers the reaction of magnesium strips with N,N-dimethyl-3-chloropropylamine to form Intermediate 1. The reaction only needs to be carried out under the condition of complete isola...

Embodiment 2

[0050] Step 1: In a 20L glass reaction kettle, add a mixed solvent of toluene and tetrahydrofuran (toluene: tetrahydrofuran mass ratio 3:1), stir and add magnesium strips, iodine powder with 0.002 times the moles of magnesium strips, and 0.1 times the moles of magnesium strips Methyl iodide, heated to 50°C, and after initiation, slowly add N,N-dimethyl-3-chloropropylamine with an equimolar number on the magnesium bar, and react for 1 hour after the addition is complete, to obtain intermediate 1, which can be used directly Next reaction.

[0051] Step 2: In a 20L glass reactor, add 6,11-dihydrodibenzo[b,e]oxepin-11-one (compound A), toluene as the reaction solvent, slowly add 1.4 times the molar amount in Intermediate 1 of compound A, after the addition, react at 40°C for 2 hours, add purified water to quench the reaction, filter with suction, wash the filtrate with water, extract the organic layer, concentrate under reduced pressure to obtain crystals, and dry to obtain the crud...

Embodiment 3

[0056] Step 1: In a 20L glass reaction kettle, add a mixed solvent of toluene and tetrahydrofuran (toluene: tetrahydrofuran mass ratio 2:1), stir and add magnesium strips, iodine powder with 0.002 times the moles of magnesium strips, and 0.05 times the moles of magnesium strips Methyl iodide, heated to 45°C, and after initiation, slowly add N,N-dimethyl-3-chloropropylamine with an equimolar number on the magnesium strip, and react for 2 hours after the addition is complete, to obtain intermediate 1, which can be used directly Next reaction.

[0057] Step 2: In a 20L glass reactor, add 6,11-dihydrodibenzo[b,e]oxepin-11-one (compound A), toluene as the reaction solvent, slowly add 1.3 times the molar amount in Intermediate 1 of compound A, after the addition, react at 50°C for 1 hour, add purified water to quench the reaction, filter with suction, wash the filtrate with water, extract the organic layer, concentrate under reduced pressure to obtain crystals, and dry to obtain the...

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Abstract

The invention discloses a method for synthesizing doxepin hydrochloride. It uses N,N-dimethyl-3-chloropropylamine as a starting material, firstly performs a Grignard reaction, and then reacts the reaction product with 6,11-di The hydrogen dibenzo[b,e]oxepin-11-one undergoes an addition reaction, followed by an elimination reaction and a salt-forming reaction to synthesize the final product. In the present invention, high-purity doxepin hydrochloride can be obtained through four-step synthesis, and the method does not need substitution reaction, and the yield of the obtained product is relatively high. Compared with the existing synthetic process, the present invention has the advantages of less synthetic steps, simple process, short production cycle, low cost and the like.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a synthesis method of doxepin hydrochloride. Background technique [0002] Doxepin Hydrochloride, also known as Doxepin, chemical name is N,N-dimethyl-3-dibenzo[b,e]- Heptin-11(6H)ylidene-1-propanamine hydrochloride, there are cis and trans isomers, Chemical Abstracts Number (CAS): 1229-29-4; (E)-isomer[4698-39- 9], (Z)-isomer [25127-31-5]. The structural formula is as follows: [0003] [0004] Doxepin hydrochloride is a drug used for the treatment of depression and anxiety neurosis. It is a commonly used tricyclic antidepressant and is a non-selective monoamine uptake inhibitor. It can inhibit norepinephrine (NE) and 5 - Serotonin (5-HT) reuptake increases the concentration of the synaptic cleft, and is mainly used clinically to treat depression, depressive neurosis and depressive state of schizophrenia. [0005] CN105085465A discloses a method for synthesizing doxepin hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 张腾石召华朱仁政江思远张洋郭威林
Owner WUHAN AIMIN PHARMA
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