Synthetic method of demethylated doxepin hydrochloride

Abstract

The invention discloses a synthetic method of demethylated doxepin hydrochloride, which comprises the following step of by using doxepin hydrochloride as an initial raw material, acylating, reducing,salifying and purifying to obtain the final product. The method overcomes the defects of harsh reaction conditions, tedious process steps, long reaction time and the like of the existing demethylateddoxepin hydrochloride synthesis process, the reaction time does not exceed 6 hours, and the whole preparation period does not exceed 10 hours, so that the preparation efficiency is greatly improved, and the preparation cost is reduced; the method has the advantages of highest product purity, highest yield and the like.

Description

technical field

[0001] The invention relates to a method for synthesizing demethylated doxepin hydrochloride, which belongs to the field of drug synthesis. Background technique

[0002] Doxepin hydrochloride is a commonly used tricyclic antidepressant. It is a non-selective monoamine uptake inhibitor, which can increase the sudden release by inhibiting the reuptake of norepinephrine (NE) and 5-hydroxytryptamine (5-HT). It is mainly used clinically to treat depression, depressive neurosis and depressive state of schizophrenia.

[0003] After oral administration, doxepin hydrochloride is metabolized through oxidation and demethylation, and the main metabolite is nordoxepin. The chemical structure of demethyl doxepin hydrochloride is as follows: Chemical name: N-methyl-3-dibenzo[b,e]- Heptin-11(6H)ylidene-1-propanamine hydrochloride, Chemical Abstracts Number (CAS): 2887-91-4.

[0004]

[0005] At present, the research on demethyl doxepin hydrochloride mainly focuses on ...

Examples

Embodiment 1

[0032] In a 500ml three-necked flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of dichloromethane. After dissolving, transfer to an ice-water bath, add 6.14g (0.048mol) of N,N-diisopropylethylamine, and slowly 8 g (0.038 mol) of chloroformic acid-2,2,2-trichloroethyl was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 3 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0033] In a 500ml three-necked flask, add the above preparation intermediate A, 250ml tetrahydrofuran, 25g zinc powder, 25g 1mol / L sodium dihydrogen phosphate (pH=5.5), control the temperature at 30-50°C and stir for 1 hour. After the reaction, filter, add appropriate amount of ethyl a...

Embodiment 2

[0036] In a 500ml three-necked flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of chloroform. After dissolving, transfer to an ice-water bath, add 10.23g (0.079mol) of N,N-diisopropylethylamine, and slowly 10.73 g (0.051 mol) of 2,2,2-trichloroethyl chloroformate was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 2 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0037] Into a 500ml three-neck flask, add the above-mentioned preparation intermediate A, 200ml tetrahydrofuran, 35g zinc powder, and 35g glacial acetic acid, and stir and react at 30-45°C for 3 hours. After the reaction, filter, add appropriate amount of ethyl acetate and 10% NaOH aqueous...

Embodiment 3

[0040] In a 500ml three-neck flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of dichloromethane. After dissolving, transfer to an ice-water bath, add 8.18g (0.063mol) of N,N-diisopropylethylamine, and slowly 10.73 g (0.051 mol) of 2,2,2-trichloroethyl chloroformate was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 2 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0041] In a 500ml three-neck flask, add the above-mentioned preparation intermediate A, 200ml tetrahydrofuran, 30g zinc powder, and 25g glacial acetic acid, and stir and react at 35-50°C for 2.5 hours. After the reaction, filter, add appropriate amount of ethyl acetate and 10% NaOH aqueo...

technical field

[0001] The invention relates to a method for synthesizing demethylated doxepin hydrochloride, which belongs to the field of drug synthesis. Background technique

[0002] Doxepin hydrochloride is a commonly used tricyclic antidepressant. It is a non-selective monoamine uptake inhibitor, which can increase the sudden release by inhibiting the reuptake of norepinephrine (NE) and 5-hydroxytryptamine (5-HT). It is mainly used clinically to treat depression, depressive neurosis and depressive state of schizophrenia.

[0003] After oral administration, doxepin hydrochloride is metabolized through oxidation and demethylation, and the main metabolite is nordoxepin. The chemical structure of demethyl doxepin hydrochloride is as follows: Chemical name: N-methyl-3-dibenzo[b,e]- Heptin-11(6H)ylidene-1-propanamine hydrochloride, Chemical Abstracts Number (CAS): 2887-91-4.

[0004]

[0005] At present, the research on demethyl doxepin hydrochloride mainly focuses on ...

Examples

Embodiment 1

[0032] In a 500ml three-necked flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of dichloromethane. After dissolving, transfer to an ice-water bath, add 6.14g (0.048mol) of N,N-diisopropylethylamine, and slowly 8 g (0.038 mol) of chloroformic acid-2,2,2-trichloroethyl was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 3 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0033] In a 500ml three-necked flask, add the above preparation intermediate A, 250ml tetrahydrofuran, 25g zinc powder, 25g 1mol / L sodium dihydrogen phosphate (pH=5.5), control the temperature at 30-50°C and stir for 1 hour. After the reaction, filter, add appropriate amount of ethyl a...

Embodiment 2

[0036] In a 500ml three-necked flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of chloroform. After dissolving, transfer to an ice-water bath, add 10.23g (0.079mol) of N,N-diisopropylethylamine, and slowly 10.73 g (0.051 mol) of 2,2,2-trichloroethyl chloroformate was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 2 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0037] Into a 500ml three-neck flask, add the above-mentioned preparation intermediate A, 200ml tetrahydrofuran, 35g zinc powder, and 35g glacial acetic acid, and stir and react at 30-45°C for 3 hours. After the reaction, filter, add appropriate amount of ethyl acetate and 10% NaOH aqueous...

Embodiment 3

[0040] In a 500ml three-neck flask, add 10g (0.032mol) of doxepin hydrochloride and 180ml of dichloromethane. After dissolving, transfer to an ice-water bath, add 8.18g (0.063mol) of N,N-diisopropylethylamine, and slowly 10.73 g (0.051 mol) of 2,2,2-trichloroethyl chloroformate was added dropwise, and after the dropwise addition was completed, the reaction was stirred for 2 hours. After the reaction was completed, 10% NaOH aqueous solution was added in an ice-water bath to adjust the pH to 12, the organic layer was extracted, washed with an appropriate amount of water until the aqueous layer was neutral, and the organic layer was concentrated to obtain a yellow oil, which was Intermediate A.

[0041] In a 500ml three-neck flask, add the above-mentioned preparation intermediate A, 200ml tetrahydrofuran, 30g zinc powder, and 25g glacial acetic acid, and stir and react at 35-50°C for 2.5 hours. After the reaction, filter, add appropriate amount of ethyl acetate and 10% NaOH aqueo...

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