Synthesis method of doxepin hydrochloride

Abstract

The invention discloses a synthesis method of doxepin hydrochloride. The synthesis method comprises the following steps: carrying out nucleophilic addition reaction on 6,11-dihydrodibenzo[b,e]oxepin-11-one (compound A) and 3-chloropropyl-tert-butyl ether (compound B) by adding magnesium powder and using THF (tetrahydrofuran) and / or anhydrous aether as a solvent; heating hydroxy compounds in a strongly-alkaline alcohol solvent to perform elimination reaction; carrying out nucleophilic substitution reaction on olefin compounds in the presence of haloid acid; carrying out nucleophilic substitution reaction on halide and dimethylamine in the presence of an ether solvent by adding an organic lithium compound; and carrying out neutralization reaction on doxepin and hydrochloric acid to obtain the doxepin hydrochloride. The fourth reaction step is performed in the ether solvent by using the organic lithium compound, so that the organic lithium compound and dimethylamine form an ammonium lithium salt disclosed in the specification; and the ammonium lithium salt and halide perform alkylation reaction to enhance the tertiary amine yield, thereby ensuring the yield and purity of the final doxepin hydrochloride.

Description

technical field

[0001] The invention relates to the technical field of doxepin hydrochloride, in particular to a synthesis method of doxepin hydrochloride. Background technique

[0002] Doxepin hydrochloride, chemical name N,N-Dimethyl-3-dibenzo(b,e)-oxepin-11(6H)ylidene-1-alanine salt of cis-trans isomers mixture. Its CAS number is 1229-29-4, and its structural formula is

[0003]

[0004] Doxepin hydrochloride is a drug used to treat 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 neurotransmitters in the synaptic cleft Increased concentration exerts antidepressant effects, and also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption is good, and bioavailability is 13-45%, half-life (t 1 / 2 ) for 8-12 hours, the apparent volume of distribution (Vd) 9-33L / kg. It is mainly metabolized in the liver, and the active metabolite is deme...

Examples

Embodiment 1

[0031] In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.1 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder twice the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 35°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 5 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0032] In a 20L reaction vessel, put the ethanol solution (mass concentration 10wt%) of the above-mentioned hydroxy compound and sodium hydroxide 1.5 times the mass of the hydroxy compound, heat to 65°C...

Embodiment 2

[0037]In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.5 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder with 2.4 times the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5 to 7 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 40°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 2 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0038] Put the ethanol solution (mass concentration 70wt%) of the above-mentioned hydroxy compound and sodium hydroxide 5 times the mass of the hydroxy compound in a 20L reaction vessel, he...

Embodiment 3

[0043] In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.3 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder with 2.2 times the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5-7 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 38°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 3.5 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0044] Put the ethanol solution (mass concentration 40wt%) of the above-mentioned hydroxy compound and sodium hydroxide 3 times the mass of the hydroxy compound in a 20L reaction vessel, he...

technical field

[0001] The invention relates to the technical field of doxepin hydrochloride, in particular to a synthesis method of doxepin hydrochloride. Background technique

[0002] Doxepin hydrochloride, chemical name N,N-Dimethyl-3-dibenzo(b,e)-oxepin-11(6H)ylidene-1-alanine salt of cis-trans isomers mixture. Its CAS number is 1229-29-4, and its structural formula is

[0003]

[0004] Doxepin hydrochloride is a drug used to treat 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 neurotransmitters in the synaptic cleft Increased concentration exerts antidepressant effects, and also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption is good, and bioavailability is 13-45%, half-life (t 1 / 2 ) for 8-12 hours, the apparent volume of distribution (Vd) 9-33L / kg. It is mainly metabolized in the liver, and the active metabolite is deme...

Examples

Embodiment 1

[0031] In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.1 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder twice the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 35°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 5 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0032] In a 20L reaction vessel, put the ethanol solution (mass concentration 10wt%) of the above-mentioned hydroxy compound and sodium hydroxide 1.5 times the mass of the hydroxy compound, heat to 65°C...

Embodiment 2

[0037]In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.5 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder with 2.4 times the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5 to 7 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 40°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 2 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0038] Put the ethanol solution (mass concentration 70wt%) of the above-mentioned hydroxy compound and sodium hydroxide 5 times the mass of the hydroxy compound in a 20L reaction vessel, he...

Embodiment 3

[0043] In a 20L reaction vessel, put 6,11-dihydrodibenzo[b,e]oxepin-11-one, 1.3 times the molar ratio of 6,11-dihydrodibenzo[b,e]oxa 3-chloropropanyl tert-butyl ether of heptin-11-one, magnesium powder with 2.2 times the mass of 6,11-dihydrodibenzo[b,e]oxepin-11-one, all THF Two-fifths (5-7 times the mass of THF of 6,11-dihydrodibenzo[b,e]oxepin-11-one), and heated to 38°C to make it react. After the reaction started, the remaining 3 / 5 of THF was added dropwise. After a total reaction time of 3.5 h, the reaction was stopped. Then the system was cooled and poured into saturated ammonium chloride solution, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate for 5 hours, and the obtained crude product was recrystallized with petroleum ether to obtain hydroxyl compounds.

[0044] Put the ethanol solution (mass concentration 40wt%) of the above-mentioned hydroxy compound and sodium hydroxide 3 times the mass of the hydroxy compound in a 20L reaction vessel, he...

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