Method for synthesizing doxepin hydrochloride

Abstract

The invention provides a method for synthesizing doxepin hydrochloride. The method comprises the following steps of: 1, carrying out an addition reaction on 6,11-dihydrobenz [b,e] oxepin-11-one and 3-chloropropyl-methyl tert-butyl ether to obtain alcohol compounds; 2, removing hydroxyl from the alcohol compounds under the condition of concentrated hydrochloric acid to obtain olefin compounds; 3, reacting the olefin compounds with thionyl chloride in a reaction solvent to obtain chloride; 4, coupling the chloride with N,N-dimethyl methylamine to obtain doxepin; and 5, preparing the doxepin into hydrochloride of the doxepin to obtain the doxepin hydrochloride. An Ni(OAc)2 / PPh3 system is creatively used in C-N coupling reaction in the step 4, thus the doxepin hydrochloride has the characteristics of good reaction selectivity, high yield and environmental friendliness; and the catalyst is can be recycled after being simply filtered, thus the production cost is greatly lowered. The whole method has the advantages of simpleness in operation, and easy obtaining and low cost of raw materials, accords with the requirement of industrial production, and is expected to be industrially applied.

Description

technical field

[0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing doxepin hydrochloride. Background technique

[0002] Doxepin Hydrochloride (Doxepin Hydrochloride) is a drug used to treat depression and anxiety neurosis. Its function is to inhibit the reuptake of serotonin 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-dibe...

Examples

Embodiment 1

[0035] (1)

[0036]

[0037] 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%.

[0038] (2)

[...

Embodiment 2

[0051] (1)

[0052]

[0053] 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%.

[0054] (2)

[0055]

[0056] Add 1.4Kg of the ...

Embodiment 3

[0067] Compared with embodiment 1, the difference of this embodiment only lies in:

[0068] 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 .

[0069] 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.

[0070] In step 3, ...

technical field

[0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing doxepin hydrochloride. Background technique

[0002] Doxepin Hydrochloride (Doxepin Hydrochloride) is a drug used to treat depression and anxiety neurosis. Its function is to inhibit the reuptake of serotonin 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-dibe...

Examples

Embodiment 1

[0035] (1)

[0036]

[0037] 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%.

[0038] (2)

[...

Embodiment 2

[0051] (1)

[0052]

[0053] 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%.

[0054] (2)

[0055]

[0056] Add 1.4Kg of the ...

Embodiment 3

[0067] Compared with embodiment 1, the difference of this embodiment only lies in:

[0068] 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 .

[0069] 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.

[0070] In step 3, ...

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