阅读说明：本技术 一种盐酸多塞平的精制方法 (Refining method of doxepin hydrochloride ) 是由 杨建楠 陆滢炎 李斯 赵璐 李金玲 魏伟业 赵卿 霍立茹 李战 于 2019-10-29 设计创作，主要内容包括：本发明属于药物合成领域,涉及一种盐酸多塞平的精制方法。本发明所述的盐酸多塞平的精制方法包含以下步骤：将盐酸多塞平粗产品加入水中,碱液调节pH,二氯甲烷萃取,有机相旋干,得到游离的多塞平。游离的多塞平溶于乙醚和乙醇混合溶剂中,在所控制的温度范围下,加入马来酸,搅拌后析出多塞平马来酸盐。多塞平马来酸盐再加入水中,碱液调节pH,二氯甲烷萃取,有机相旋干,得到游离的多塞平。向游离的多塞平中滴加异丙醚氯化氢,搅拌析晶,盐酸多塞平。本发明的方法得到产品Z构型盐酸多塞平含量处于17％～18.5％。(The invention belongs to the field of drug synthesis, and relates to a refining method of doxepin hydrochloride. The refining method of doxepin hydrochloride comprises the following steps: and adding the crude doxepin hydrochloride product into water, adjusting the pH value with alkali liquor, extracting with dichloromethane, and spin-drying an organic phase to obtain free doxepin. Dissolving the free doxepin in a mixed solvent of ether and ethanol, adding maleic acid in a controlled temperature range, and stirring to separate out doxepin maleate. Adding the doxepin maleate into water, adjusting the pH value with alkali liquor, extracting with dichloromethane, and spin-drying the organic phase to obtain free doxepin. And (3) adding isopropyl ether hydrogen chloride dropwise into the free doxepin, stirring and crystallizing, and obtaining doxepin hydrochloride. The content of the product Z-shaped doxepin hydrochloride prepared by the method is 17-18.5%.)

1. A refining method of doxepin maleate is characterized in that free doxepin is dissolved by adding diethyl ether and absolute ethyl alcohol, maleic acid is added, and crystallization is carried out to obtain the doxepin maleate, wherein the volume mass ratio of the diethyl ether to the doxepin is 2.4-2.6, and the volume mass ratio of the absolute ethyl alcohol to the doxepin is 2.4-2.6.

2. The method for purifying doxepin maleate according to claim 1, wherein the volume mass ratio of diethyl ether to doxepin is 2.5, and the volume mass ratio of absolute ethanol to doxepin is 2.5.

3. The process for purifying doxepin maleate as claimed in claim 1, wherein the crystallization temperature is 0 to 30 ℃.

4. The method for purifying doxepin maleate according to claim 1 wherein the mass ratio of maleic acid to doxepin is 1 to 1.02.

5. A refining method of doxepin hydrochloride is characterized by comprising the following steps:

(1) dissolving the free doxepin by using a mixed solvent of ethanol and ether, adding maleic acid at room temperature, stirring and crystallizing to obtain doxepin maleate;

(2) adding the obtained doxepin maleate into water, adjusting the pH value with alkali liquor, extracting with dichloromethane, and spin-drying the organic phase to obtain free doxepin;

(3) suspending the free doxepin in isopropyl ether, dropwise adding isopropyl ether hydrogen chloride, stirring and crystallizing to obtain doxepin hydrochloride.

6. The refining method of doxepin hydrochloride according to claim 5, characterized in that in the step (1), the volume mass ratio of diethyl ether to doxepin is 2.4-2.6, the volume mass ratio of absolute ethyl alcohol to doxepin is 2.4-2.6, the mass ratio of maleic acid to doxepin is 1-1.02, and the stirring crystallization time is 1.5-2 hours.

7. The refining method of doxepin hydrochloride according to claim 5, characterized in that the alkali solution in the step (2) is selected from saturated aqueous sodium bicarbonate solution, the pH is adjusted to 8-9, and the pH temperature is adjusted to 24-29 ℃.

8. The refining method of doxepin hydrochloride according to claim 5, characterized in that the ratio of the volume of the solvent isopropyl ether to the mass of doxepin in step (3) is 10 to 20.

9. The refining method of doxepin hydrochloride according to claim 5, wherein the free doxepin hydrochloride is prepared by adding crude doxepin hydrochloride to water, adjusting pH with alkali solution, extracting with dichloromethane, and spin-drying the organic phase to obtain free doxepin.

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a refining method of doxepin hydrochloride.

Background

Doxepin Hydrochloride (Doxepin Hydrochloride), a mixture of cis (Z-) and trans (E-) isomers of N, N-dimethyl-3-dibenzo (b, E) -oxepin-11 (6H) ylidene-1-alaninate, is a drug for treating depression and anxiety neurosis, which is about to inhibit the reuptake of 5-hydroxytryptamine and norepinephrine by the central nervous system, so that the concentrations of the two neurotransmitters in synaptic cleft are increased to play an anti-depression role and have an anti-anxiety and sedative role. The doxepin hydrochloride has good oral absorption, bioavailability of 13-45%, and half-life (t)_1/2) The obtained product has apparent volume (Vd) of 9-33L/kg for 8-12 hr, and is mainly metabolized in liver, active metabolite is demethylate, and metabolite is excreted by kidney. The CAS number is 1229-29-4, and the structural formula is as follows:

the content of the Z-configuration in the doxepin hydrochloride prepared by the existing industrial method is about 25 percent, the content range of the Z-configuration in the doxepin hydrochloride detected according to the European pharmacopoeia standard is 13 to 18.5 percent, the content range of the Z-configuration in the doxepin hydrochloride detected by the Chinese pharmacopoeia standard is 17 to 23 percent, if the content of the Z-configuration in the doxepin hydrochloride is between 17 and 18.5 percent, the doxepin hydrochloride raw material can accord with the international mainstream standard, and the international universal effect is achieved. Therefore, it is necessary to develop a refining method of doxepin hydrochloride which has good refining effect and high yield and can reach pharmacopeia standards.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides the method which has the advantages of simple process, convenient operation, low production cost and stable process, and can ensure that the content of the hydrochloric acid doxycycline (Z-) configuration is between 17 and 18.5 percent.

The invention provides a refining method of doxepin maleate, which comprises the steps of adding ether and absolute ethyl alcohol into free doxepin for dissolving, adding maleic acid, and crystallizing to obtain the doxepin maleate, wherein the volume mass ratio vol of the ether to the doxepin is 2.4-2.6, and the volume mass ratio vol of the absolute ethyl alcohol to the doxepin is 2.4-2.6.

Through the solvent system, the doxepin maleate with the Z-configuration content of 17-18.5% can be stably obtained, and then the doxepin hydrochloride with the Z-configuration content of 17-18.5% can be stably obtained by dissociating and hydrochlorinating the doxepin maleate.

Further, the volume mass ratio vol of the diethyl ether to the doxepin is 2.5, and the volume mass ratio vol of the absolute ethyl alcohol to the doxepin is 2.5.

Further, the crystallization temperature is 0-30 ℃, preferably 20-30 ℃.

Further, the mass ratio of the maleic acid to the doxepin is 1-1.02, preferably, the mass ratio is 1.02.

The invention provides a refining method of doxepin hydrochloride, which comprises the following steps:

(1) dissolving the free doxepin by using a mixed solvent of ethanol and ether, adding maleic acid at room temperature, stirring and crystallizing to obtain doxepin maleate;

(2) adding the obtained doxepin maleate into water, adjusting the pH value with alkali liquor, extracting with dichloromethane, and spin-drying the organic phase to obtain free doxepin;

(3) suspending the free doxepin in isopropyl ether, dropwise adding isopropyl ether hydrogen chloride, stirring and crystallizing to obtain doxepin hydrochloride.

Further, in the step (1), the volume mass ratio vol of the diethyl ether to the doxepin is 2.4-2.6, and the volume mass ratio vol of the absolute ethyl alcohol to the doxepin is 2.4-2.6. Preferably, the volume mass ratio vol of the diethyl ether to the doxepin is 2.5, and the volume mass ratio vol of the absolute ethyl alcohol to the doxepin is 2.5.

Further, the crystallization temperature is 0-30 ℃, preferably 20-30 ℃.

Further, the mass ratio of the maleic acid to the doxepin is 1-1.02, preferably, the mass ratio is 1.02.

Further, the stirring and crystallization time is 1.5-2 hours.

Further, the alkali liquor in the step (2) is selected from saturated sodium bicarbonate water solution, the pH value is adjusted to be 8-9, and the pH value temperature is adjusted to be 24-29 ℃.

Furthermore, the ratio of the volume of the solvent isopropyl ether in the step (3) to the mass of doxepin is 10-20 vol. Specifically, the concentration of the used isopropyl ether hydrogen chloride is 5.9mol/L, and the volume-to-doxepin mass ratio of the isopropyl ether hydrogen chloride is 1 vol.

Further, the free doxepin is prepared from a crude doxepin hydrochloride product, the crude doxepin hydrochloride product is added into water, the pH value is adjusted by using alkali liquor, dichloromethane is used for extraction, and an organic phase is dried in a spinning mode to obtain the free doxepin. Specifically, the alkali liquor is selected from a saturated sodium bicarbonate aqueous solution, the pH value is adjusted to be 8-9, and the pH value temperature is adjusted to be 24-29 ℃.

The purification method provided by the invention has stable process and strong reproducibility. Solves the great difficulties that the technical range of 17 percent to 18.5 percent is narrow and the process is difficult to stably reproduce, and can stably control the content of the hydrochloric acid polycide smooth (Z-) configuration to be between 17 percent to 18.5 percent. The yield of the method is between 60 and 85 percent, and the loss of the product is less.

Detailed Description

The invention is further illustrated with reference to the following examples, which, however, do not constitute any limitation of the invention.

"vol" in the present invention means a ratio of a solvent volume ml to a material mass g, i.e., a volume-to-mass ratio.

Example 1

Dissolving 10g of crude doxepin hydrochloride (with the Z configuration content of 24.53%) in 50mL of water, adding saturated aqueous sodium bicarbonate solution at room temperature, adjusting the pH to 8-9, extracting with dichloromethane, and spin-drying an organic phase to obtain free doxepin (a yellow oily substance, 8.9 g).

The free doxepin (3.6g) obtained above was taken and dissolved in 9mL of diethyl ether and 9mL of absolute ethanol. And (3) controlling the external temperature to be 20-25 ℃, adding 1.53g of maleic acid, and stirring for crystallization for 1.5 hours. 4.51g of white solid doxepin maleate is obtained, the yield is 88.43 percent, and the content of Z configuration is 17.61 percent.

The doxepin maleate (4g) obtained above was suspended in 4mL of water, and a saturated aqueous solution of sodium bicarbonate was added at R.T. (22 ℃), the pH was adjusted to 8 to 9, dichloromethane was extracted, and the organic phase was spin-dried to obtain free doxepin (yellow oil, 2.8 g).

Free doxepin (1g) obtained above was suspended in isopropyl ether (20vol, 20mL), R.T. (22 ℃ C.) while dropwise adding isopropyl ether hydrogen chloride (5.9mol/L, homemade, 1vol, 1mL) and stirring for crystallization for 18 hours, the solvent was dried by rotary evaporator, nitrogen was vented, 30mL of clean isopropyl ether was added and stirring for 0.5 hour and then spin-dried, and this was repeated twice. And (3) covering a nitrogen cover for suction filtration, quickly placing a filter cake in a vacuum drying oven, and carrying out vacuum drying for 3 days at 50 ℃ to obtain 0.65g of white solid doxepin hydrochloride, wherein the yield is 72.81 percent, and the Z-configuration content is 18.194 percent.

In conclusion, the total yield of refined doxepin hydrochloride is 64.38%, and the final Z configuration content is 18.194%.

Example 2

Dissolving 30g of crude doxepin hydrochloride (with the Z-configuration content of 24.53%) in water (5vol, 150mL), adding a saturated aqueous solution of sodium bicarbonate at R.T ℃ (28 ℃), adjusting the pH to 8-9, extracting with dichloromethane, and spin-drying an organic phase to obtain free doxepin (yellow oil, 28g)

The free doxepin (2g) obtained above was taken, and dissolved by adding diethyl ether (2.5vol, 4mL) and absolute ethanol (2.5vol, 4 mL). Maleic acid (maleic acid, 1.02eq, 0.85g) is added under the condition of controlling the external temperature to be 20-25 ℃, and stirred and crystallized for 1.5 hours. Obtained was doxepin maleate 2.39g as a white solid in 84.45% yield and 18.475% Z-configuration content.

The doxepin maleate (2g) obtained above was suspended in water (1vol, 2mL), and a saturated aqueous solution of sodium bicarbonate was added at R.T. (27 ℃), the pH was adjusted to 8 to 9, dichloromethane was extracted, and the organic phase was spin-dried to obtain free doxepin (yellow oil, 1.8 g).

Free doxepin (0.8g) obtained above was suspended in isopropyl ether (20vol, 16mL), R.T. (27 ℃ C.) and isopropyl ether hydrogen chloride (5.9mol/L, homemade, 1vol, 0.8mL) was added dropwise with stirring to crystallize for 3 days, the solvent was dried by rotation with a rotary evaporator, nitrogen was vented, 30mL of clean isopropyl ether was added and stirred for 0.5 hour and then dried by rotation, and this was repeated twice. And (3) covering a nitrogen cover for suction filtration, quickly placing a filter cake in a vacuum drying oven, and carrying out vacuum drying for 21 hours at 50 ℃ to obtain 0.77g of white solid doxepin hydrochloride, wherein the yield is 85.13%, and the Z-configuration content is 18.31%.

In conclusion, the total yield of the refined doxepin hydrochloride is 71.89%, and the final Z configuration content is 18.31%.

Example 3

Dissolving 30g of crude doxepin hydrochloride (with the Z-configuration content of 24.53%) in water (5vol, 150mL), adding a saturated aqueous solution of sodium bicarbonate at room temperature, adjusting the pH to 8-9, extracting with dichloromethane, and spin-drying an organic phase to obtain free doxepin (yellow oil, 28g)

The free doxepin (3.6g) obtained above was taken and added to a recrystallization solvent. And (3) controlling the external temperature to be 20-25 ℃, adding 1.53g of maleic acid, and stirring for crystallization for 1.5 hours. White solid doxepin maleate was obtained.

Suspending the obtained doxepin maleate in 4mL of water, adding a saturated sodium bicarbonate aqueous solution at room temperature, adjusting the pH to 8-9, extracting with dichloromethane, and spin-drying an organic phase to obtain free doxepin.

Suspending the free doxepin obtained in the above step in isopropyl ether (20vol), dropwise adding isopropyl ether hydrogen chloride (5.9mol/L, self-made, 1vol) at room temperature, stirring and crystallizing for 18 hours, using a rotary evaporator to spin dry the solvent, discharging nitrogen, adding 80mL of isopropyl ether, stirring for 0.5 hour, then spinning, and repeating the steps twice. And (3) covering a nitrogen cover for suction filtration, quickly placing the filter cake in a vacuum drying oven, and carrying out vacuum drying at 50 ℃ for 3 days to obtain the white solid doxepin hydrochloride.

The yield and configuration data were as follows, from multiple replicates:

1. ethanol solvent system

Numbering	Doxepin maleate recrystallization system	Precipitation temperature	Yield of refined doxepin hydrochloride	Yield of	Z-configuration product content
						1-1	2.5vol ethanol	R.T.(24℃)	2.77g	68.08％	14.02％
1-2	2.5vol ethanol	0-5℃	3.06g	75.17％	15.92％
						1-3	5vol ethanol	R.T.(24℃)	2.74g	67.33％	14.12％
1-4	5vol ethanol	0-5℃	3.26g	80.14％	15.98％
						1-5	7.5vol ethanol	R.T.(24℃)	3.18g	78.01％	14.39％
1-6	7.5vol ethanol	0-5℃	3.41g	83.69％	16.20％

From this set of experiments, it is seen that the content of the product in the Z configuration is less than 17% under the condition of ethanol regardless of the crystallization temperature or the amount of ethanol used, and the product does not meet the technical standard of the invention.

2. Mixed solvent system composed of methyl tert-butyl ether and ethanol

Numbering	Recrystallization system	Precipitation temperature	Yield of the product	Yield of	Z-configuration product content
						2-1	5vol methyl tert-butyl ether +15vol ethanol	R.T.(24℃)	2.71g	66.67％	8.63％
2-2	2.5vol methyl tert-butyl ether +2.5vol ethanol	R.T.(24℃)	3.12g	76.60％	16.27％
						2-3	2.5vol methyl tert-butyl ether +2.5vol ethanol	10-15℃	3.27g	80.28％	11.56％
2-4	5vol ethanol +5vol methyl tert-butyl ether	R.T.(24℃)	3.32g	81.69％	17.36％
						2-5	5vol ethanol +5vol methyl tert-butyl ether	R.T.(25℃)	2.87g	70.42％	14.47％
2-6	5vol ethanol +5vol methyl tert-butyl ether	R.T.(25℃)	3.09g	76.06％	14.37％
						2-7	5vol ethanol +5vol methyl tert-butyl ether	R.T.(24℃)	3.21g	78.87％	14.34％

In the group of experiments, the volume ratio of methyl tert-butyl ether to ethanol is 1: in case 1, 2-4 has Z configuration content meeting the standard, but the repeated experiments (2-5, 2-6 and 2-7) can not be completely reproduced, the group of solvents can not be accurately controlled on the final Z/E structural ratio, and other unknown factors have larger influence.

3. Mixed solvent system composed of isopropyl ether and ethanol

In the test group, the volume ratio of isopropyl ether to ethanol is 1: in case 1, 3-4 has Z configuration content meeting the standard, but the repeated experiments (3-5, 3-6 and 3-7) can not be completely reproduced, the group of solvents can not be accurately controlled on the final Z/E structural ratio, and other unknown factors have larger influence.

4. Mixed solvent system composed of ether and ethanol

In the experiment group, under the condition of room temperature, 2.5vol ethyl ether and 2.5vol ethanol, the technical indexes required by the invention can be obtained by repeating the experiment for 3 times. Meanwhile, the temperature is slightly reduced, the content of the Z configuration is not greatly changed, and the process is stable.

Z/E structure detection method for doxepin hydrochloride and doxepin maleate

Octadecylsilane chemically bonded silica is used as a filling agent; a0.2 mol/L sodium dihydrogen phosphate solution containing 0.1% triethylamine

Alcohol (65:35) (pH adjusted to 2.5 with 2mol/L phosphoric acid) as mobile phase; the detection wavelength is 254 nm; the column temperature was 50 ℃. The theoretical plate number is not less than 1500 according to the cis-isomer (Z), and the separation degree of the trans-isomer (E) and the cis-isomer (Z) peaks is in accordance with the requirement.

The determination method comprises precisely weighing the product, dissolving with mobile phase, diluting to obtain solution containing 0.l m g per l m l, precisely measuring 20m1, injecting into liquid chromatograph, and recording chromatogram; taking another reference substance of doxepin hydrochloride, and determining by the same method. And calculating by the sum of the areas of the two peaks of the multi-Saiping according to an external standard method.