阅读说明：本技术 一种盐酸克林霉素棕榈酸酯的精制方法 (Refining method of clindamycin palmitate hydrochloride ) 是由 韦家华 刘玉 于 2020-12-31 设计创作，主要内容包括：本发明提供了一种盐酸克林霉素棕榈酸酯的精制方法,通过用水溶解盐酸克林霉素棕榈酸酯粗品,去除制备时残留的水不溶物,再采用超声处理,使盐酸克林霉素棕榈酸酯能够充分溶解,便于将杂质和盐酸克林霉素棕榈酸的分离,利于后续盐酸克林霉素棕榈酸酯的析出,加入盐酸饱和乙醇溶液后继续加热再加入保护剂,保护盐酸克林霉素棕榈酸酯在后续去除杂质的反应中不受影响,便于去除与盐酸克林霉素棕榈酸酯性质相近的杂质,最后再用乙腈析出盐酸克林霉素棕榈酸酯,有效提高了盐酸克林霉素棕榈酸纯度。本发明利用低纯度盐酸克林霉素棕榈酸酯粗品进行精制,充分利用了在制备盐酸克林霉素棕榈酸酯产品的过程中产生的质量较低产品资源。(The invention provides a refining method of clindamycin palmitate hydrochloride, which comprises the steps of dissolving a crude clindamycin palmitate hydrochloride product by using water, removing residual water-insoluble substances during preparation, performing ultrasonic treatment to enable the clindamycin palmitate hydrochloride to be fully dissolved, facilitating separation of impurities and clindamycin palmitate hydrochloride, facilitating separation of subsequent clindamycin palmitate hydrochloride, adding a saturated ethanol solution of hydrochloric acid, continuing heating, adding a protective agent to protect the clindamycin palmitate hydrochloride from being affected in subsequent impurity removal reaction, facilitating removal of impurities with properties similar to those of the clindamycin palmitate hydrochloride, and finally separating the clindamycin palmitate hydrochloride by using acetonitrile, so that the purity of the clindamycin palmitate hydrochloride is effectively improved. The invention refines the low-purity clindamycin palmitate hydrochloride crude product, and fully utilizes the low-quality product resources generated in the process of preparing the clindamycin palmitate hydrochloride product.)

1. A refining method of clindamycin palmitate hydrochloride is characterized by comprising the following steps:

(1) mixing the crude clindamycin palmitate hydrochloride product with water, heating, cooling and filtering to obtain a filtrate;

(2) adding a solvent into the filtrate obtained in the step (1), carrying out ultrasonic treatment, cooling, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 2-3, continuing to heat, adding a protective agent and water, separating out a precipitate, centrifuging, taking supernate, adding hydrochloric acid to adjust the pH value to 2-3, carrying out reduced pressure concentration until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and then dripping acetonitrile at room temperature to separate out a white precipitate;

(3) and (3) pressurizing and filtering the white precipitate in the step (2) in a neutral atmosphere, performing vacuum reduced pressure suction filtration, and drying to obtain the clindamycin palmitate hydrochloride.

2. The method for refining clindamycin palmitate hydrochloride according to claim 1, wherein in the step (1), the crude clindamycin palmitate hydrochloride is 10-60% by mass of clindamycin palmitate hydrochloride calculated as an anhydride.

3. The refining method of clindamycin palmitate hydrochloride according to claim 1, wherein in the step (1), the mass ratio of the crude clindamycin palmitate hydrochloride to the water is 1: 3-6; the heating is carried out by heating to 60-75 ℃ and preserving the heat for 20-30 min.

4. The refining method of clindamycin palmitate hydrochloride according to claim 1, wherein in the step (2), the solvents are acetone, ethanol and chloroform, and the ratio of the solvents is (1.1-1.3): 1:1.2 in mass ratio.

5. The refining method of clindamycin palmitate hydrochloride according to claim 1, wherein in the step (2), the mass ratio of the filtrate to the solvent is 1: 7 to 8.

6. The refining method of clindamycin palmitate hydrochloride as claimed in claim 1, wherein in the step (2), the ultrasonic treatment is ultrasonic treatment at 40-50 ℃ for 10-30 min, and the ultrasonic power is 300-350 kw; and continuously heating to 50-65 ℃, and keeping the temperature for 10-15 min.

7. The refining method of clindamycin palmitate hydrochloride as defined in claim 1, wherein in the step (2), the protective agent is prepared by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1 (1.8-2.3) to (0.5-1.2); the mass ratio of the filtrate, the protective agent and the water is 1 (0.3-0.5) to 1.

8. The refining method of clindamycin palmitate hydrochloride according to claim 1, wherein in the step (2), the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6 (12-18).

9. The refining method of clindamycin palmitate hydrochloride as claimed in claim 1, wherein in the step (3), the neutral atmosphere is one of nitrogen, helium and oxygen.

10. The refining method of clindamycin palmitate hydrochloride as claimed in claim 1, wherein the pressure of the pressure filtration in the step (3) is 1.6-2.0 MPa.

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a refining method of clindamycin palmitate hydrochloride.

Background

The clindamycin palmitate hydrochloride is a derivative of clindamycin, has no antibacterial activity in vitro, and is hydrolyzed by esterase in vivo to form clindamycin to play the antibacterial activity, and the action mechanism of the clindamycin is to inhibit the synthesis of bacterial cell walls.

Patent CN100368419C discloses a method for industrially producing clindamycin palmitate hydrochloride, which comprises the steps of dissolving a crude clindamycin palmitate hydrochloride product by adopting fatty alcohol reflux of C1-C5, evaporating a solvent, adding acetone for crystallization, and obtaining the clindamycin palmitate hydrochloride with high yield but more than 5% of related substances.

Patent CN1332967C discloses a preparation method of clindamycin palmitate hydrochloride, which comprises reacting ketals clindamycin, triethylamine solution and palmitoyl chloride dissolved in chloroform in water bath at 50-90 ℃ under stirring to obtain brown thick substance; dissolving the obtained viscous substance in glacial acetic acid and water, hydrolyzing, drying, adding anhydrous hydrogen chloride saturated lower alcohol solution, and concentrating under reduced pressure to obtain light yellow waxy solid; dissolving the mixture with chloroform, and then violently stirring and dropping acetonitrile to separate out loose solid white fine powder; filtering under reduced pressure, and vacuum drying to obtain clindamycin palmitate hydrochloride, wherein the content of related substances is more than 5%.

Patent CN110894207A discloses a purification method of clindamycin palmitate hydrochloride, which adopts an ionic liquid-salt aqueous two-phase system constructed by 1-butyl-3-methylimidazolium chloride ([ C4mim ] Cl) and potassium phosphate to perform microwave extraction on a crude product of clindamycin palmitate hydrochloride, wherein the content of related substances of clindamycin palmitate hydrochloride is more than 3%.

In 2015, 19 th phase, Guangzhou chemical engineering, recorded "clindamycin palmitate hydrochloride crystallization process research" written by Shehu Chong et al, discloses that acetone n-butanol is used for dissolving crude clindamycin palmitate hydrochloride, and cooling crystallization is carried out to obtain clindamycin palmitate hydrochloride, wherein the content of related substances is less than 3%, but the purification efficiency of the method is low and is 10-30%.

The methods can effectively prepare the clindamycin palmitate hydrochloride, but the methods have the defects of low purification efficiency and incapability of fully utilizing crude product resources of the clindamycin palmitate hydrochloride because related substances for preparing the clindamycin palmitate hydrochloride are more, and the impurities in the existing crude clindamycin palmitate hydrochloride product are intermediate products with similar properties to the clindamycin palmitate hydrochloride except for part of reaction solvents, so that the reduction of the impurities is not researched in the prior art.

Disclosure of Invention

Aiming at the problems, the invention discloses a refining method of clindamycin palmitate hydrochloride. The method is realized according to the following steps:

(1) mixing the crude clindamycin palmitate hydrochloride product with water, heating, cooling and filtering to obtain a filtrate;

(2) adding a solvent into the filtrate obtained in the step (1), carrying out ultrasonic treatment, cooling, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 2-3, continuing to heat, adding a protective agent and water, separating out a precipitate, centrifuging, taking supernate, adding hydrochloric acid to adjust the pH value to 2-3, carrying out reduced pressure concentration until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and then dripping acetonitrile at room temperature to separate out a white precipitate;

(3) and (3) pressurizing and filtering the white precipitate in the step (2) in a neutral atmosphere, performing vacuum reduced pressure suction filtration, and drying to obtain the clindamycin palmitate hydrochloride.

Preferably, in the step (1), the crude clindamycin palmitate hydrochloride product is clindamycin palmitate hydrochloride with the mass percentage of 10-60% calculated on anhydrous basis.

Preferably, in the step (1), the mass ratio of the crude clindamycin palmitate hydrochloride to the water is 1: 3 to 6.

Preferably, in the step (1), the heating is carried out to 60-75 ℃, and the temperature is kept for 20-30 min.

Preferably, in the step (2), the solvent is obtained by mixing acetone, ethanol and chloroform according to the mass ratio of (1.1-1.3) to 1: 1.2.

Preferably, in the step (2), the mass ratio of the filtrate to the solvent is 1: 7 to 8.

Preferably, in the step (2), the ultrasonic treatment is ultrasonic treatment at 40-50 ℃ for 10-30 min, and the ultrasonic power is 300-350 kw.

Preferably, in the step (2), the heating is continued until the temperature is 50-65 ℃, and the heat preservation is carried out for 10-15 min.

Preferably, in the step (2), the protective agent is obtained by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1 (1.8-2.3) to (0.5-1.2).

Preferably, in the step (2), the centrifugation is carried out for 5-10 min under the condition of 1000-2000 r/min.

Preferably, in the step (2), the mass ratio of the filtrate, the protective agent and the water is 1 (0.3-0.5): 1.

Preferably, in the step (2), the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6 (12-18).

Preferably, in the step (3), the neutral atmosphere is one of nitrogen, helium and oxygen.

Preferably, in the step (3), the pressure of the pressure filtration is 1.6-2.0 MPa.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, the crude clindamycin palmitate hydrochloride product is dissolved by water, residual water-insoluble substances during preparation are removed, ultrasonic treatment is adopted, clindamycin palmitate hydrochloride can be fully dissolved, impurities and clindamycin palmitate hydrochloride can be conveniently separated, the subsequent separation of the clindamycin palmitate hydrochloride is facilitated, a saturated ethanol solution of hydrochloric acid is added, then heating is continued, and a protective agent is added, so that the clindamycin palmitate hydrochloride is protected from being affected in the subsequent impurity removal reaction, the removal of the impurities with the properties similar to those of the clindamycin palmitate hydrochloride is facilitated, and finally the clindamycin palmitate hydrochloride is separated out by using acetonitrile, so that the purity of the clindamycin palmitate hydrochloride is effectively improved.

Further, the method adopts a solvent prepared by mixing acetone, ethanol and chloroform for ultrasonic treatment, so that the clindamycin palmitate hydrochloride in the crude product can be fully dissolved in the solvent, and by adding a protective agent prepared from trimethylsilylether, hexane and acetone, the clindamycin palmitate hydrochloride is protected from being influenced in the subsequent impurity removal reaction, and the loss of the clindamycin palmitate hydrochloride is reduced; the invention refines the clindamycin palmitate hydrochloride crude product with lower purity obtained in the preparation process to obtain clindamycin palmitate hydrochloride with less related substances and high purity, and fully utilizes the product resources with lower quality generated in the process of preparing the clindamycin palmitate hydrochloride product.

Detailed Description

The crude clindamycin palmitate hydrochloride product aimed at by the refining method provided by the invention is the crude clindamycin palmitate hydrochloride product prepared by the currently known synthetic method, or the crude clindamycin palmitate hydrochloride product sold in the market, or the crude clindamycin palmitate hydrochloride product prepared by the following method, which is hereinafter referred to as the crude clindamycin palmitate hydrochloride product.

Adding clindamycin hydrochloride and acetone into a reaction container, dissolving, sequentially adding methyl benzenesulfonic acid and 2, 2-dimethoxypropane, reacting for 3h at 35-45 ℃, cooling to 0 ℃, standing for 24h, performing suction filtration, and preparing a filter cake into an aqueous solution with the mass concentration of 20-30%. Adding water, sodium carbonate and acetone into a reaction container, stirring and dissolving, carrying out ice bath to-10-0 ℃, dropwise adding the aqueous solution, heating to 0-5 ℃, stirring until crystallization occurs, standing for 24 hours, carrying out suction filtration, and drying to obtain a white solid. Adding white solid, pyridine and chloroform into a reaction container, stirring, dropwise adding palmitoyl chloride at 0-5 ℃, heating to 25 ℃, reacting for 1h, and distilling at 60 ℃ under reduced pressure to obtain a viscous substance. Mixing the viscous substance with trichloromethane, adding dilute hydrochloric acid, heating to 35-45 ℃, concentrating under reduced pressure, dissolving with ethanol, adding active carbon for treating for 30min, filtering, adding acetonitrile into the filtrate, stirring at-10-0 ℃ for 4h, and filtering to obtain a crude clindamycin palmitate hydrochloride product.

In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.

Example 1

A refining method of clindamycin palmitate hydrochloride comprises the following steps:

(1) mixing the crude clindamycin palmitate hydrochloride product with water, wherein the mass ratio of the crude clindamycin palmitate hydrochloride product to the water is 1: 5, heating to 65 ℃, preserving heat for 25min, cooling and filtering to obtain filtrate;

(2) adding a solvent obtained by mixing acetone, ethanol and chloroform according to the mass ratio of 1.2:1:1.2 into the filtrate obtained in the step (1), wherein the mass ratio of the filtrate to the solvent is 1: 7, carrying out ultrasonic treatment for 15min at 42 ℃, wherein the ultrasonic power is 300kw, cooling, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 3, continuing to heat to 55 ℃, keeping the temperature for 15min, adding a protective agent and water, separating out a precipitate, centrifuging for 5min at 1500r/min, taking a supernatant, adding hydrochloric acid to adjust the pH value to 3, concentrating under reduced pressure until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and dripping acetonitrile at room temperature to separate out a white precipitate; wherein the protective agent is obtained by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1:2: 0.8; the mass ratio of the filtrate to the protective agent to the water is 1:0.3: 1; the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6: 16;

(3) and (3) performing pressure filtration on the white precipitate in the step (2) under the nitrogen atmosphere, wherein the pressure of the pressure filtration is 1.85MPa, and performing vacuum reduced pressure suction filtration and drying to obtain the clindamycin palmitate hydrochloride.

Example 2

A refining method of clindamycin palmitate hydrochloride comprises the following steps:

(1) mixing the crude clindamycin palmitate hydrochloride product with water, wherein the mass ratio of the crude clindamycin palmitate hydrochloride product to the water is 1:6, heating to 75 ℃, preserving heat for 20min, cooling and filtering to obtain filtrate;

(2) adding a solvent obtained by mixing acetone, ethanol and chloroform according to the mass ratio of 1.3:1:1.2 into the filtrate obtained in the step (1), wherein the mass ratio of the filtrate to the solvent is 1: 8, carrying out ultrasonic treatment for 10min at 50 ℃, wherein the ultrasonic power is 320kw, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 2, continuing to heat to 65 ℃, keeping the temperature for 12min, adding a protective agent and water, separating out a precipitate, centrifuging for 8min at 2000r/min, taking a supernatant, adding hydrochloric acid to adjust the pH value to 2, concentrating under reduced pressure until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and then dripping acetonitrile at room temperature to separate out a white precipitate; wherein the protective agent is obtained by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1:2.3: 1.2; the mass ratio of the filtrate to the protective agent to the water is 1:0.5: 1; the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6: 12;

(3) and (3) performing pressure filtration on the white precipitate in the step (2) in an oxygen atmosphere, wherein the pressure of the pressure filtration is 1.6MPa, and performing vacuum reduced pressure suction filtration and drying to obtain the clindamycin palmitate hydrochloride.

Example 3

Example 3 differs from example 1 in that:

in the step (2), the solvent is chloroform.

Example 4

Example 4 differs from example 1 in that:

in the step (2), the ultrasonic treatment is carried out for 30min at the temperature of 35 ℃, and the ultrasonic power is 380 kw.

Example 5

Example 5 differs from example 1 in that:

in the step (2), the heating is continued until the temperature is 45 ℃ and the temperature is kept for 15 min.

Example 6

Example 6 differs from example 1 in that:

in the step (2), the protective agent is trimethylsilyl ether.

Comparative example 1

A refining method of clindamycin palmitate hydrochloride comprises the following steps:

(1) mixing the clindamycin palmitate hydrochloride crude product with a solvent obtained by mixing acetone, ethanol and chloroform according to the mass ratio of 1.2:1:1.2, wherein the mass ratio of the clindamycin palmitate hydrochloride crude product to the solvent is 1: 8, carrying out ultrasonic treatment for 15min at 42 ℃, wherein the ultrasonic power is 300kw, cooling, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 3, continuing to heat to 55 ℃, keeping the temperature for 15min, adding a protective agent and water, separating out a precipitate, centrifuging for 5min at 1500r/min, taking a supernatant, adding hydrochloric acid to adjust the pH value to 3, concentrating under reduced pressure until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and dripping acetonitrile at room temperature to separate out a white precipitate; wherein the protective agent is obtained by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1:2: 0.8; the mass ratio of the filtrate to the protective agent to the water is 1:0.3: 1; the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6: 16;

(2) and (2) performing pressure filtration on the white precipitate in the step (1) under the nitrogen atmosphere, wherein the pressure of the pressure filtration is 1.85MPa, and performing vacuum reduced pressure suction filtration and drying to obtain the clindamycin palmitate hydrochloride.

Comparative example 2

Comparative example 2 differs from example 1 in that:

and (2) adding a solvent obtained by mixing acetone, ethanol and chloroform according to the mass ratio of 1.2:1:1.2 into the filtrate obtained in the step (1), wherein the mass ratio of the filtrate to the solvent is 1: 7, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 3, heating to 55 ℃, keeping the temperature for 15min, adding a protective agent and water, separating out a precipitate, centrifuging for 5min under the condition of 1500r/min, taking supernate, adding hydrochloric acid to adjust the pH value to 3, concentrating under reduced pressure until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and dripping acetonitrile at room temperature to separate out a white precipitate; wherein the protective agent is obtained by mixing trimethylsilyl ether, hexane and acetone according to the mass ratio of 1:2: 0.8; the mass ratio of the filtrate to the protective agent to the water is 1:0.3: 1; the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6: 16.

Comparative example 3

Comparative example 3 differs from example 1 in that:

and (2) adding a solvent obtained by mixing acetone, ethanol and chloroform according to the mass ratio of 1.2:1:1.2 into the filtrate obtained in the step (1), wherein the mass ratio of the filtrate to the solvent is 1: 7, carrying out ultrasonic treatment for 15min at 42 ℃ with the ultrasonic power of 300kw, cooling, adding a hydrochloric acid saturated ethanol solution to adjust the pH value to 3, continuing to heat to 55 ℃, keeping the temperature for 15min, concentrating under reduced pressure until a solid appears, filtering to obtain a filter cake, dissolving the filter cake with chloroform, and then dripping acetonitrile at room temperature to separate out a white precipitate; wherein the mass ratio of the filter cake to the chloroform to the acetonitrile is 1:6: 16.

Comparative example 4

A crystallization process of clindamycin palmitate hydrochloride comprises the following steps:

(1) mixing the crude clindamycin palmitate hydrochloride product with acetone, stirring, heating to 80 ℃, refluxing for 15min, dropwise adding n-butanol, continuously refluxing for 15min after dropwise adding, and slowly cooling to 25 ℃; wherein the mass ratio of the clindamycin palmitate hydrochloride crude product to the acetone to the n-butanol is 1: 7.5: 1.8;

(2) and (2) after the crystals are separated out in the step (1), stirring for 1h, cooling to 0 ℃, preserving heat for 30min, filtering, washing a filter cake by using a small amount of acetone, and drying at 80 ℃ under reduced pressure to obtain the clindamycin palmitate hydrochloride.

Test examples

Before refining, detecting the clindamycin content of a crude clindamycin palmitate hydrochloride product, and then taking the clindamycin palmitate hydrochloride prepared in the examples and the comparative examples to detect the clindamycin content and related substances of a sample, wherein the results are shown in the following table;

and (3) content detection: taking 100g of clindamycin palmitate hydrochloride, and determining the content of the clindamycin palmitate hydrochloride according to the first part of the text variety of the 'Chinese pharmacopoeia 2015 edition';

and (3) related substance detection: taking 100g of clindamycin palmitate hydrochloride, and referring to the first part of the text variety of the 'Chinese pharmacopoeia 2015 edition' in the second part, checking the 'clindamycin palmitate hydrochloride';

the purification efficiency is sample content-crude product content/crude product content x 100%;

the maximum single impurity peak is the highest impurity peak in the chromatogram for detecting related substances.

Group of	Crude content/%)	Content of sample/%)	Purification efficiency/%	Related substance/%)	Maximum single miscellaneous peak/%)
						Pharmacopeia standard	-	≥55.0	-	≤7.00	-
Example 1	43.5	62.9	44.6	1.21	0.258
						Example 2	46.8	66.4	41.9	1.48	0.255
Example 3	55.9	75.5	35.1	1.65	0.284
						Example 4	46.6	63.8	36.9	1.94	0.278
Example 5	44.8	60.3	34.5	1.56	0.345
						Example 6	46.4	61.6	32.8	1.41	0.254
Comparative example 1	38.5	50.1	29.9	5.25	2.686
						Comparative example 2	49.7	60.2	21.1	5.65	3.155
Comparative example 3	47.9	58.8	22.8	4.30	2.568
						Comparative example 4	45.4	54.6	20.3	3.49	1.751

According to experimental results, the method can effectively improve the content of the clindamycin palmitate hydrochloride in the product and reduce related substances, the obtained clindamycin palmitate hydrochloride product has high purity and few related substances, and the method is simple in process, convenient to operate and easy to popularize. Compared with the example 1, the comparative example 1 has no water treatment before extraction, and the obtained sample has more related substances; comparative example 2 is not subjected to ultrasonic treatment, the component of the clindamycin palmitate hydrochloride in the crude product is not sufficiently dissolved, the separation effect is poor, the obtained sample has low content, many related substances and poor purification efficiency; comparative example 3 no protective agent treatment was added, the obtained sample was low in content, the maximum single impurity content was high; comparative example 4 the sample prepared by the conventional refining method had a low content and a poor purification efficiency.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.