A separation method of clindamycin phosphate and its product

Abstract

The invention provides a separation method of clindamycin phosphate and its product, belonging to the technical field of clindamycin phosphate. The method comprises the following steps: (1) adding alkaline water to the clindamycin phosphate reaction hydrolyzate, adjusting the pH value of the system, adding a precipitation reagent to react and generate a precipitate, filtering, and obtaining a clindamycin phosphate precipitate; (2) adding the clindamycin phosphate precipitate to water and ethanol, stirring and heating, adding concentrated hydrochloric acid until it is completely dissolved and controlling the pH value of the system to 3.5-4.5, adding activated carbon for decolorization, filtering out the activated carbon and insoluble impurities while hot, and obtaining a decolorized solution; (3) adding ethanol to the decolorized solution, stirring, cooling, crystallizing, filtering, and drying to obtain clindamycin phosphate. The preparation process of the invention is simple to operate, has low energy consumption, is easy to control the production process, does not need to add a large amount of reagents, reduces wastewater discharge, and has the technical effects of high efficiency and environmental protection. The clindamycin phosphate prepared by the method has high purity and high yield, and is particularly suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of clindamycin phosphate, and particularly relates to a separation method of clindamycin phosphate and a product thereof. Background Art

[0002] Clindamycin phosphate is a derivative of lincomycin (cleanserin), the chemical name is 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-a-D-pyranosylgalactoside-2-dihydrogen phosphate, the molecular formula is C 18 H 34 ClN2O8PS, the structural formula is

[0003]

[0004] It is an antibiotic drug with no antibacterial activity in vitro. It can be rapidly hydrolyzed into clindamycin with antibacterial activity after entering the body. It has strong antibacterial effects on various Gram-positive bacteria and is a broad-spectrum antibiotic with anti-anaerobic and aerobic effects. Compared with clindamycin, it has the characteristics of high antibacterial activity, rapid absorption, strong fat solubility and permeability, and few side effects. Therefore, it is widely used in clinical practice.

[0005] In the prior art, after the reaction of clindamycin phosphate is completed, alkaline water is usually added for hydrolysis reaction, and then the product is placed in a macroporous resin for adsorption, washing, methanol analysis, concentration, and crystallization to obtain clindamycin phosphate. However, the prior art has the following shortcomings: First, the production cycle is relatively long, the adsorption and analysis process of the macroporous resin needs real-time monitoring, and the operation and control are complicated. Second, the washing and analysis process requires a large amount of water and organic solvents, and the direct discharge of wastewater is wasteful and pollutes the environment. In addition, as patent ZL201810065089.8, a method for synthesizing clindamycin phosphate, introduces a post-processing method for the reaction solution of clindamycin phosphate, but the process route requires the use of a new organic solvent, and the amount of solvent used has a certain effect on the reaction.

[0006] In summary, how to develop a new method for separating clindamycin phosphate with a simple process route and green and environmentally friendly reaction is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0007] The object of the present invention is to provide a method for separating clindamycin phosphate, which abandons the conventional adsorption, water washing, analysis and other steps in the prior art. By designing the added reagents and the dosage thereof, high-purity clindamycin phosphate can be effectively separated. The overall process route is simple, the dependence on equipment and operators is reduced, and the production time is shortened.

[0008] To achieve the above object, the present invention provides a method for separating clindamycin phosphate, which specifically comprises the following steps:

[0009] (1) adding alkaline water to the clindamycin phosphate reaction hydrolyzate, adjusting the pH value of the system, adding a precipitation reagent to react to generate a precipitate, and filtering to obtain a clindamycin phosphate precipitate;

[0010] (2) adding the clindamycin phosphate precipitate to water and ethanol, stirring and heating, adding concentrated hydrochloric acid until it is completely dissolved and controlling the pH of the system to 3.5-4.5, adding activated carbon for decolorization, filtering out the activated carbon and insoluble impurities while hot, and obtaining a decolorized solution;

[0011] (3) Add ethanol to the decolorizing solution and slowly cool it down to allow crystallization. After filtering and drying, clindamycin phosphate is obtained.

[0012] In a preferred embodiment, in step (1), the preparation method of the clindamycin phosphate reaction hydrolyzate is as follows: add clindamycin hydrochloride ethanolate to acetone, control the temperature below 5°C, sequentially dropwise add 40% to 50% of the mass of phosphorus oxychloride, pyridine, and the remaining 50% to 60% of phosphorus oxychloride, and keep the temperature for reaction for 6 to 10 hours after the dropwise addition. After the reaction is completed, add water, react at room temperature for 5 hours, and evaporate the acetone under reduced pressure to obtain the clindamycin phosphate reaction hydrolyzate; wherein the structural formula of the clindamycin hydrochloride ethanolate is:

[0013]

[0014] , molecular formula: C 18 H 33 ClN2O5S.HCl.C2H5OH can be prepared by conventional methods known to those skilled in the art, such as the preparation method described in CN101205245A.

[0015] In a preferred embodiment, in the method for preparing the clindamycin phosphate reaction hydrolyzate, the mass ratio of the clindamycin hydrochloride ethanolate, acetone, phosphorus oxychloride, pyridine, and water is 1: (2-4):

[0016] (0.6~1.6):(0.16~0.4):(6~10).

[0017] In a preferred embodiment, in step (1), the alkaline water is a sodium hydroxide solution with a mass percentage concentration of 30% to 35%, and the pH value of the system is adjusted to 4 to 5. In this pH environment, the precipitation reagent can fully react with the clindamycin phosphate in the hydrolyzate to form a precipitate, thereby obtaining clindamycin phosphate salt.

[0018] In a preferred embodiment, in step (1), the precipitant is an alkali or metal oxide that can react with phosphoric acid to form a precipitated salt; preferably, the precipitating agent includes one or more of calcium oxide, calcium hydroxide, calcium acetate, and magnesium oxide. The above precipitating agents can quickly and efficiently precipitate clindamycin phosphate in the hydrolyzate in a system of pH 4 to 5, and the obtained products include clindamycin phosphate calcium salt and clindamycin phosphate magnesium salt.

[0019] In a preferred embodiment, in step (1), the ratio of the amount of the precipitating agent to the amount of clindamycin phosphate in the clindamycin phosphate reaction hydrolyzate is (1-1.1): 1. The above ratio can not only fully generate clindamycin phosphate salt, but also avoid adding too much precipitating agent to cause waste and generate waste liquid.

[0020] In a preferred embodiment, in step (1), after adding the precipitating agent, the preferred reaction temperature is 20 to 40° C., and the reaction time is 1 to 5 hours.

[0021] In a preferred embodiment, in step (2), the weight ratio of the clindamycin phosphate precipitate, water and ethanol is 1:(0-3):(1-5). The purpose of adding ethanol and water to the clindamycin phosphate precipitate in the present invention is to dissolve the clindamycin phosphate precipitate. Ethanol is safe, environmentally friendly, low in cost, and can also be used as a crystallization solvent for crystallization reaction. In terms of dosage, if the ethanol is too little, the precipitate cannot be fully dissolved, and if the ethanol is too much, waste will be generated.

[0022] In a preferred embodiment, in step (2), the stirring temperature is raised to 70-80° C. At this temperature, the activated carbon decolorization effect is best. In addition, in the present invention, by adding concentrated hydrochloric acid and controlling the system pH at 3.5-4.5, clindamycin phosphate can be obtained by reaction under this condition, and the chloride ions in the hydrochloric acid are not easy to introduce impurities.

[0023] In a preferred embodiment, in step (2), the weight ratio of the activated carbon to the clindamycin phosphate precipitate is (0.01-0.05): 1. In the present invention, by providing a system suitable for activated carbon reaction, only a very small amount of activated carbon needs to be added to achieve a good decolorization effect.

[0024] In a preferred embodiment, in step (2), the activated carbon decolorization temperature is 70-80° C., and the decolorization time is 0.5-2 hours.

[0025] In a preferred embodiment, in step (3), the weight ratio of ethanol to clindamycin phosphate precipitate is (2-6):1. The purpose of adding ethanol to the decolorizing solution is to increase the amount of solvent and increase the proportion of ethanol in the crystallization solvent, thereby achieving a better crystallization effect. Preferably, the volume percentage concentration of ethanol is 95%.

[0026] In a preferred embodiment, in step (3), the slow cooling refers to cooling to 20-30°C at a rate of 0.5-5°C / min, stirring the reaction for 2-12 hours, and then cooling to 0-5°C at a rate of 0.5-5°C / min.

[0027] In a preferred embodiment, in step (3), the drying can be carried out in a conventional manner known to those skilled in the art, and the present invention is not limited thereto. For example, the drying can be carried out at 60-80° C. for 2-8 hours.

[0028] Another object of the present invention is to provide a clindamycin phosphate prepared by any one of the above methods.

[0029] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0030] (1) The separation method of clindamycin phosphate provided by the present invention has a simple process route, does not require the upper column separation process in the prior art, and can effectively separate and purify the clindamycin phosphate finished product, thereby improving production efficiency. Meanwhile, since adsorption, washing and analytical processes are not required, the operation process is reduced, and labor intensity is reduced. Further, the use of a large amount of water and solvent is also avoided, wastewater discharge is reduced, environmental pollution is reduced, and the on-site operating environment is improved.

[0031] (2) In the present invention, the insoluble matter is generated by the reaction of clindamycin phosphate in the hydrolyzate with a precipitating agent, which is precipitated from the aqueous medium, thereby being separated from the salt substances generated by the reaction. The insoluble matter is then dissolved in hydrochloric acid water and ethanol to obtain clindamycin phosphate and equimolar chloride salts, which are dissolved in water and ethanol. After cooling, clindamycin phosphate is precipitated from water and ethanol, thereby effectively separating pure clindamycin phosphate. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] These and / or other aspects and advantages of the present invention will become more clear and easier to understand from the following detailed description of the embodiments of the present invention in conjunction with the accompanying drawings, in which:

[0033] Figure 1 The HPLC spectrum of the clindamycin phosphate product prepared in Example 1 of the present invention.

[0034] Figure 2 The HPLC spectrum of the clindamycin phosphate product prepared in Example 2 of the present invention.

[0035] Figure 3 The HPLC spectrum of the clindamycin phosphate product prepared in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0036] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods, but it should be understood that the protection scope of the present invention is not limited to the specific implementation methods.

[0037] The embodiment of the present invention provides a separation method of clindamycin phosphate and a product thereof, thereby solving the cumbersome steps of adding alkaline water to carry out hydrolysis reaction, then entering macroporous resin to carry out adsorption, water washing, methanol analysis, concentration, and crystallization to obtain clindamycin phosphate in the prior art solution.

[0038] Unless otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art, and the various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods. The reagents used in the present invention are analytically pure unless otherwise specified, and the concentrated hydrochloric acid used in the present invention is commercially available concentrated hydrochloric acid with a mass percentage concentration of 36% to 38%.

[0039] Example 1

[0040] Preparation of clindamycin phosphate reaction hydrolyzate: add 20g of clindamycin hydrochloride ethanolate to 60g of acetone, cool to 0°C, add 10g of phosphorus oxychloride, 6g of pyridine, and 14g of phosphorus oxychloride dropwise in sequence, react for 6 hours after the addition is complete, add to 160ml of water, react at room temperature for 5 hours, evaporate the acetone under reduced pressure, and obtain a hydrolyzate containing a theoretical value of 19.9g of clindamycin phosphate.

[0041] Separation and preparation of clindamycin phosphate: add 30% sodium hydroxide solution to the clindamycin phosphate hydrolyzate prepared above, adjust the pH to 4, add 2.3g calcium oxide, react at 40°C for 2 hours, filter by suction to obtain 23.5g filter cake, add 60g 95% ethanol, stir and warm to 70°C, add concentrated hydrochloric acid to adjust the pH to 4, add 0.4g activated carbon, decolorize at 75°C for 1 hour, filter, remove activated carbon and insoluble matter, add 60g ethanol to the filtrate, cool to 25°C at 0.5°C / min, stir and react for 8 hours, continue to cool to 5°C at 0.5°C / min, filter by suction and dry, and obtain 17.1g of clindamycin phosphate finished product, which is detected by the clindamycin phosphate detection method in the Chinese Pharmacopoeia, and the chromatographic purity is 99.1%.

[0042] Example 2

[0043] Preparation of clindamycin phosphate reaction hydrolyzate: add 20g of clindamycin hydrochloride ethanolate to 60g of acetone, cool to 0°C, add 10g of phosphorus oxychloride, 6g of pyridine, and 14g of phosphorus oxychloride dropwise in sequence, react for 6 hours after the addition is complete, add to 160ml of water, react at room temperature for 5 hours, evaporate the acetone under reduced pressure, and obtain a hydrolyzate containing a theoretical value of 19.9g of clindamycin phosphate.

[0044] Separation and preparation of clindamycin phosphate: add 30% sodium hydroxide solution to the clindamycin phosphate hydrolyzate prepared above, adjust the pH to 4.5, add 2.3g calcium oxide, react at 40°C for 2 hours, filter by suction to obtain 23.6g filter cake, add 60g 95% ethanol, stir and warm to 70°C, add concentrated hydrochloric acid to adjust the pH to 3.5, add 0.4g activated carbon, decolorize at 75°C for 1 hour, filter, remove activated carbon and insoluble matter, add 60g ethanol to the filtrate, cool to 20°C with 0.5°C / min speed, stir and react for 10 hours, continue to cool to 5°C with 0.5°C / min speed, filter by suction and dry, and obtain 17.0g of clindamycin phosphate finished product, which is detected by the clindamycin phosphate detection method in the Chinese Pharmacopoeia, and the chromatographic purity is 99.3%.

[0045] Comparative Example

[0046] Preparation of clindamycin phosphate reaction hydrolyzate: add 20g of clindamycin hydrochloride ethanolate to 60g of acetone, cool to 0°C, add 10g of phosphorus oxychloride, 6g of pyridine, and 14g of phosphorus oxychloride dropwise in sequence, react for 6 hours after the addition is complete, add to 160ml of water, react at room temperature for 5 hours, evaporate the acetone under reduced pressure, and obtain a hydrolyzate containing a theoretical value of 19.9g of clindamycin phosphate.

[0047] Separation and preparation of clindamycin phosphate: The clindamycin phosphate hydrolyzate prepared above was slowly added to an adsorption column filled with a macroporous resin at a speed of 300 ml / h, and then 800 g of water was slowly added to the adsorption column for washing until the water flowing out below was neutral, and 600 g of methanol was used for analysis. After the analysis was completed, the methanol was distilled off under reduced pressure, 120 g of ethanol was added, and 0.4 g of activated carbon was decolorized and crystallized to obtain 16.2 g of clindamycin phosphate product. According to the clindamycin phosphate detection method in the Chinese Pharmacopoeia, the chromatographic purity was 98.7%.

[0048] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A method for separating clindamycin phosphate, characterized in that: The specific steps include: (1) adding alkaline water to the clindamycin phosphate reaction hydrolyzate, adjusting the pH value of the system, adding a precipitation reagent to react to generate a precipitate, and filtering to obtain a clindamycin phosphate precipitate; (2) adding the clindamycin phosphate precipitate to water and ethanol, stirring and heating, adding concentrated hydrochloric acid until it is completely dissolved and controlling the pH of the system to 3.5-4.5, adding activated carbon for decolorization, filtering out the activated carbon and insoluble impurities while hot, and obtaining a decolorized solution; (3) adding ethanol to the decolorizing solution to slowly cool and crystallize, filtering and drying to obtain clindamycin phosphate; Wherein, in step (1), the preparation method of the clindamycin phosphate reaction hydrolyzate is as follows: add clindamycin hydrochloride ethanolate to acetone, control the temperature below 5°C, sequentially add dropwise 40% to 50% of the mass of phosphorus oxychloride, pyridine, and the remaining 50% to 60% of phosphorus oxychloride, and keep the temperature for reaction for 6 to 10 hours after the addition is completed. After the reaction is completed, add water, react at room temperature for 5 hours, and evaporate the acetone under reduced pressure to obtain the clindamycin phosphate reaction hydrolyzate; The precipitation reagent includes one or more of calcium oxide, calcium hydroxide, calcium acetate and magnesium oxide.

2. The method for separating clindamycin phosphate according to claim 1, wherein In the preparation method of the clindamycin phosphate reaction hydrolyzate, the mass ratio of the clindamycin hydrochloride ethanolate, acetone, phosphorus oxychloride, pyridine and water is 1: (2-4): (0.6-1.6): (0.16-0.4): (6-10).

3. The method for separating clindamycin phosphate according to claim 1, wherein In step (1), the alkaline water is a sodium hydroxide solution with a mass percentage concentration of 30% to 35%, and the pH value of the system is adjusted to 4 to 5.

4. The method for separating clindamycin phosphate according to claim 1, wherein In step (1), the molar ratio of the precipitation reagent to clindamycin phosphate is (1-1.1):

1.

5. The method for separating clindamycin phosphate according to claim 1, wherein In step (2), the weight ratio of the clindamycin phosphate precipitate, water and ethanol is 1:(0-3):(1-5).

6. The method for separating clindamycin phosphate according to claim 1, wherein In step (2), the weight ratio of the activated carbon to the clindamycin phosphate precipitate is (0.01-0.05):1, the activated carbon decolorization temperature is 70-80°C, and the decolorization time is 0.5-2 hours.

7. The method for separating clindamycin phosphate according to claim 1, wherein In step (3), the weight ratio of the ethanol to the clindamycin phosphate precipitate is (2-6):1.

Images