A method for preparing lincomycin phosphate using clindamycin phosphate

Abstract

The present application belongs to the technical field of chemical drug synthesis, and specifically relates to a method for preparing lincomycin phosphate using clindamycin phosphate. The method (1) adds clindamycin phosphate to a solvent and fully dissolves it, then adds a base, heats it to 50-100°C, and performs a hydrolysis reaction for 1-20 hours; (2) after the reaction in step (1) is completed, the mixed solution is successively subjected to resin adsorption, desorption, and recrystallization to obtain lincomycin phosphate. The main purpose of the present application is to successfully prepare the impurity, thereby providing a high-purity standard product for the qualitative and quantitative analysis of impurities in the subsequent preparation or storage of clindamycin phosphate, thereby laying a good foundation for the stable quality and safe use of clindamycin phosphate, and also laying a good product foundation for the in-depth study of the antibacterial properties of lincomycin phosphate. Therefore, the present application has good practical application significance.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug synthesis, and specifically relates to a method for preparing lincomycin phosphate by utilizing clindamycin phosphate. Background Art

[0002] Clindamycin phosphate is a lincomycin (lincomycin) derivative, belonging to the class of antibiotic drugs. It has no antibacterial activity in vitro, but can be rapidly hydrolyzed into clindamycin after entering the body and exhibits pharmacological activity, so its antibacterial spectrum, antibacterial activity and therapeutic effect are the same as those of clindamycin. And because its lipid solubility and permeability are better than those of clindamycin, it is mainly used clinically for the prevention and treatment of diseases such as osteomyelitis, infections caused by anaerobic bacteria, respiratory infections, biliary infections, endocarditis, otitis media, skin and soft tissue infections and sepsis. In short, it is widely used at home and abroad due to its high antibacterial activity, rapid absorption, good water solubility and few side effects.

[0003] However, studies have shown that clindamycin phosphate is prone to degradation during storage due to its unstable chemical properties. There are two ways of degradation and the main degradation impurities produced after degradation: one is that the phosphate bond in the clindamycin phosphate molecule is broken and converted into clindamycin, that is, returning to the structure of the raw material; the other is that the chlorine atom at the 7th position of clindamycin phosphate is replaced by a hydroxyl group and converted into lincomycin phosphate (chemical name is 7-hydroxy-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-pyranosylgalactoside-2-dihydrogenphosphate). However, the existing technology lacks in-depth research on the synthesis and preparation of lincomycin phosphate, which has also had a certain impact on the in-depth research on the synthesis and preparation of clindamycin phosphate. Summary of the invention

[0004] The purpose of this application is to provide a method for preparing lincomycin phosphate, thereby laying a certain technical foundation for subsequent further process improvements such as preparation, synthesis, purification, and storage of clindamycin phosphate.

[0005] The technical solution adopted in this application is briefly introduced as follows.

[0006] A method for preparing lincomycin phosphate by using clindamycin phosphate comprises the following steps: (1) After clindamycin phosphate is fully dissolved in a solvent, a base is added, and the temperature is raised to 50 to 100° C. for hydrolysis reaction for 1 to 20 hours; The alkali is a mixture of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate in any proportion; In terms of molar ratio, clindamycin phosphate: base = 1:1~10; The solvent is a miscible mixture of one or more of water, methanol, ethanol, acetone, isopropanol, acetonitrile and tetrahydrofuran in any proportion; (2) after the reaction in step (1) is completed, the mixed solution is subjected to resin adsorption, desorption and recrystallization in sequence to obtain lincomycin phosphate; The resin adsorption, for example, uses macroporous resin LX-22 or LX-20; The desorption is carried out using methanol or ethanol as solvent.

[0007] Although lincomycin phosphate is a common impurity in the preparation or storage of clindamycin phosphate, it also has antibacterial properties. However, since the prior art lacks in-depth research on the preparation method of this impurity, the actual use of this impurity and how to eliminate the impurity generated during the preparation or storage of clindamycin phosphate have a certain impact.

[0008] In general, the main purpose of this application is to provide a high-purity standard product for the qualitative and quantitative analysis of impurities in the subsequent preparation or storage process of clindamycin phosphate through the successful preparation of the impurity, thereby laying a good foundation for the stable quality and safe use of clindamycin phosphate, and also laying a good product foundation for the in-depth study of the antibacterial properties of lincomycin phosphate. Therefore, this application has good practical application significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 The HPLC spectrum of lincomycin phosphate prepared according to the preparation method of the present invention; Figure 2 It is a reference chart of existing clindamycin phosphate HPLC; Figure 3 The HPLC spectrum of lincomycin phosphate and clindamycin phosphate mixture. DETAILED DESCRIPTION

[0010] The present application is further explained below in conjunction with the embodiments. Before introducing the specific embodiments, some experimental backgrounds in the following embodiments are briefly introduced as follows.

[0011] The HPLC analysis of clindamycin phosphate and its impurities in the following examples was performed in accordance with the operating requirements for the detection items of related substances of clindamycin phosphate in the Chinese Pharmacopoeia 2020; Since the applicant is an actual pharmaceutical manufacturer and has built its own relevant production lines, the relevant materials in the following embodiments are randomly taken from the actual production lines (or purchased from public channels).

[0012] Example 1 The synthetic route for preparing lincomycin phosphate using clindamycin phosphate provided in the present application is as follows.

[0013]

[0014] Taking the specific material dosage and process as an example, the specific preparation process and effect of lincomycin phosphate are briefly described as follows.

[0015] (1) In a 1000 mL three-necked reaction flask, add 600 mL of water and 60 g (0.19 mol) of clindamycin phosphate. After fully dissolving, add 20 g (0.50 mol) of sodium hydroxide. Under stirring, heat to 80°C for 8 hours for hydrolysis reaction; After the reaction was completed, the temperature was lowered to 25°C, water was added to dilute the volume to 1000 mL, and hydrochloric acid was used to adjust the pH to 3.5.

[0016] (2) Take the mixed solution after the reaction in step (1) and load it onto a LX-20 macroporous resin column (the effective volume of the resin column is D (diameter) × H (height) = 6 cm × 50 cm); control the flow rate of loading onto the column to 350 mL / h (approximately 3 hours to complete loading); then wash the column with 1500 mL of water at the same flow rate; After the column is washed, methanol is added for desorption, and the methanol desorption liquid is collected; The collected methanol desorption liquid was concentrated under reduced pressure until no methanol flowed out, 400 mL of 95° ethanol was added, the temperature was raised and refluxed until the solution was clear, 2.5 g of activated carbon was added, and after refluxing for half an hour, the solution was filtered, the filtrate was cooled to 0°C, and allowed to stand for 5 hours (for recrystallization); After standing, filter, wash with an appropriate amount of 95° ethanol, and dry to obtain a white solid, which is lincomycin phosphate.

[0017] The measurement and calculation results showed that 46.7 g of lincomycin phosphate was obtained, with a weight yield of 77.8% and a HPLC purity of 99.15% (e.g. Figure 1 as shown).

[0018] Compared with the existing clindamycin phosphate ( Figure 2 ), and existing clindamycin phosphate containing lincomycin phosphate impurities ( Figure 3 ) can be seen from the HPLC comparison that the product prepared in the present application is indeed lincomycin phosphate with good purity, and is expected to be used as an impurity control in subsequent clindamycin phosphate detection.

[0019] Example 2 The preparation method of lincomycin phosphate in this embodiment is the same as that in Example 1, except that some materials and reaction conditions are adjusted as follows: In step (1), the solvent is 600 mL of methanol and 60 g (0.19 mol) of clindamycin phosphate, and the base is 25 g (0.44 mol) of potassium hydroxide; the reaction is carried out at 65° C. for 12 hours; after the reaction is completed, methanol is added to dilute the volume to 1000 mL, and hydrochloric acid is used to adjust the pH to 3.5; In step (2), an LX-22 resin column is used (the effective volume of the resin column is D (diameter) × H (height) = 6 cm × 50 cm, and the flow rate is the same as in Example 1).

[0020] The measurement and calculation results showed that 45.3 g of lincomycin phosphate was finally obtained, with a weight yield of 75.3% and an HPLC purity of 99.09%.

[0021] Example 3 The preparation method of lincomycin phosphate in this embodiment is the same as that in Example 1, except that some materials and reaction conditions are adjusted as follows: In step (1), the solvent is 600 mL of water and 60 g (0.19 mol) of clindamycin phosphate, and the base is 60 g (0.57 mol) of sodium carbonate; the reaction is carried out at 90° C. for 15 hours; after the reaction is completed, the mixture is diluted with water to 1000 mL, and the pH is adjusted to 3.8 with hydrochloric acid; In step (2), an LX-20 resin column is used (the effective volume of the resin column is D (diameter) × H (height) = 6 cm × 50 cm, and the flow rate is the same as in Example 1).

[0022] The measurement and calculation results showed that 45.7 g of lincomycin phosphate was finally obtained, with a weight yield of 76.2% and an HPLC purity of 99.13%.

[0023] Example 4 The preparation method of lincomycin phosphate in this embodiment is the same as that in Example 1, except that some materials and reaction conditions are adjusted as follows: In step (1), the solvent is 600 mL of ethanol and 60 g (0.19 mol) of clindamycin phosphate, and the base is 30 g (0.75 mol) of sodium hydroxide; the reaction is carried out at 80° C. for 10 hours; after the reaction is completed, ethanol is added to dilute the volume to 1000 mL, and hydrochloric acid is used to adjust the pH to 3.7; In step (2), an LX-22 resin column is used (the effective volume of the resin column is D (diameter) × H (height) = 6 cm × 50 cm, and the flow rate is the same as in Example 1).

[0024] The measurement and calculation results showed that 47.5 g of lincomycin phosphate was finally obtained, with a weight yield of 79.2% and an HPLC purity of 99.18%.

Claims

1. A method for preparing lincomycin phosphate using clindamycin phosphate, characterized in that: The method comprises the following steps: (1) After clindamycin phosphate is fully dissolved in a solvent, a base is added, and the temperature is raised to 50 to 100° C. for hydrolysis reaction for 1 to 20 hours; (2) After the reaction in step (1) is completed, the mixed solution is subjected to resin adsorption, desorption and recrystallization in sequence to obtain lincomycin phosphate.

2. The method for preparing lincomycin phosphate using clindamycin phosphate as claimed in claim 1, characterized in that: In step (1), the alkali is a mixture of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate in any proportion.

3. The method for preparing lincomycin phosphate using clindamycin phosphate as claimed in claim 1, characterized in that: In step (1), the molar ratio of clindamycin phosphate to base is 1:1-10.

4. The method for preparing lincomycin phosphate using clindamycin phosphate as claimed in claim 1, characterized in that: In step (1), the solvent is a miscible mixture of one or more of water, methanol, ethanol, acetone, isopropanol, acetonitrile and tetrahydrofuran in any proportion.

5. The method for preparing lincomycin phosphate using clindamycin phosphate as claimed in claim 1, characterized in that: In step (2), the resin adsorption adopts macroporous resin LX-22 or LX-20.

6. The method for preparing lincomycin phosphate using clindamycin phosphate as claimed in claim 1, characterized in that: In step (2), the desorption is carried out using a solvent such as methanol or ethanol.

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