A process for the preparation of a clindamycin phosphate intermediate

Abstract

The present application relates to the technical field of drug synthesis, and particularly relates to a preparation method of clindamycin phosphate intermediate. The preparation method of the clindamycin phosphate intermediate provided by the present application takes hydrochloric acid lincomycin and Vilsmeier reagent as starting materials, and precisely controls the material ratio through a micro-mixer and a micro-channel reactor, so that the stereochemical selectivity of the chlorination step is significantly improved, the reaction rate is effectively improved, the generation of 7-epi-clindamycin impurities is reduced through continuous preparation, the subsequent purification cost is reduced, the control of 7-epi-clindamycin impurities is realized, the 7-epi-clindamycin impurities can be completely removed after one-time crystallization of the product, and the yield reaches 95-98%.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing a clindamycin phosphate intermediate. Background Art

[0002] Clindamycin phosphate is a semisynthetic clindamycin derivative and a broad-spectrum antibiotic. It is clinically used primarily for various infections caused by anaerobic and Gram-positive aerobic bacteria, including respiratory tract infections, urinary tract infections, bone and joint infections, pelvic infections, abdominal infections, and skin and soft tissue infections caused by susceptible bacteria. Clindamycin phosphate is a prodrug that lacks antibacterial activity in vitro. Upon entering the human body, it rapidly hydrolyzes to clindamycin, where it exhibits its pharmacological activity, achieving its antibacterial effect by inhibiting bacterial cell wall protein synthesis. Clindamycin phosphate has an antibacterial spectrum, antibacterial activity, and therapeutic efficacy nearly identical to those of clindamycin, but boasts superior lipid solubility and permeability. It can be administered orally, intramuscularly, or intravenously.

[0003] For example, Chinese patent CN101439022A discloses a purification process for clindamycin phosphate, which includes crude product purification, crystallization, centrifugation, washing, and rapid drying of the wet product. Advantages of this process include high water solubility, uniform crystal particles, low specific volume, high bulk density, good fluidity, and low solvent residue, significantly improving product quality.

[0004] For example, Chinese patent CN101298463A discloses a method for preparing clindamycin phosphate. This involves chlorinating lincomycin hydrochloride with solid light in chloroform at 50-80°C. The reaction then undergoes alcoholization and ketonization, followed by esterification with phosphorus oxychloride in acetone under the catalytic action of pyridine and triethylamine. This process has the advantages of alleviating environmental pressures, reducing the content of 7-epi-clindamycin impurities in the finished product, lowering costs, and improving yield.

[0005] For example, Chinese patent CN103172683A discloses a method for preparing clindamycin hydrochloride, which specifically comprises: (1) using lincomycin hydrochloride and Vilsmeier reagent to carry out a chlorination reaction to obtain a reaction solution containing crude clindamycin hydrochloride; (2) hydrolyzing, extracting, and concentrating the reaction solution to obtain clindamycin free base, and then keeping the clindamycin free base at 90-120°C for 20-120 minutes; (3) subjecting the clindamycin free base to a salt-forming reaction in an ethanol aqueous solution having a volume percentage concentration of 90%-95% to obtain clindamycin hydrochloride ethanolate; and (4) dealcoholizing the clindamycin hydrochloride ethanolate to obtain the clindamycin hydrochloride. This method effectively controls and significantly reduces the impurity content through process optimization, thereby obtaining high-quality clindamycin hydrochloride with a finished product purity of more than 99.5%, especially with a 7-epi-clindamycin content of <0.1% and no 4-chloro-clindamycin detected.

[0006] As can be seen, in the Clindamycin Phosphate synthesis technique, Clindamycin alcoholate has a key effect as intermediate in the whole synthesis technique. However, in the traditional synthesis technique, all directly take Clindamycin Phosphate as target product, and the research for directly synthesizing Clindamycin alcoholate is then reported less. Even if the traditional Clindamycin Phosphate synthesis technique also exists that reactions steps are long, reaction yield is lower and cost is higher, it is not suitable for suitability for industrialized production. Summary of the Invention

[0007] Therefore, the technical problem to be solved by the present invention is to provide a method for preparing a clindamycin phosphate intermediate, which has the advantages of mild reaction conditions, high reaction yield and low cost, and is suitable for industrial production.

[0008] To solve the above technical problems, a method for preparing a clindamycin phosphate intermediate comprises the following steps:

[0009] (1) using lincomycin hydrochloride and Vilsmeier reagent as raw materials, mixing them in a micro mixer to obtain a reaction raw material liquid;

[0010] (2) placing the reaction raw material liquid in a microchannel reactor to carry out a chlorination reaction, collecting the reactants and performing cooling hydrolysis to obtain clindamycin free base;

[0011] (3) adding the clindamycin free base into an alkali solution to carry out a hydrolysis reaction to obtain the product.

[0012] The preparation method of the clindamycin phosphate intermediate of the present invention has the following specific synthetic route:

[0013]

[0014] Specifically, in the method for preparing the clindamycin phosphate intermediate, the molar ratio of the Vilsmeier reagent to the clindamycin hydrochloride is 1.0-5.5:1. In the reaction, the Vilsmeier reagent is 1.0 eq to 5.5 eq, preferably 1.0-2.0 eq, and more preferably 1.2-1.4 eq, of lincomycin hydrochloride on a molar basis.

[0015] Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (1), the mixing step includes the step of simultaneously introducing the Vilsmeier reagent and the lincomycin hydrochloride into the micromixer through two channels using metering pumps for mixing.

[0016] Specifically, the method for preparing the clindamycin phosphate intermediate, in the step (1), further comprises the step of preparing a solution of the Vilsmeier reagent and / or the clindamycin hydrochloride;

[0017] Preferably, the concentration of the Vilsmeier reagent solution is controlled to be 0.1-0.2 g / mL, preferably 0.14 g / mL, and the flow rate is 6-10 mL / min, preferably 8.2 mL / min;

[0018] Preferably, the concentration of the lincomycin hydrochloride solution is controlled to be 0.3-0.8 g / mL, preferably 0.5 g / mL, and the flow rate is controlled to be 2-10 mL / min, preferably 6.2 mL / min.

[0019] Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (2), in the chlorination reaction step:

[0020] Controlling the reaction gauge pressure of the microchannel reactor to be 1.2-1.6 MPa; and / or,

[0021] Controlling the reaction temperature of the microchannel reactor to 95-105° C.; and / or,

[0022] The residence time of the reaction raw material liquid in the microchannel reactor is 18-20s.

[0023] Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (2), the cooling hydrolysis step includes the step of cooling the reactants to 0-10°C.

[0024] Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (3), the alkali solution includes a NaOH solution.

[0025] Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (3), the temperature of the hydrolysis reaction step is 25-35° C., the pH of the reaction system is controlled to be 12-14, and the hydrolysis reaction time is 1 hour.

[0026] Specifically, the method for preparing the clindamycin phosphate intermediate, in the step (3), further comprises the step of collecting the hydrolysis reaction product for purification;

[0027] The purification step comprises: collecting the hydrolysis reaction product and allowing it to stand until the organic phase is separated, collecting the organic phase, concentrating it under reduced pressure, adding anhydrous ethanol and water in sequence, mixing, adjusting the system temperature to 40±3°C and pH 1-3 to react, then cooling to 0±2°C to carry out insulation reaction, filtering and collecting the filter cake, washing, and drying to obtain the product.

[0028] The invention also discloses the application of the preparation method of the clindamycin phosphate intermediate in the field of clindamycin phosphate synthesis.

[0029] The method for preparing a clindamycin phosphate intermediate of the present invention uses lincomycin hydrochloride and Vilsmeier reagent as starting materials, and obtains clindamycin alcoholate through chlorination and hydrolysis reactions based on a traditional process. The method for preparing the clindamycin phosphate intermediate of the present invention utilizes a micromixer and a microchannel reactor to precisely control the material ratio, thereby significantly improving the stereochemical selectivity of the chlorination step and effectively increasing the reaction rate. The continuous preparation method reduces the generation of 7-epi-clindamycin impurities, reduces subsequent purification costs, and achieves control of 7-epi-clindamycin impurities. The product can completely remove 7-epi-clindamycin impurities after primary crystallization, achieving a yield of 95-98%.

[0030] The method for preparing a clindamycin phosphate intermediate of the present invention uses a micromixer and a microchannel reactor to precisely control the material ratio, thereby effectively controlling the difficult-to-remove impurity 7-epi-clindamycin phosphate, thereby reducing the impurity level from 1.0% to less than 0.05%. The method also significantly improves the product yield. Compared with a traditional reactor reaction process, the product yield is increased from approximately 80% to over 95%, significantly improving the quality and yield levels, significantly reducing material costs, and having good application prospects.

[0031] The present invention's method for preparing a clindamycin phosphate intermediate utilizes a microchannel reactor for synthesis, effectively controlling the molar ratio of Vilsmeier reagent to lincomycin through precise flow control of the two streams. Furthermore, the reaction proceeds within the microchannel, ensuring uniform heating of the materials. Furthermore, the product is promptly discharged from the reaction system through the microchannel, significantly enhancing the stereochemical selectivity of the chlorination process. Practice has demonstrated that the present method for preparing a clindamycin phosphate intermediate can control the impurity level of 7-epi-clindamycin phosphate in the synthesized product to within 0.05%, resulting in a high product purity that meets product performance requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below based on specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0033] Figure 1 is a process flow chart of the clindamycin phosphate intermediate of the present invention;

[0034] Figure 2 The figure shows the preparation of the clindamycin phosphate intermediate product using the continuous flow reaction process in Example 1;

[0035] Figure 3 This is a graph showing the preparation of the clindamycin phosphate intermediate product using the traditional kettle reaction process in Comparative Example 1. DETAILED DESCRIPTION

[0036] In the following embodiments of the present invention, the process flow diagram of the clindamycin phosphate intermediate is as follows Figure 1 As shown, the specific synthesis process is as follows, that is, clindamycin alcoholate (III) is prepared from lincomycin hydrochloride (I) as a raw material:

[0037]

[0038] In the following examples of the present invention, the micromixer selected is a device known in the art, the purpose of which is to achieve fine control of materials. The effects of different structural devices are basically the same. As an exemplary embodiment, the model of the micromixer is C0-60-6 produced by Shandong Jinde.

[0039] In the following examples of the present invention, the microchannel reactor selected is a device known in the art, the purpose of which is to achieve fine control of the entire chlorination reaction, and the effects between devices of different structures are basically the same. As an exemplary embodiment, the model of the microchannel reactor is C0-60-6 produced by Shandong Jinde.

[0040] In the following examples of the present invention, the reagents used may be commercially available products or may be prepared by methods known to those skilled in the art. For example, Vilsmeier reagent (dichloromethylenedimethylammonium chloride) may be prepared using corresponding methods disclosed in the art.

[0041] Example 1

[0042] Vilsmeier reagent solution: Dissolve 43 g of solid light in 228 mL of chloroform to prepare a solution, control the temperature at 4°C and add it dropwise into 25 mL of DMF. After the addition is complete, keep it warm at 4°C for 1 hour.

[0043] Lincomycin hydrochloride solution: Add 100 g of solid lincomycin hydrochloride to 200 mL of DMF, mix well, heat to 50-60°C to dissolve, and store in the dark.

[0044] The Vilsmeier reagent solution and lincomycin hydrochloride solution prepared above were simultaneously introduced into a micromixer through two channels using metering pumps for mixing. The flow rate of the lincomycin hydrochloride solution was controlled to 8.2 mL / min, and the flow rate of the clindamycin hydrochloride solution was controlled to 4.8 mL / min to obtain a reaction raw material solution. The molar ratio of Vilsmeier reagent to lincomycin hydrochloride in the reaction raw material solution was 1.2:1. The reaction raw material solution was then introduced into a microchannel reactor for reaction. The reaction gauge pressure of the microchannel reactor was controlled to be 1.2 MPa, the reaction temperature was controlled to be 95°C, and the residence time of the reaction raw material solution in the microchannel reactor was controlled to be 20 seconds.

[0045] Get another reaction flask and add 300mL water and 171mL, 30%NaOH and mix for subsequent use.Above-mentioned reaction solution is cooled to 4 ℃, and is added drop-wise in described reaction flask, and temperature is 30 ℃ in control, with 30%NaOH, adjust solution system pH12, control feed liquid temperature and hydrolysis 1 hour at 25 ℃, and add ice-crystallization cooling quenching.After hydrolysis finishes, stand for 0.5 hour to organic phase layering, wash with 417mL, after standing and layering again, separate organic phase and carry out concentrating under reduced pressure at 65-80 ℃ and obtain chloroform.Continue to add 200mL absolute ethanol, stir until molten clear, add 30mL water, control temperature to 40 ± 3 ℃, drip hydrochloric acid and regulate feed liquid pH at 2, after dropwising, stir 30 minutes, be cooled to 0 ± 2 ℃, be incubated 2 hours, filter back and collect filter cake and wash with 50mL ethanol, obtain clindamycin hydrochloride alcoholate wet product.

[0046] The collected wet product was placed in a vacuum drying oven and dried at 80° C. for 10 hours to obtain a dry product of clindamycin hydrochloride alcoholate. The weight yield of the clindamycin hydrochloride alcoholate was determined to be 110%.

[0047] The spectrum of the dry product of clindamycin hydrochloride alcoholate in this embodiment is shown in Figure 1. Figure 2 As can be seen, the product of this embodiment has a higher purity.

[0048] Example 2

[0049] Vilsmeier reagent solution: 28 g solid phosphorus oxide was dissolved in 228 mL chloroform to form a solution, which was added dropwise into 42 mL DMF at a temperature of -15 to 15 °C. After the dropwise addition was completed, the solution was kept at a temperature of 0 to 5 °C for 1 h.

[0050] Clindamycin hydrochloride solution: 100 g solid clindamycin hydrochloride was mixed with 150 mL DMF, and the mixture was dissolved at a temperature of 50 to 60 °C. The solution was kept in the dark.

[0051] The Vilsmeier reagent solution and the clindamycin hydrochloride solution were simultaneously introduced into the micro-mixer through two channels by using a metering pump, the flow rate of the Vilsmeier reagent solution was controlled at 8.2 mL / min, and the flow rate of the clindamycin hydrochloride solution was controlled at 6.8 mL / min, to obtain a reaction raw material solution. In the reaction raw material solution, the molar ratio of the Vilsmeier reagent to clindamycin hydrochloride was 5.2:1. Then the reaction raw material solution was introduced into the micro-channel reactor for reaction, the reaction was carried out at a reaction pressure of 1.6 MPa and a reaction temperature of 105 °C, and the residence time of the reaction raw material solution in the micro-channel reactor was 18 s.

[0052] Another reaction bottle was taken and 300 mL water and 170 mL 30% NaOH were mixed to prepare a solution. The above reaction solution was cooled to a temperature of 8 °C, and was then added dropwise into the reaction bottle. The internal temperature was controlled at 32 °C, the pH of the solution system was adjusted to 14 by using 30% NaOH, the temperature of the solution was controlled at 35 °C, and the hydrolysis was carried out for 1 h. Then ice water was added to quench the crystallization. After the hydrolysis was completed, the organic phase was separated after standing for 0.5 h, 420 mL water was added for washing, and the separation was continued. The organic phase was separated and concentrated under reduced pressure to obtain chloroform. Then 200 mL anhydrous ethanol was added, and the solution was stirred until it became clear. Then 30 mL water was added, the temperature was controlled at 40±3 °C, hydrochloric acid was added dropwise to adjust the pH of the solution to 3, and after the dropwise addition was completed, the solution was stirred for 30 min. Then the temperature was lowered to 0±2 °C, and the solution was kept at this temperature for 2 h. The solution was filtered, and the filter cake was washed with 50 mL ethanol to obtain wet clindamycin hydrochloride alcoholate.

[0053] The wet product was placed in a vacuum drying oven, and was dried at a temperature of 80 °C for 12 h to obtain dry clindamycin hydrochloride alcoholate. It was determined that the weight yield of clindamycin hydrochloride alcoholate was 104%.

[0054] Example 3

[0055] The preparation method of clindamycin hydrochloride alcoholate described in this example is the same as that in Example 1, except that the Vilsmeier reagent concentration is controlled to 0.14 g / mL, the Vilsmeier reagent flow rate is controlled to 8.2 mL / min, the lincomycin hydrochloride concentration is controlled to 0.5 g / mL, and the lincomycin hydrochloride solution flow rate is controlled to 2.8 g / mL. The reaction raw material solution is introduced into the microchannel reactor at a reaction temperature of 85°C, and the residence time of the reaction raw material solution in the microchannel reactor is 20 s.

[0056] The weight yield of clindamycin hydrochloride alcoholate was determined to be 106%.

[0057] Example 4

[0058] The preparation method of clindamycin hydrochloride alcoholate described in this example is the same as that in Example 1, except that the Vilsmeier reagent concentration is controlled to 0.14 g / mL, the Vilsmeier reagent flow rate is controlled to 8.2 mL / min, the lincomycin hydrochloride concentration is controlled to 0.5 g / mL, and the lincomycin hydrochloride solution flow rate is controlled to 8.8 g / mL. The reaction raw material solution is introduced into the microchannel reactor at a reaction temperature of 95°C, and the residence time of the reaction raw material solution in the microchannel reactor is 20 s.

[0059] The weight yield of clindamycin hydrochloride alcoholate was determined to be 109%.

[0060] Example 5

[0061] The preparation method of clindamycin hydrochloride alcoholate described in this example is the same as that in Example 1, except that the Vilsmeier reagent concentration is controlled to 0.14 g / mL, the Vilsmeier reagent flow rate is controlled to 6.2 mL / min, the lincomycin hydrochloride concentration is controlled to 0.5 g / mL, and the lincomycin hydrochloride solution flow rate is controlled to 8.8 g / mL. The reaction raw material solution is introduced into the microchannel reactor at a reaction temperature of 105°C, and the residence time of the reaction raw material solution in the microchannel reactor is controlled to 20 s.

[0062] The weight yield of clindamycin hydrochloride alcoholate was determined to be 107%.

[0063] Comparative Example 1

[0064] The preparation method of the clindamycin phosphate intermediate, i.e., clindamycin hydrochloride alcoholate, described in this comparative example is the same as that in Example 1, except that a conventional autoclave reactor is used for the reaction.

[0065] In this comparative example, the collection of the dried product of clindamycin hydrochloride alcoholate is shown in the attached diagram. Figure 3 As shown in FIG. 1 , it can be seen that the product prepared by the traditional tank reactor has a low purity.

[0066] As can be seen, the use of traditional kettle reactors for the synthesis of clindamycin hydrochloride alcoholate results in a high impurity content in the product. This is primarily due to the following unavoidable issues with traditional kettle reactions: a) excessive material ratios in certain areas, b) local overheating, and c) the coexistence of product in the reaction system, making it difficult to effectively control the selectivity of the substrate, lincomycin hydrochloride, during the chlorination process. Actual processes have shown that when using kettle reactions for synthesis, the impurity content of 7-epi-clindamycin often exceeds 1.0%, requiring multiple refining steps to meet quality standards. Excessive refining steps lead to decreased yield, increased costs, and low production efficiency.

[0067] In summary, the method for preparing the clindamycin phosphate intermediate, i.e., clindamycin hydrochloride alcoholate, of the present invention utilizes continuous equipment and precisely controls the material ratio through a micromixer and a microchannel reactor, thereby significantly controlling the impurity content in the product and effectively improving the purity and yield of the target product.

[0068] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for preparing a clindamycin phosphate intermediate, characterized in that: The steps include: (1) preparing a Vilsmeier reagent solution, and controlling the concentration of the Vilsmeier reagent solution to be 0.1-0.2 g / mL; (2) preparing the lincomycin hydrochloride into a solution, and controlling the concentration of the lincomycin hydrochloride solution to be 0.3-0.8 g / mL; (3) mixing the Vilsmeier reagent solution and the lincomycin hydrochloride solution in a micromixer, controlling the flow rate of the Vilsmeier reagent solution to 6-10 mL / min and the flow rate of the lincomycin hydrochloride solution to 2-10 mL / min, to obtain a reaction raw material solution; (4) placing the reaction raw material liquid in a microchannel reactor for chlorination reaction, controlling the reaction gauge pressure of the microchannel reactor to be 1.2-1.6 MPa, the reaction temperature to be 95-105° C., the residence time of the reaction raw material liquid in the microchannel reactor to be 18-20 s, collecting the reactants and cooling and hydrolyzing them to obtain clindamycin free base; (5) Adding alkaline solution to the clindamycin free base to carry out hydrolysis reaction to obtain the clindamycin free base.

2. The method for preparing a clindamycin phosphate intermediate according to claim 1, wherein In the step (3), the mixing step includes the step of simultaneously introducing the Vilsmeier reagent solution and the lincomycin hydrochloride solution into the micromixer through two channels using metering pumps for mixing.

3. The method for preparing a clindamycin phosphate intermediate according to claim 1, wherein In the step (4), the cooling and hydrolysis step includes the step of cooling the reactants to 0-10°C.

4. The method for preparing a clindamycin phosphate intermediate according to claim 1, wherein In the step (5), the alkali solution is a NaOH solution.

5. The method for preparing a clindamycin phosphate intermediate according to claim 1, wherein In the step (5), the temperature of the hydrolysis reaction step is 25-35° C., the pH of the reaction system is controlled to be 12-14, and the hydrolysis reaction time is 1 hour.

6. The method for preparing a clindamycin phosphate intermediate according to claim 1, wherein The step (5) further includes collecting the hydrolysis reaction product for purification; The purification step comprises: collecting the hydrolysis reaction product and allowing it to stand until the organic phase is separated, collecting the organic phase, concentrating it under reduced pressure, adding anhydrous ethanol and water in sequence, mixing, adjusting the system temperature to 40±3°C and the pH to 1-3 for reaction, then cooling to 0±2°C for heat preservation reaction, filtering and collecting the filter cake, washing, and drying to obtain the product.

7. Application of the method for preparing the clindamycin phosphate intermediate according to any one of claims 1 to 6 in the field of clindamycin phosphate synthesis.

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