Preparation method of clindamycin phosphate intermediate

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a clindamycin phosphate intermediate. According to the preparation method of the clindamycin phosphate intermediate, the lincomycin hydrochloride and the Vilsmeier reagent are used as starting raw materials, the material ratio is accurately controlled through the micro-mixer and the micro-channel reactor, the stereochemical selectivity of the chlorination step is remarkably improved, the reaction rate is effectively increased, and through continuous preparation, the yield of the clindamycin phosphate intermediate is increased. Compared with the prior art, the method provided by the invention has the advantages that the production of 7-epiclindamycin impurities is reduced, the subsequent purification cost is reduced, the control of the 7-epiclindamycin impurities is realized, the 7-epiclindamycin impurities can be completely removed after the product is crystallized once, and the yield reaches 95-98%.

Description

Technical Field

[0001] The 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 chemically semi-synthetic clindamycin derivative and a broad-spectrum antibiotic. It is mainly used clinically for various infections caused by anaerobic bacteria and Gram-positive aerobic bacteria, such as respiratory tract infections, urinary tract infections, bone and joint infections, pelvic infections, abdominal infections, skin and soft tissue infections caused by sensitive bacteria, and is widely used in clinical practice. Clindamycin phosphate is a prodrug that has no antibacterial activity in vitro. After entering the human body, it is rapidly hydrolyzed into clindamycin and exhibits its pharmacological activity, achieving an antibacterial effect by inhibiting the synthesis of bacterial cell wall proteins. The antibacterial spectrum, antibacterial activity and therapeutic effect of clindamycin phosphate are almost the same as those of clindamycin, but its fat solubility and permeability are better than those of clindamycin. It can be taken orally, or by intramuscular injection or intravenous drip.

[0003] For example, Chinese patent CN101439022A discloses a purification process of clindamycin phosphate, the main steps of which include crude product purification, crystallization, centrifugal separation, washing, rapid heating and drying of wet products, etc. The advantages of this process are that the obtained clindamycin phosphate has good water solubility, uniform crystal particles, small specific volume, large bulk density, good fluidity, low solvent residue, etc., and the product quality is significantly improved.

[0004] For example, Chinese patent CN101298463A discloses a method for preparing clindamycin phosphate, which uses lincomycin hydrochloride and solid light to carry out chlorination reaction in chloroform solvent at 50-80°C, and then undergoes alcoholization, ketonization, and then esterification with phosphorus oxychloride in acetone solvent under the catalytic action of pyridine and triethylamine. The advantage of this process is that it reduces environmental pressure, reduces the content of 7-epi-clindamycin impurities in the finished product, reduces costs, and improves yield.

[0005] Another example is Chinese patent CN103172683A, which discloses a method for preparing clindamycin hydrochloride, which specifically includes: (1) using lincomycin hydrochloride and Vilsmeier reagent to carry out 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) in an ethanol aqueous solution with a volume percentage concentration of 90%-95%, the clindamycin free base undergoes a salt-forming reaction to obtain clindamycin hydrochloride ethanolate; (4) dealcoholizing the clindamycin hydrochloride ethanolate to obtain the clindamycin hydrochloride. The method effectively controls and significantly reduces the impurity content through process optimization, and obtains high-quality clindamycin hydrochloride, with a finished product purity of more than 99.5%, especially 7-epiclindamycin content <0.1%, and 4-chloroclindamycin is not detected.

[0006] As can be seen, in the Clindamycin Phosphate synthesis technique, Clindamycin alcoholate plays a key role as an intermediate in the whole synthesis technique. However, in the traditional synthesis technique, all directly use Clindamycin Phosphate as the target product, and the research on the direct synthesis of Clindamycin alcoholate is less reported. Even the traditional Clindamycin Phosphate synthesis technique also has the problems of long reactions steps, low reaction yield and high cost, which is not suitable for industrialized production. Summary of the invention

[0007] To this end, 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] In order 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 cooling and hydrolyzing them to obtain clindamycin free base;

[0011] (3) adding alkaline solution to carry out hydrolysis reaction of the clindamycin free base to obtain the product.

[0012] The preparation method of the clindamycin phosphate intermediate of the present invention, the specific synthesis route is as follows:

[0013]

[0014] Specifically, in the preparation method of 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 1.0eq-5.5eq of lincomycin hydrochloride by mole, preferably 1.0-2.0eq, and more preferably 1.2-1.4eq.

[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 be 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 method for preparing 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 method for preparing 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 standing it 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 for reaction, then cooling to 0±2°C for heat preservation reaction, filtering and collecting the filter cake, washing and drying, and obtaining 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 preparation method of the clindamycin phosphate intermediate of the present invention uses lincomycin hydrochloride and Vilsmeier reagent as starting materials on the basis of traditional technology, and obtains clindamycin alcoholate through chlorination reaction and hydrolysis reaction. The preparation method of the clindamycin phosphate intermediate of the present invention uses a micro mixer and a microchannel reactor to accurately control the material ratio, so that the stereochemical selectivity of the chlorination step is significantly improved, the reaction rate is effectively improved, and the generation of 7-epi-clindamycin impurities is reduced through continuous preparation, the subsequent purification cost is reduced, and the control of 7-epi-clindamycin impurities is achieved. The product can completely remove 7-epi-clindamycin impurities after primary crystallization, and the yield reaches 95-98%.

[0030] The preparation method of the clindamycin phosphate intermediate of the present invention accurately controls the material ratio through a micro mixer and a microchannel reactor, not only realizes the effective control of the difficult-to-remove impurity 7-epi-clindamycin phosphate, so that the impurity level is reduced from 1.0% to less than 0.05%, but also the product yield is significantly improved. Compared with the traditional reactor reaction process, the product yield is increased from about 80% to more than 95%, greatly improving the quality level and yield level, significantly reducing the material cost, and having good application prospects.

[0031] The preparation method of the clindamycin phosphate intermediate of the present invention uses a microchannel reactor for process synthesis, and can effectively control the molar ratio of Vilsmeier reagent and lincomycin through precise flow control of two streams of materials; and the reaction is carried out in the microchannel, and the materials are heated evenly; and the product is discharged from the reaction system in time through the microchannel, and the stereochemical selectivity of the chlorination process is greatly improved. Practice has proved that the preparation method of the clindamycin phosphate intermediate of the present invention can control the impurity level of 7-epiclindamycin phosphate in the synthetic product within 0.05%, and the product purity is high, which can meet the 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 according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

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

[0034] Figure 2 The figure is a diagram of the clindamycin phosphate intermediate product prepared by the continuous flow reaction process in Example 1;

[0035] Figure 3 This is a graph of the clindamycin phosphate intermediate product prepared 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 embodiments of the present invention, the selected micro-mixer is a device known in the art, and its purpose is to achieve fine control of materials. The effects of devices with different structures are basically the same. As an exemplary embodiment, the model of the micro-mixer is C0-60-6 produced by Shandong Jinde.

[0039] In the following embodiments of the present invention, the selected microchannel reactor is a device known in the art, and its purpose is to achieve fine control of the entire chlorination reaction. The effects of devices with 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 embodiments of the present invention, the reagents may be commercially available products or may be prepared by methods known to those skilled in the art, such as Vilsmeier reagent (dichloromethylenedimethylammonium chloride) which may be prepared by 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, and drip it into 25 mL of DMF at 4°C. 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 into 200 mL of DMF, mix well, heat to 50-60°C to dissolve, and store away from light.

[0044] The prepared Vilsmeier reagent solution and lincomycin hydrochloride solution are respectively introduced into a micro mixer through two channels by metering pumps for mixing, and the flow rate of the lincomycin hydrochloride solution is controlled to be 8.2 mL / min, and the flow rate of the clindamycin hydrochloride solution is controlled to be 4.8 mL / min, to obtain a reaction raw material liquid. The molar ratio of Vilsmeier reagent to lincomycin hydrochloride in the reaction raw material liquid is 1.2:1. Then the reaction raw material liquid is introduced into a microchannel reactor for reaction, and the reaction gauge pressure of the microchannel reactor is controlled to be 1.2 MPa, the reaction temperature is 95°C, and the residence time of the reaction raw material liquid in the microchannel reactor is 20 s.

[0045] Take another reaction bottle and add 300mL water and 171mL, 30% NaOH to mix for standby use. The above reaction solution is cooled to 4°C and added dropwise to the reaction bottle, the internal temperature is controlled to 30°C, the solution system pH is adjusted to 12 with 30% NaOH, the feed liquid temperature is controlled to be kept at 25°C for hydrolysis for 1 hour, and ice water is added to cool and quench the crystallization. After the hydrolysis is completed, stand for 0.5 hour until the organic phase is layered, wash with 417mL, stand for layering again, separate the organic phase and concentrate under reduced pressure at 65-80°C to obtain chloroform. Continue to add 200mL of anhydrous ethanol, stir until it is dissolved, add 30mL of water, control the temperature to 40±3°C, drip hydrochloric acid to adjust the feed liquid pH to 2, after the dropwise addition is complete, stir for 30 minutes, cool to 0±2°C, keep warm for 2 hours, collect the filter cake after filtration and wash with 50mL of ethanol to obtain the wet product of clindamycin hydrochloride alcoholate.

[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] In the present embodiment, the spectrum of the dried product of clindamycin hydrochloride alcoholate is as shown in the attached Figure 2 As shown, it can be seen that the product of this embodiment has a higher purity.

[0048] Example 2

[0049] Vilsmeier reagent solution: dissolve 28g of solid light in 228mL of chloroform to make a solution, and drip it into 42mL of DMF at -15 to 15℃. After the addition is complete, keep it warm at 0-5℃ for 1h.

[0050] Clindamycin hydrochloride solution: Add 100g solid lincomycin hydrochloride to 150mL DMF, mix, heat to 50-60℃ to dissolve, and store away from light.

[0051] The Vilsmeier reagent solution and the lincomycin hydrochloride solution are respectively introduced into a micro mixer through two channels by metering pumps for mixing, and the introduction flow rate of the Vilsmeier reagent solution is controlled to be 8.2 mL / min, and the introduction flow rate of the clindamycin hydrochloride solution is controlled to be 6.8 mL / min to obtain a reaction raw material liquid. In the reaction raw material liquid, the molar ratio of the Vilsmeier reagent to the clindamycin hydrochloride is 5.2:1. Then the reaction raw material liquid is introduced into a microchannel reactor for reaction, and the reaction gauge pressure of the microchannel reactor is controlled to be 1.6 MPa, the reaction temperature is 105°C, and the residence time of the reaction raw material liquid in the microchannel reactor is 18 s.

[0052] Take another reaction bottle and add 300mL water and 170mL 30% NaOH to mix for standby use. Cool the above reaction solution to 8°C and add it dropwise to the reaction bottle, control the internal temperature to 32°C, adjust the solution system pH to 14 with 30% NaOH, control the feed liquid temperature to 35°C for hydrolysis for 1 hour, and add ice water to cool and quench the crystals. After the hydrolysis is completed, stand for 0.5 hour until the organic phase is separated, add 420mL water to wash and continue to stand for separation, separate the organic phase and concentrate under reduced pressure at 65-80°C to obtain chloroform. Continue to add 200mL of anhydrous ethanol, stir until it is dissolved, add 30mL of water, control the temperature to 40±3°C, add hydrochloric acid to adjust the feed liquid pH to 3, stir for 30 minutes after the dropwise addition is complete, cool to 0±2°C, and keep warm for 2 hours. Filter and collect the filter cake and wash it with 50mL of ethanol to obtain the wet product of clindamycin hydrochloride alcoholate.

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

[0054] Example 3

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

[0056] It was determined that the weight yield of clindamycin hydrochloride alcoholate was 106%.

[0057] Example 4

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

[0059] It was determined that the weight yield of clindamycin hydrochloride alcoholate was 109%.

[0060] Example 5

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

[0062] It was determined that the weight yield of clindamycin hydrochloride alcoholate was 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 spectrum of the dried product of clindamycin hydrochloride alcoholate is collected as shown in the attached Figure 3 As shown, it can be seen that the product prepared by the traditional tank reactor has a low purity.

[0066] It can be seen that the product of clindamycin hydrochloride alcoholate synthesized by conventional autoclave reactor has a large impurity content, which is mainly due to the inevitable existence of the conventional autoclave reaction: a) the problem of excessive local material ratio, b) the problem of local overheating, and c) the problem of product coexisting in the reaction system, making it difficult to effectively control the selectivity of the substrate lincomycin hydrochloride in the chlorination process. The actual process shows that the impurities of 7-epi-clindamycin must exceed 1.0% under the synthesis process using autoclave reaction, and it needs to be refined several times to meet the quality standard requirements. The multiple refining times will lead to a decrease in yield, an increase in cost, and a low production efficiency.

[0067] In summary, the preparation method of the clindamycin phosphate intermediate, i.e., clindamycin hydrochloride alcoholate, of the present invention utilizes continuous equipment, accurately controls the material ratio through a micromixer and a microchannel reactor, greatly controls the impurity content in the product, and effectively improves the purity and yield of the target product.

[0068] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for preparing a clindamycin phosphate intermediate, characterized in that: The steps include: (1) using lincomycin hydrochloride and Vilsmeier reagent as raw materials, mixing them in a micro mixer to obtain a reaction raw material liquid; (2) placing the reaction raw material liquid in a microchannel reactor to carry out a chlorination reaction, collecting the reactants and cooling and hydrolyzing them to obtain clindamycin free base; (3) adding alkaline solution to carry out hydrolysis reaction of the clindamycin free base to obtain the product.

2. The method for preparing a clindamycin phosphate intermediate according to claim 1, characterized in that: The molar ratio of the Vilsmeier reagent to the clindamycin hydrochloride is 1.0-5.5:

1.

3. The method for preparing a clindamycin phosphate intermediate according to claim 1 or 2, characterized in that: In the step (1), the mixing step includes the step of introducing the Vilsmeier reagent and the lincomycin hydrochloride into the micromixer through two channels respectively by using metering pumps to mix them.

4. The method for preparing a clindamycin phosphate intermediate according to claim 3, characterized in that: The step (1) further comprises the step of preparing a solution of the Vilsmeier reagent and / or the clindamycin hydrochloride; Preferably, the concentration of the Vilsmeier reagent solution is controlled to be 0.1-0.2 g / mL, and the flow rate is 6-10 mL / min; Preferably, the concentration of the clindamycin hydrochloride solution is controlled to be 0.3-0.8 g / mL, and the flow rate is controlled to be 2-10 mL / min.

5. The method for preparing a clindamycin phosphate intermediate according to any one of claims 1 to 4, characterized in that: In the step (2), in the chlorination step: Controlling the reaction gauge pressure of the microchannel reactor to be 1.2-1.6 MPa; and / or, Controlling the reaction temperature of the microchannel reactor to be 95-105° C.; and / or, The residence time of the reaction raw material liquid in the microchannel reactor is 18-20s.

6. The method for preparing a clindamycin phosphate intermediate according to any one of claims 1 to 5, characterized in that: In the step (2), the cooling and hydrolysis step includes the step of cooling the reactants to 0-10°C.

7. The method for preparing a clindamycin phosphate intermediate according to any one of claims 1 to 6, characterized in that: In the step (3), the alkali solution includes a NaOH solution.

8. The method for preparing a clindamycin phosphate intermediate according to any one of claims 1 to 7, characterized in that: 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.

9. The method for preparing a clindamycin phosphate intermediate according to any one of claims 1 to 8, characterized in that: The step (3) further includes collecting the hydrolysis reaction product for purification; The purification step comprises: collecting the hydrolysis reaction product and standing it 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 for reaction, then cooling to 0±2°C for heat preservation reaction, filtering and collecting the filter cake, washing and drying, and obtaining the product.

10. Application of the method for preparing the clindamycin phosphate intermediate according to any one of claims 1 to 9 in the field of clindamycin phosphate synthesis.

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