CN119569800A - Preparation method of clindamycin phosphate intermediate - Google Patents

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of clindamycin phosphate intermediate. According to the preparation method of the clindamycin phosphate intermediate, the lincomycin hydrochloride and the Vilsmeier reagent are used as starting materials, the material ratio is precisely controlled through the micromixer and the microchannel reactor, so that the stereochemical selectivity of the chlorination step is obviously improved, the reaction rate is effectively improved, the production of 7-clindamycin impurities is reduced through continuous preparation, the subsequent purification cost is reduced, the control of the 7-clindamycin impurities is realized, the 7-clindamycin impurities can be completely removed after primary crystallization, and the yield reaches 95-98%.

Description

Preparation method of clindamycin phosphate intermediate

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of clindamycin phosphate intermediate.

Background

Clindamycin phosphate (CLINDAMYCIN PHOSPHATE) is a chemical semisynthetic clindamycin derivative, is a broad-spectrum antibiotic, is mainly used for various infections caused by anaerobic bacteria and gram-positive aerobic bacteria clinically, such as respiratory tract infection, urinary tract infection, bone and joint infection, pelvic infection, abdominal cavity infection, skin soft tissue infection and the like caused by sensitive bacteria, and has extremely wide clinical application. Clindamycin phosphate is a prodrug which has no antibacterial activity in vitro, is rapidly hydrolyzed into clindamycin after entering a human body to display the pharmacological activity of the clindamycin phosphate, and achieves the 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 clindamycin, but the fat solubility and permeability are better than clindamycin, and the clindamycin phosphate can be orally taken, and can also be used for intramuscular injection and intravenous drip administration.

For example, chinese patent CN101439022A discloses a purification process of clindamycin phosphate, which mainly comprises the steps of crude product purification, crystal growth crystallization, centrifugal separation, washing, quick heating and drying of wet products and the like. The process has the advantages that the prepared clindamycin phosphate has good water solubility, uniform crystal form particles, small specific volume, large bulk density, good fluidity, low solvent residue and the like, and the product quality is obviously improved.

In another example, chinese patent CN101298463a discloses a preparation method of clindamycin phosphate, which uses lincomycin hydrochloride and solid light to carry out chlorination reaction in chloroform solvent at 50-80 ℃, and then carries out esterification with phosphorus oxychloride in acetone solvent under the combined catalysis of pyridine and triethylamine after alcoholization and ketonization. The process has the advantages of reducing environmental protection pressure, reducing the content of 7-epiclindamycin impurities in the finished product, reducing cost and improving yield.

A preparation method of clindamycin hydrochloride is disclosed in Chinese patent CN103172683A, and specifically comprises (1) performing chlorination reaction on clindamycin hydrochloride and Vilsmeier reagent to obtain a reaction solution containing clindamycin hydrochloride crude product, (2) hydrolyzing, extracting and concentrating the reaction solution to obtain clindamycin free base, then preserving the temperature of the clindamycin free base at 90-120 ℃ for 20-120 minutes, (3) performing salification reaction on the clindamycin free base in ethanol aqueous solution with the volume percentage concentration of 90-95% to obtain clindamycin hydrochloride ethanol, and (4) dealcoholizing the clindamycin hydrochloride ethanol to obtain clindamycin hydrochloride. The method effectively controls and obviously reduces the impurity content through process optimization, and obtains high-quality clindamycin hydrochloride, wherein the purity of a finished product is more than 99.5%, and especially the content of 7-epiclindamycin is less than 0.1%, and 4-clindamycin is not detected.

It can be seen that in the clindamycin phosphate synthesis process, clindamycin alcoholate as an intermediate plays a key role in the whole synthesis process. However, in the traditional synthesis process, clindamycin phosphate is directly used as a target product, and few researches on directly synthesizing clindamycin alcoholate are reported. Even the traditional clindamycin phosphate synthesis process has the problems of long reaction steps, lower reaction yield, higher cost and the like, and is not suitable for industrial production.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to provide the preparation method of the clindamycin phosphate intermediate, which has the advantages of mild reaction conditions, higher reaction yield and lower cost, and is suitable for industrial production.

In order to solve the technical problems, the preparation method of the clindamycin phosphate intermediate comprises the following steps:

(1) Mixing lincomycin hydrochloride and Vilsmeier reagent serving as raw materials in a micromixer to obtain reaction raw material liquid;

(2) Placing the reaction raw material liquid into a micro-channel reactor for chlorination reaction, collecting reactants for cooling and hydrolyzing to obtain clindamycin free alkali;

(3) And adding clindamycin free alkali into alkali liquor for hydrolysis reaction to obtain the clindamycin free alkali.

The preparation method of the clindamycin phosphate intermediate comprises the following specific synthetic routes:

Specifically, the preparation method of the clindamycin phosphate intermediate comprises the step that 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, preferably 1.0 eq-2.0 eq, more preferably 1.2 eq-1.4 eq of lincomycin hydrochloride by molar amount.

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

Specifically, the preparation method of the clindamycin phosphate intermediate further comprises the step of preparing a solution by using the Vilsmeier reagent and/or the clindamycin hydrochloride in the step (1);

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

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

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

controlling the reaction gauge pressure of the microchannel reactor to be 1.2-1.6Mpa and/or,

Controlling the reaction temperature of the microchannel reactor to be 95-105 ℃ and/or,

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

Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (2), the cooling hydrolysis step comprises the step of cooling the reactant to 0-10 ℃.

Specifically, in the preparation method of the clindamycin phosphate intermediate, in the step (3), the alkali liquor comprises NaOH solution.

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

Specifically, the preparation method of the clindamycin phosphate intermediate, in the step (3), further comprises the step of collecting hydrolysis reaction products for purification;

The purification step comprises the steps of collecting hydrolysis reaction products, standing until an organic phase is layered, collecting the organic phase, concentrating under reduced pressure, sequentially adding absolute ethyl alcohol and water, mixing, adjusting the system temperature to 40+/-3℃, pH & lt 1 & gt-3 for reaction, then cooling to 0+/-2 ℃ for heat preservation reaction, filtering, collecting filter cakes, washing and drying to obtain the product.

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

According to the preparation method of the clindamycin phosphate intermediate, on the basis of the traditional process, lincomycin hydrochloride and Vilsmeier reagent are used as starting materials, and the clindamycin alcoholate is obtained through chlorination reaction and hydrolysis reaction. According to the preparation method of the clindamycin phosphate intermediate, the material ratio is precisely controlled through the micromixer and the microchannel reactor, so that the stereochemical selectivity of the chlorination step is obviously improved, the reaction rate is effectively improved, the production of 7-clindamycin impurities is reduced through continuous preparation, the subsequent purification cost is reduced, the control of the 7-clindamycin impurities is realized, the 7-clindamycin impurities can be completely removed after primary crystallization, and the yield reaches 95-98%.

According to the preparation method of the clindamycin phosphate intermediate, disclosed by the invention, the material ratio is accurately controlled through the micromixer and the microchannel reactor, so that the effective control of the impurity 7-clindamycin phosphate which is difficult to remove is realized, the impurity level is reduced from 1.0% to within 0.05%, the product yield is obviously improved, and compared with the traditional reaction kettle reaction process, the product yield is improved from about 80% to more than 95%, the quality level and the yield level are greatly improved, the material cost is obviously reduced, and the preparation method has a good application prospect.

The preparation method of the clindamycin phosphate intermediate adopts a microchannel reactor for process synthesis, the molar ratio of Vilsmeier reagent to lincomycin can be effectively controlled through precise flow control of two materials, the reaction is carried out in the microchannel, the materials are heated uniformly, and the product is discharged out of a reaction system in time through the microchannel, so that the stereochemical selectivity in the chlorination process is greatly improved. Practice proves that the impurity level of the 7-epiclindamycin phosphate in the synthesized product can be controlled within 0.05%, the product purity is higher, and the product performance requirement can be met.

Drawings

In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which,

FIG. 1 is a process flow diagram of a clindamycin phosphate intermediate of the present invention;

FIG. 2 is a graph of the preparation of clindamycin phosphate intermediate product using the continuous flow reaction process of example 1;

Fig. 3 is a graph of a clindamycin phosphate intermediate product prepared by a conventional kettle reaction process in comparative example 1.

Detailed Description

In the following examples, the process flow diagram of the clindamycin phosphate intermediate is shown in fig. 1, and the specific synthesis process is as follows, namely, the clindamycin alcoholate (III) is prepared from lincomycin hydrochloride (I) as a raw material:

In the following examples, the micromixer is a known device in the art, and is aimed at realizing fine control of materials, and effects among devices with different structures are basically consistent, and as an exemplary embodiment, the micromixer is manufactured by Shandong gold and has a model number of C0-60-6.

In the following examples, the micro-channel reactor is a known device in the art, which aims to realize fine regulation and control of the whole chlorination reaction, and the effects of different structural devices are basically consistent, and the model of the micro-channel reactor is C0-60-6 produced by Shandong Jinde as an exemplary implementation mode.

In the following examples, reagents are commercially available, or may be formulated by methods known to those skilled in the art, such as Vilsmeier reagent (dichloromethylene dimethyl ammonium chloride) using methods known in the art.

Example 1

Vilsmeier reagent solution 43g of solid light is dissolved in 228mL of chloroform to prepare a solution, the temperature is controlled to be 4 ℃ and the solution is dripped into 25mL of DMF, and the solution is kept for 1h at 4 ℃ after the dripping is finished.

Lincomycin hydrochloride solution 100g solid lincomycin hydrochloride is added into 200mL DMF and mixed evenly, and the temperature is raised to 50-60 ℃ for dissolution and the solution is preserved in a dark place.

And respectively and simultaneously introducing the prepared Vilsmeier reagent solution and the lincomycin hydrochloride solution into a micromixer through two channels by using a metering pump to mix, controlling the flow rate of the lincomycin hydrochloride solution to be 8.2mL/min, and controlling the flow rate of the lincomycin hydrochloride solution to be 4.8mL/min to obtain a reaction raw material liquid. Wherein the mol ratio of the Vilsmeier reagent to the lincomycin hydrochloride in the reaction raw material liquid is 1.2:1. And then introducing the reaction raw material liquid into a microchannel reactor for reaction, controlling the reaction gauge pressure of the microchannel reactor to be 1.2Mpa, and controlling the reaction temperature to be 95 ℃, wherein the residence time of the reaction raw material liquid in the microchannel reactor is 20s.

Another reaction flask was taken and 300mL of water and 171mL of 30% NaOH were added and mixed for later use. The reaction liquid is cooled to 4 ℃ and is dripped into a reaction bottle, the internal temperature is controlled to be 30 ℃, the pH of a solution system is regulated to be 12 by 30 percent NaOH, the temperature of the feed liquid is controlled to be 25 ℃ for heat preservation and hydrolysis for 1 hour, and ice water is added for cooling and quenching crystallization. After the hydrolysis, the mixture was allowed to stand for 0.5 hour until the organic phase was separated, washed with 417mL of water, and after the separation by standing again, the organic phase was separated and concentrated under reduced pressure at 65 to 80℃to obtain chloroform. Continuously adding 200mL of absolute ethyl alcohol, stirring until the absolute ethyl alcohol is clear, adding 30mL of water, controlling the temperature to 40+/-3 ℃, dropwise adding hydrochloric acid to adjust the pH of the feed liquid to 2, stirring for 30 minutes after the dropwise adding, cooling to 0+/-2 ℃, preserving the heat for 2 hours, filtering, collecting a filter cake, and washing with 50mL of ethanol to obtain a clindamycin hydrochloride alcoholized wet product.

And (3) putting the collected wet product into a vacuum drying oven, drying for 10 hours at the temperature of 80 ℃, and collecting the material to obtain a clindamycin hydrochloride alcoholized product, wherein the weight yield of the clindamycin hydrochloride alcoholized product is 110 percent according to the measurement.

In this example, the figure of clindamycin hydrochloride alcoholate dry product is shown in figure 2. It can be seen that the product purity is higher in this example scheme.

Example 2

28G of solid light is dissolved in 228mL of chloroform to prepare a solution, the solution is dripped into 42mLDMF at the temperature of-15 ℃, and the temperature is kept for 1h at the temperature of 0-5 ℃ after the dripping is finished.

And (3) adding 100g of solid lincomycin hydrochloride into 150mLDMF, mixing, heating to 50-60 ℃ for dissolution, and preserving in a dark place.

And respectively introducing the Vilsmeier reagent solution and the lincomycin hydrochloride solution into a micromixer from two channels by using a metering pump for mixing, controlling the introducing flow of the Vilsmeier reagent solution to be 8.2mL/min, and controlling the introducing flow of the lincomycin hydrochloride solution to be 6.8mL/min to obtain 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. And then introducing the reaction raw material liquid into a micro-channel reactor for reaction, controlling the reaction gauge pressure of the micro-channel reactor to be 1.6Mpa and the reaction temperature to be 105 ℃, wherein the residence time of the reaction raw material liquid in the micro-channel reactor is 18s.

Another reaction flask was taken and mixed with 300mL of water and 170mL of 30% NaOH. The reaction liquid is cooled to 8 ℃ and is added into the reaction bottle in a dropwise manner, the internal temperature is controlled to be 32 ℃, the pH14 of a solution system is regulated by 30 percent NaOH, the temperature of the feed liquid is controlled to be 35 ℃ for preserving heat and hydrolyzing for 1 hour, and ice water is added for cooling and quenching crystallization. After the hydrolysis is finished, standing for 0.5 hour until the organic phase is layered, adding 420mL of water for washing, continuing to stand for layering, separating out the organic phase, and concentrating under reduced pressure at 65-80 ℃ to obtain chloroform. Continuously adding 200mL of absolute ethyl alcohol, stirring until the absolute ethyl alcohol is dissolved, adding 30mL of water, controlling the temperature to 40+/-3 ℃, dropwise adding hydrochloric acid to adjust the pH of the feed liquid to 3, stirring for 30 minutes after the dropwise adding is finished, cooling to 0+/-2 ℃, and preserving the heat for 2 hours. Filtering and collecting filter cakes, and washing the filter cakes with 50mL of ethanol to obtain a clindamycin hydrochloride alcoholized wet product.

And (3) placing the wet product into a vacuum drying oven, drying for 12 hours at the temperature of 80 ℃, and collecting the material to obtain a clindamycin hydrochloride alcoholized product dry product. The weight yield of clindamycin hydrochloride alcoholate was determined to be 104%.

Example 3

The preparation method of the clindamycin hydrochloride alcoholized product in the embodiment is the same as that in the embodiment 1, and the difference is that the concentration of the Vilsmeier reagent is controlled to be 0.14g/mL, the flow rate of the Vilsmeier reagent is controlled to be 8.2mL/min, the concentration of the lincomycin hydrochloride is controlled to be 0.5g/mL, and the flow rate of the lincomycin hydrochloride solution is controlled to be 2.8g/mL. The reaction temperature of the reaction raw material liquid in the micro-channel reactor is 85 ℃, and the residence time of the reaction raw material liquid in the micro-channel reactor is 20s.

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

Example 4

The preparation method of the clindamycin hydrochloride alcoholized product in the embodiment is the same as that in the embodiment 1, the difference is that the concentration of the Vilsmeier reagent is controlled to be 0.14g/mL, the flow rate of the Vilsmeier reagent is controlled to be 8.2mL/min, the concentration of the lincomycin hydrochloride is controlled to be 0.5g/mL, and the flow rate of the lincomycin hydrochloride solution is controlled to be 8.8g/mL. The reaction temperature of the reaction raw material liquid in the micro-channel reactor is 95 ℃, and the residence time of the reaction raw material liquid in the micro-channel reactor is 20s.

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

Example 5

The preparation method of the clindamycin hydrochloride alcoholized product in the embodiment is the same as that in the embodiment 1, the difference is that the concentration of the Vilsmeier reagent is controlled to be 0.14g/mL, the flow rate of the Vilsmeier reagent is controlled to be 6.2mL/min, the concentration of the lincomycin hydrochloride is controlled to be 0.5g/mL, and the flow rate of the lincomycin hydrochloride solution is controlled to be 8.8g/mL. The reaction temperature of the reaction raw material liquid in the micro-channel reactor is 105 ℃, and the residence time of the reaction raw material liquid in the micro-channel reactor is 20s.

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

Comparative example 1

The preparation method of clindamycin phosphate intermediate, namely clindamycin hydrochloride alcoholate, in this comparative example is the same as that in example 1, except that the reaction is carried out using a conventional tank reactor.

In this comparative example, the figure of the collection of clindamycin hydrochloride alcoholate dry product is shown in figure 3. It can be seen that the purity of the product prepared in the conventional tank reactor is low.

Therefore, the traditional kettle-type reactor is adopted to synthesize the clindamycin hydrochloride alcoholate, and the impurity content in the product is larger, mainly because the traditional kettle-type reaction inevitably has the problems of a) overlarge local material proportion, b) local overtemperature and c) the coexistence of the product in a reaction system, so that the selectivity of the substrate lincomycin hydrochloride in the chlorination process is difficult to effectively control. The actual process shows that under the synthesis process by utilizing the kettle reaction, the impurity of the 7-epiclindamycin is more than 1.0 percent, the quality standard requirement can be met by a plurality of refining methods, the yield is reduced due to the plurality of times of refining, the cost is increased, and the production efficiency is low.

In summary, the preparation method of clindamycin phosphate intermediate, namely clindamycin hydrochloride alcoholate, utilizes continuous equipment, precisely controls the material ratio through a micromixer and a microchannel reactor, greatly controls the content of impurities in the product, and effectively improves the purity and the yield of the target product.

It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims (10)

1. A method for preparing a clindamycin phosphate intermediate, comprising the steps of: (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 the 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 the clindamycin phosphate intermediate according to claim 1 or 2, characterized in that, in the step (1), the mixing step comprises the step of introducing the Vilsmeier reagent and the lincomycin hydrochloride into the micromixer through two channels respectively by using metering pumps for mixing. 4. The method for preparing the clindamycin phosphate intermediate according to claim 3, characterized in that, in the step (1), it also 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 the clindamycin phosphate intermediate according to any one of claims 1 to 5, characterized in that in the step (2), the cooling and hydrolysis step comprises a step of cooling the reactants to 0-10°C. 7. The method for preparing the clindamycin phosphate intermediate according to any one of claims 1 to 6, characterized in that in the step (3), the alkali solution comprises a NaOH solution. 8. The method for preparing the 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 the clindamycin phosphate intermediate according to any one of claims 1 to 8, characterized in that, in the step (3), it also comprises the step of 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.