Continuous flow synthesis process of clindamycin palmitate hydrochloride

Abstract

The invention relates to the technical field of medicines, in particular to a continuous flow synthesis process of clindamycin hydrochloride palmitate, which comprises the following steps of: reacting clindamycin hydrochloride serving as a starting material with triethyl orthoformate, p-toluenesulfonic acid and acetone under a heating condition to obtain 3, 4-O-isopropylidene-clindamycin, and reacting the 3, 4-O-isopropylidene-clindamycin in a continuous flow reactor to obtain the clindamycin hydrochloride palmitate. The preparation method comprises the following steps: fully mixing 3, 4-O-isopropylidene-clindamycin with palmitoyl chloride, carrying out a heating reaction under a pyridine condition to obtain 3, 4-O-isopropylidene-clindamycin palmitate, removing a protecting group through an acid to obtain a high-purity clindamycin palmitate hydrochloride crude product, pulping the crude product through acetone, and purifying to obtain the high-purity clindamycin palmitate hydrochloride. According to the process, continuous flow ester formation and protecting group removal are adopted, so that a high-purity crude product is obtained, the quality and yield of the product are improved, the production time is greatly saved, and the production efficiency is improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicine, and in particular to a continuous flow synthesis process of clindamycin palmitate hydrochloride. Background Art

[0002] Clindamycin palmitate hydrochloride is synthesized by the esterification reaction of the 2-hydroxyl group of clindamycin hydrochloride with palmitoyl chloride. Clindamycin palmitate hydrochloride is currently the only antibiotic in the clindamycin fatty acid ester series that is approved by the FDA and widely used in clinical practice. Clindamycin has good water solubility, but its oral bioavailability is low. Clindamycin tastes extremely bitter, while clindamycin palmitate as a prodrug has significantly reduced bitterness and is suitable for oral administration. Clindamycin palmitate, as a prodrug of clindamycin, does not show antibacterial effect in vitro, but is converted into clindamycin by esterase hydrolysis in vivo, thereby showing its antibacterial properties. The antibacterial mechanism of clindamycin is similar to that of macrolide antibiotics. It effectively inhibits the growth of peptide chains and the production of bacterial proteins by binding to the 50s subunit of bacterial ribonucleoproteins. Therefore, it can be used as a broad-spectrum antibacterial drug for the treatment of Gram-positive bacterial infections and infectious diseases caused by anaerobic bacteria. It can also remove the A protein and the villi-like outer layer on the surface of bacteria, making the bacteria easier to be phagocytosed and eliminated, thereby achieving the effect of inhibiting bacterial growth.

[0003] The chemical name of clindamycin palmitate hydrochloride is 6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-7(S)-chloro-6,7,8-trideoxy-L-threo-α-D-galactoctinopyranoside 2-palmitate hydrochloride, with a molecular formula of C34H63C1N2O6S.HCl, a molecular weight of 699.85, and a structural formula as follows:

[0004]

[0005] Numerous patents at home and abroad report the synthesis and purification methods of clindamycin palmitate hydrochloride.

[0006] British patent GB1205083 discloses a method for preparing clindamycin palmitate hydrochloride, in which 3,4-hydroxyl-protected clindamycin hydrochloride is prepared by refluxing water with fenvalerate as a protective agent and reacting with palmitoyl chloride, and then hydrolyzing and deprotecting to prepare clindamycin palmitate hydrochloride. The patent obtains the final product by dissolving the reaction residue in acetone, pouring the obtained solution into acetonitrile to obtain a precipitate, and finally filtering under nitrogen protection, and drying in the presence of nitrogen flow to obtain the finished product.

[0007] Bulgarian patent BG61652 adopts a method similar to GB1205083. When obtaining the final product, the crude product after the reaction is dissolved in water, and then the water is removed by a method similar to spray drying to obtain the finished product.

[0008] Chinese patent CN1332967C discloses a method for preparing clindamycin palmitate hydrochloride, which comprises reacting clindamycin ketal, triethylamine solution and palmitoyl chloride dissolved in chloroform in a water bath at 50-90°C under stirring to obtain a brown viscous substance; the obtained viscous substance is completely dissolved in glacial acetic acid and water, dried after hydrolysis, added with anhydrous hydrogen chloride saturated lower alcohol solution, and concentrated under reduced pressure to obtain a light yellow waxy solid; dissolved in chloroform, stirred vigorously, and acetonitrile is added dropwise to precipitate a white fine powder loose solid; filtered under reduced pressure and dried under vacuum to obtain clindamycin palmitate hydrochloride.

[0009] These methods can effectively prepare clindamycin palmitate hydrochloride, but the target product has low purity, poor color and low content, which affects the quality effect of its preparation. Summary of the invention

[0010] The purpose of the present invention is to provide a continuous flow synthesis process of clindamycin palmitate hydrochloride, so as to solve the problem that the preparation method of clindamycin palmitate hydrochloride in the prior art can effectively prepare clindamycin palmitate hydrochloride, but the purity of the target product is low, the color is poor, the content is low, and the quality effect of the preparation is affected.

[0011] To achieve the above object, the present invention provides a continuous flow synthesis process of clindamycin palmitate hydrochloride, the continuous flow synthesis process of clindamycin palmitate hydrochloride comprising the following steps:

[0012] S1: Add acetone, orthoformate triester, clindamycin hydrochloride and p-toluenesulfonic acid into a reaction flask to prepare 3,4-O-isopropylidene-clindamycin condensate;

[0013] S2: using a continuous flow reactor to complete an esterification reaction at the 2-position of the 3,4-O-isopropylidene-clindamycin condensate, and evaporating the organic phase under reduced pressure to obtain a crude product of clindamycin palmitate hydrochloride;

[0014] S3: Add acetone to the obtained concentrated solution and heat it to 55-60°C for hot slurrying, slowly cool it to 10-15°C, and after crystallization for 2 hours, filter it by suction to obtain a filter cake, wash the filter cake with a small amount of acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride.

[0015] The specific steps of step S1 are:

[0016] First, add acetone, triester orthoformate, clindamycin hydrochloride and p-toluenesulfonic acid into a reaction bottle, heat and react for 2 hours under stirring, cool to -5-15°C, crystallize for 2 hours, filter with suction, then add water and sodium carbonate into the reaction bottle, stir and dissolve, cool to 0-5°C, then dissolve the filter cake with water and add it dropwise into the alkali solution at 0-5°C to react, finally, filter after the reaction is completed, and dry the filter cake to obtain 3,4-O-isopropylidene-clindamycin condensate.

[0017] Wherein, in step S1, the mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid is 1: (1.0-5.0): (1.0-3.0): (0.01-0.1);

[0018] The mass ratio of clindamycin hydrochloride: water: sodium carbonate is 1: (7-20): (0.1-1.0);

[0019] The alkali solution can be prepared by using one or more of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, and N,N-dimethylformamide.

[0020] The specific steps of step S2 are:

[0021] First, evacuate the equipment with dichloromethane at a flow rate of 50-60 ml / min;

[0022] Secondly, dissolving 3,4-O-isopropylidene-clindamycin condensate in dichloromethane to obtain solution A, dissolving palmitoyl chloride in dichloromethane to obtain reaction solution B, and diluting pyridine with dichloromethane to obtain solution C;

[0023] Simultaneously, solution A, reaction solution B and solution C are introduced into a continuous flow reactor A, and the temperature is controlled to 10-40° C. to obtain reaction solution A;

[0024] The reaction solution A and solution D are simultaneously introduced into a continuous flow reactor B, and the temperature is raised to 25-30° C. to obtain a reaction solution B. The reaction solution B is allowed to stand for stratification, and the organic phase is evaporated under reduced pressure to obtain a crude product of clindamycin palmitate hydrochloride.

[0025] Wherein, in step S2, the reaction solution A is 3,4-O-isopropylidene-clindamycin palmitate condensate, and the reaction feed ratio is 3,4-O-isopropylidene-clindamycin condensate: dichloromethane: palmitoyl chloride: pyridine mass ratio 1: (6-9): (0.8-1.2): (0.1-0.3);

[0026] Reaction solution B is a crude product of clindamycin palmitate hydrochloride, and the reaction feed ratio is 3,4-O-isopropylidene-clindamycin condensate: hydrochloric acid = 1: (0.1-1).

[0027] Wherein, in step S2, solution D is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.

[0028] Wherein, in step S3, the solvent for purifying the crude clindamycin palmitate hydrochloride is selected from at least one or more of acetone, ethanol, and acetonitrile.

[0029] The invention discloses a continuous flow synthesis process of clindamycin hydrochloride palmitate. The process comprises the following steps: using clindamycin hydrochloride as a starting material, reacting with triethyl orthoformate, p-toluenesulfonic acid and acetone under heating conditions; after the reaction is completed, controlling the temperature at -5 to 15°C for crystallization and filtration to obtain a filter cake; controlling the temperature at 0 to 5°C for alkalization of the filter cake to obtain 3,4-O-isopropylidene-clindamycin; using a continuous flow reactor, fully mixing 3,4-O-isopropylidene-clindamycin and palmitoyl chloride; and heating the mixture under pyridine conditions to react the mixture so as to fully react, improve the reaction efficiency and facilitate the subsequent generation of purity. The invention discloses a method for preparing the clindamycin palmitate hydrochloride, which is a kind of clindamycin palmitate synthesized by the method of the present invention. The method comprises the following steps: first, the first step is to prepare the clindamycin palmitate hydrochloride, and the second step is to prepare the clindamycin palmitate hydrochloride. The first step is to prepare the clindamycin palmitate hydrochloride. The second ... BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0031] Figure 1 The invention discloses a flow chart of the steps of a continuous flow synthesis process of clindamycin palmitate hydrochloride.

[0032] Figure 2 The invention discloses a synthetic route of clindamycin palmitate hydrochloride.

[0033] Figure 3 It is a reaction flow chart of a continuous flow reactor provided by the present invention. DETAILED DESCRIPTION

[0034] Embodiments of the present invention are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present invention, and should not be construed as limiting the present invention.

[0035] See also Figures 1 to 3 The present invention provides a continuous flow synthesis process of clindamycin palmitate hydrochloride, and the continuous flow synthesis process of clindamycin palmitate hydrochloride comprises the following steps:

[0036] S1: Add acetone, orthoformate triester, clindamycin hydrochloride and p-toluenesulfonic acid into a reaction flask to prepare 3,4-O-isopropylidene-clindamycin condensate;

[0037] S2: using a continuous flow reactor to complete an esterification reaction at the 2-position of the 3,4-O-isopropylidene-clindamycin condensate, and evaporating the organic phase under reduced pressure to obtain a crude product of clindamycin palmitate hydrochloride;

[0038] S3: Add acetone to the obtained concentrated solution and heat it to 55-60°C for hot slurrying, slowly cool it to 10-15°C, and after crystallization for 2 hours, filter it by suction to obtain a filter cake, wash the filter cake with a small amount of acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride.

[0039] In this embodiment, clindamycin hydrochloride is used as a starting material, and is reacted with triethyl orthoformate, p-toluenesulfonic acid and acetone under heating conditions. After the reaction is completed, the temperature is controlled at -5-15°C for crystallization and filtration to obtain a filter cake, and the filter cake is alkalized at 0-5°C to obtain 3,4-O-isopropylidene-clindamycin. A continuous flow reactor is used to fully mix 3,4-O-isopropylidene-clindamycin and palmitoyl chloride, and the mixture is heated under pyridine conditions to fully react, improve the reaction efficiency, facilitate the subsequent generation of a high-purity product, and improve the product content, and then continue in a continuous flow, after removing the protecting group by acidolysis, the organic phase is concentrated under reduced pressure, the organic phase is hot-beaten with acetone at a temperature of 55-60°C, slowly cooled to 10-15°C for crystallization for 2 hours, and then filtered, and the filter cake is washed with acetone to obtain the final product, which reduces the production of by-products and improves the product yield and quality. The quality and yield of the clindamycin palmitate obtained by the synthesis method of this invention are greatly improved compared with the previous process, and the operation is simple, the production cost is low, and there are great quality and cost advantages.

[0040] Embodiment 1:

[0041] The present invention provides a continuous flow synthesis process of clindamycin palmitate hydrochloride, and the continuous flow synthesis process of clindamycin palmitate hydrochloride comprises the following steps:

[0042] S101: Add acetone, triethyl orthoformate, clindamycin hydrochloride and p-toluenesulfonic acid to a reaction flask, heat to 35°C for reaction for 2h under stirring, cool to 0-5°C for recrystallization for 2h, and filter with suction. Prepare alkali solution, add water and sodium carbonate to the reaction flask, stir and dissolve, and then cool the solution to 0-5°C. Dissolve the filter cake in water and add it dropwise to the alkali solution at 0-5°C for reaction for 2h. After the reaction is completed, filter with suction, and wash the filter cake with tap water of equal mass of clindamycin hydrochloride. Dry the filter cake to obtain 3,4-O-isopropylidene-clindamycin condensate. The mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid is 1:3.5:1.2:0.02. The mass ratio of clindamycin hydrochloride: water: sodium carbonate is 1:8:0.2.

[0043] S102: First, the equipment is emptied with dichloromethane at a flow rate of 50-60 ml / min; secondly, 3,4-O-isopropylidene-clindamycin condensate is dissolved in dichloromethane to obtain solution A, palmitoyl chloride is dissolved in dichloromethane to obtain reaction solution B, pyridine is diluted with dichloromethane to obtain solution C, and reaction solution A, reaction solution B and solution C are simultaneously input into continuous flow reactor A at room temperature, and the temperature is controlled at 25°C to obtain reaction solution A. Reaction solution A is 3,4-O-isopropylidene-clindamycin palmitate condensate. Dilute hydrochloric acid is used as solution D, and reaction solution A and solution D are simultaneously input into continuous flow reactor B, and the temperature is controlled at 25°C to obtain reaction solution B. The liquid is separated by standing, and the filtrate is concentrated to dryness under reduced pressure. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: dichloromethane: palmitoyl chloride: pyridine is 1:7:1:0.1. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: concentrated hydrochloric acid is 1:0.10.

[0044] S103: Add acetone to the concentrate, heat to 55°C for hot beating for 7h, gradually cool to 15°C, and crystallize for 2h. Finally, filter to obtain a filter cake, wash the filter cake with a little acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: acetone is 1:11.

[0045] Embodiment 2:

[0046] The present invention provides a continuous flow synthesis process of clindamycin palmitate hydrochloride, and the continuous flow synthesis process of clindamycin palmitate hydrochloride comprises the following steps:

[0047] S201: Add acetone, triethyl orthoformate, clindamycin hydrochloride and p-toluenesulfonic acid to the reaction flask, heat to 40°C for reaction for 2h under stirring, cool to -5-0°C for recrystallization for 2h, and filter with suction. Prepare alkali solution, add water and sodium carbonate to the reaction flask, stir and dissolve, and then cool the solution to 0-5°C. Dissolve the filter cake in water and add it dropwise to the alkali solution at 0-5°C for reaction for 2h. After the reaction is completed, filter with suction, and wash the filter cake with tap water of equal mass of clindamycin hydrochloride. Dry the filter cake to obtain 3,4-O-isopropylidene-clindamycin condensate. The mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid is 1:3.8:1.3:0.01. The mass ratio of clindamycin hydrochloride: water: sodium carbonate is 1:7:0.1.

[0048] S202: First, the equipment is emptied with dichloromethane at a flow rate of 50-60 ml / min; secondly, 3,4-O-isopropylidene-clindamycin condensate is dissolved in dichloromethane to obtain solution A, palmitoyl chloride is dissolved in dichloromethane to obtain reaction solution B, pyridine is diluted with dichloromethane to obtain solution C, and reaction solution A, reaction solution B and solution C are simultaneously input into a continuous flow reactor D at room temperature, and the temperature is controlled at 25°C to obtain reaction solution A. Reaction solution A is 3,4-O-isopropylidene-clindamycin palmitate condensate. Dilute hydrochloric acid is used as solution D, and reaction solution A and solution D are simultaneously input into a continuous flow reactor B, and the temperature is controlled at 25°C to obtain reaction solution B. The liquid is allowed to stand for separation, and the filtrate is concentrated to dryness under reduced pressure. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: dichloromethane: palmitoyl chloride: pyridine is 1:9:1.0:0.3. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: hydrochloric acid is 1:0.08.

[0049] S203: Add acetone to the product and heat it to 55°C for hot beating for 7 hours, gradually cool it to 15°C, and crystallize it for 2 hours. Finally, filter the filter cake by suction and wash it with a little acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate: acetone is 1:12.

[0050] Embodiment 3:

[0051] S301: Add acetone, triethyl orthoformate, clindamycin hydrochloride and p-toluenesulfonic acid to the reaction flask, heat to 40°C for reaction for 2h under stirring, cool to -5-0°C for recrystallization for 2h, and filter with suction. Prepare alkali solution, add water and sodium carbonate to the reaction flask, stir and dissolve, and then cool the solution to 0-5°C. Dissolve the filter cake in water and add it dropwise to the alkali solution at 0-5°C for reaction for 2h. After the reaction is completed, filter with suction, and wash the filter cake with tap water of equal mass of clindamycin hydrochloride. Dry the filter cake to obtain 3,4-O-isopropylidene-clindamycin condensate (intermediate I). The mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid is 1:3.8:1.3:0.01. The mass ratio of clindamycin hydrochloride: water: sodium carbonate is 1:7:0.1.

[0052] S302: Under nitrogen protection, add dichloromethane and intermediate I to the reaction bottle, dissolve palmitoyl chloride in dichloromethane and add to the reaction bottle, dilute pyridine with dichloromethane and add to the reaction bottle, heat to 25°C, react for 3h to obtain 3,4-O-isopropylidene-clindamycin palmitate condensate. The mass ratio of 3,4-O-isopropylidene-clindamycin condensate: dichloromethane: palmitoyl chloride: pyridine is 1:7:1:0.1.

[0053] S303: Add acetone to the product and heat it to 55°C for hot beating for 7 hours, then gradually cool it to 15°C and crystallize it for 2 hours. Finally, filter the filter cake by suction and wash it with a little acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride. The mass ratio of the 3,4-O-isopropylidene-clindamycin condensate to acetone is 1:12.

[0054] In summary, Example 3 is different from Example 1 and Example 2 in that the esterification reaction at the 2-position of the 3,4-O-isopropylidene-clindamycin condensate is not completed using a continuous flow reactor.

[0055] Test quality inspection:

[0056] The yield of clindamycin palmitate prepared in the example was calculated, and the content and related substances were tested. The results are shown in the following table:

[0057] Content: Take 100g of clindamycin palmitate hydrochloride and test according to (the content determination of "Clindamycin palmitate hydrochloride" in the first part of the second text of the 2015 edition of the Chinese Pharmacopoeia):

[0058] Related substance detection: Take 100g of clindamycin palmitate hydrochloride and test according to (the first part of the second text variety of the 2015 edition of the Chinese Pharmacopoeia "Clindamycin Palmitate Hydrochloride" inspection):

[0059] Yield (%) = weight of clindamycin palmitate hydrochloride / amount of 3,4-O-isopropylidene-clindamycin condensate × 100%

[0060] Group Yield / % content / % Related substances Pharmacopoeia Standards - ≥55.00 ≤7.00 Example 1 84.60％ 59.9％ 1.3 Example 2 83.30％ 59.7％ 1.4 Example 3 78.80％ 59.2％ 3.0

[0061] According to the experimental results, the synthesis process of the present invention is used to prepare clindamycin palmitate hydrochloride, and the product has high yield, high content, and few related impurities. Among them, compared with Examples 1 and 2, Example 3 does not use a continuous flow reactor to carry out esterification reaction at the 2-hydroxyl group, and the yield of the finished product is reduced, the content is low, and the related substances are high. Compared with Example 1 and Example 2, the mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid and the mass ratio of clindamycin hydrochloride: water: sodium carbonate are changed, and the yield, content and related substances of the product will be affected.

[0062] What is disclosed above is only a preferred embodiment of the present invention, and it certainly cannot be used to limit the scope of rights of the present invention. Ordinary technicians in this field can understand that all or part of the processes of the above embodiment and equivalent changes made according to the claims of the present invention still fall within the scope of the invention.

Claims

1. A continuous flow synthesis process for clindamycin palmitate hydrochloride, characterized in that: The steps include: S1: Add acetone, orthoformate triester, clindamycin hydrochloride and p-toluenesulfonic acid into a reaction flask to prepare 3,4-O-isopropylidene-clindamycin condensate; S2: using a continuous flow reactor to complete an esterification reaction at the 2-position of the 3,4-O-isopropylidene-clindamycin condensate, and evaporating the organic phase under reduced pressure to obtain a crude product of clindamycin palmitate hydrochloride; S3: Add acetone to the obtained concentrated solution and heat it to 55-60°C for hot slurrying, slowly cool it to 10-15°C, and after crystallization for 2 hours, filter it by suction to obtain a filter cake, wash the filter cake with a small amount of acetone, and dry the filter cake to obtain the product clindamycin palmitate hydrochloride.

2. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 1, characterized in that: The specific steps of step S1 are: First, add acetone, triester orthoformate, clindamycin hydrochloride and p-toluenesulfonic acid into a reaction bottle, heat and react for 2 hours under stirring, cool to -5-15°C, crystallize for 2 hours, filter with suction, then add water and sodium carbonate into the reaction bottle, stir and dissolve, cool to 0-5°C, then dissolve the filter cake with water and add it dropwise into the alkali solution at 0-5°C to react, finally, filter after the reaction is completed, and dry the filter cake to obtain 3,4-O-isopropylidene-clindamycin condensate.

3. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 2, characterized in that: In step S1, the mass ratio of clindamycin hydrochloride: acetone: triethyl orthoformate: p-toluenesulfonic acid is 1: (1.0-5.0): (1.0-3.0): (0.01-0.1); The mass ratio of clindamycin hydrochloride: water: sodium carbonate is 1: (7-20): (0.1-1.0); The alkali solution can be prepared by using one or more of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, and N,N-dimethylformamide.

4. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 3, characterized in that: The specific steps of step S2 are: First, evacuate the equipment with dichloromethane at a flow rate of 50-60 ml / min; Secondly, dissolving 3,4-O-isopropylidene-clindamycin condensate in dichloromethane to obtain solution A, dissolving palmitoyl chloride in dichloromethane to obtain reaction solution B, and diluting pyridine with dichloromethane to obtain solution C; Simultaneously, solution A, reaction solution B and solution C are introduced into a continuous flow reactor A, and the temperature is controlled to 10-40° C. to obtain reaction solution A; The reaction solution A and solution D are simultaneously introduced into a continuous flow reactor B, and the temperature is raised to 25-30° C. to obtain a reaction solution B. The reaction solution B is allowed to stand for stratification, and the organic phase is evaporated under reduced pressure to obtain a crude product of clindamycin palmitate hydrochloride.

5. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 4, characterized in that: In step S2, the reaction solution A is 3,4-O-isopropylidene-clindamycin palmitate condensate, and the reaction feed ratio is 3,4-O-isopropylidene-clindamycin condensate: dichloromethane: palmitoyl chloride: pyridine mass ratio 1: (6-9): (0.8-1.2): (0.1-0.3); Reaction solution B is a crude product of clindamycin palmitate hydrochloride, and the reaction feed ratio is 3,4-O-isopropylidene-clindamycin condensate: hydrochloric acid = 1: (0.1-1).

6. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 5, characterized in that: In step S2, solution D is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.

7. The continuous flow synthesis process of clindamycin palmitate hydrochloride according to claim 6, characterized in that: In step S3, the solvent for purifying the crude clindamycin palmitate hydrochloride is selected from at least one or more of acetone, ethanol, and acetonitrile.

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