Method for continuously producing clindamycin hydrochloride

Abstract

The invention provides a method for continuously producing clindamycin hydrochloride, which comprises the following steps of: 1, preparing a solution of triphosgene in DMF (Dimethyl Formamide), namely a solution A; 2, preparing a solution of lincomycin or hydrochloride thereof in chloroform, namely a solution B; step 3, pumping the solution A and the solution B into a reaction plate according to a certain flow velocity for reaction to obtain a reaction solution C; step 4, pumping the reaction liquid C into a reaction plate according to a certain flow velocity for reaction to obtain a reaction liquid D; 5, the reaction liquid D is subjected to aftertreatment, and clindamycin hydrochloride is obtained. The method is high in reaction conversion rate, few in side reaction impurities, safe in production and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for continuously producing clindamycin hydrochloride. Background Art

[0002] Clindamycin hydrochloride is an antibiotic used as a broad-spectrum antibacterial drug. Clindamycin is a structural modification of lincomycin, with chlorine atoms replacing the C of lincomycin. 7 A semi-synthetic derivative of lincomycin formed by the addition of a hydroxyl group to the hydroxyl group at the hydroxyl group. Compared with lincomycin, clindamycin is very similar in antibacterial spectrum, pharmacological properties, indications and side effects. However, clindamycin is better absorbed orally, and its antibacterial activity is enhanced by 4-8 times. It has strong antibacterial activity and a broad antibacterial spectrum, and has antibacterial activity against many Gram-positive aerobic bacteria, anaerobic bacteria, and Chlamydia, Mycoplasma, Plasmodium falciparum, and Toxoplasma. It is used to treat staphylococcal and streptococcal infections, and severe anaerobic infections caused by sensitive strains. Clindamycin hydrochloride is a preparation suitable for oral treatment of bacterial infections, with strong tissue penetration, and is particularly suitable for pediatric use.

[0003] The chemical structure of clindamycin hydrochloride is as follows:

[0004]

[0005] At present, clindamycin hydrochloride is produced by chlorination reaction of lincomycin hydrochloride and triphosgene, and the synthesis route is as follows:

[0006]

[0007] Chlorination reaction is one of the 18 key regulated hazardous processes, which is highly corrosive and has explosion hazards. Moreover, in the process of lincomycin hydrochloride and triphosgene reacting to produce clindamycin, due to the long reaction time of the existing process, over-chlorination will occur, resulting in more 4-chloroclindamycin by-product impurities, reducing the reaction conversion rate and affecting the yield and quality of the product.

[0008] Chinese patent CN101333234B discloses a method for industrial production of clindamycin or its pharmaceutically acceptable salt, comprising the following steps: reacting bistrichloromethyl carbonate or trichloromethyl chloroformate with amide in a suitable solvent to prepare a chlorinating agent; reacting the chlorinating agent with lincomycin or its pharmaceutically acceptable salt to generate clindamycin or its pharmaceutically acceptable salt; and post-treating the generated clindamycin or its pharmaceutically acceptable salt to obtain a finished product of clindamycin or its pharmaceutically acceptable salt. The post-treatment of the method involves extraction of chlorinated salt base, preparation of clindamycin hydrochloride ethanolate and preparation of clindamycin hydrochloride, and the post-treatment is very complicated and cumbersome, the product contains many impurities, and continuous production cannot be achieved.

[0009] Chinese Patent CN103172683B discloses a preparation method of clindamycin hydrochloride, which comprises the following steps: (1) carrying out a chlorination reaction on lincomycin hydrochloride with a Vilsmeier reagent to obtain a reaction solution containing crude clindamycin hydrochloride; (2) hydrolyzing, extracting and concentrating the above 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%, carrying out a salification reaction on the clindamycin free base to obtain clindamycin hydrochloride ethanolate; (4) removing alcohol from the clindamycin hydrochloride ethanolate to prepare the clindamycin hydrochloride. The post-treatment of this method is also complex and cumbersome, and continuous production cannot be achieved. There are many side reactions during the reaction process, and a large number of impurities are generated.

[0010] Therefore, there is a need in the art for a method for producing clindamycin hydrochloride with high conversion rate, few side reactions and high safety. Summary of the Invention

[0011] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a method for continuously producing clindamycin hydrochloride. This method has a high reaction conversion rate, few side reaction impurities, safe production, and is suitable for industrial production. Through a continuous reaction process, the present invention can shorten the reaction time, reduce the reaction concentration, thereby reducing the risk, reducing the generation of by-product impurities, and thus improving the yield and quality of the product.

[0012] The purpose of the present invention is achieved through the following technical solutions:

[0013] A method for continuously producing clindamycin hydrochloride, which comprises the following steps:

[0014]

[0015] Step 1: Prepare a solution of triphosgene in DMF, called solution A;

[0016] Step 2: Prepare a solution of lincomycin or its hydrochloride in chloroform, called solution B;

[0017] Step 3: Pump solution A and solution B into reaction plate 1 at a certain flow rate for reaction to obtain a reaction solution C containing clindamycin hydrochloride;

[0018] Step 4: Pump the reaction solution C and an aqueous sodium hydroxide solution into reaction plate 2 at a certain flow rate for reaction to obtain a reaction solution D containing clindamycin free base;

[0019] Step 5: The reaction solution D is subjected to post-treatment to obtain clindamycin hydrochloride.

[0020] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 1, the weight ratio of triphosgene to DMF is 1:2 - 1:4, for example, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0021] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 2, the weight ratio of lincomycin or its hydrochloride to chloroform is 1:2 - 1:4, for example, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0022] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein the weight ratio of triphosgene to lincomycin is 1:1.

[0023] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 3, the feeding flow rate of solution A is 15 g / min - 30 g / min, for example, 15 g / min, 18 g / min, 21 g / min, 24 g / min, 27 g / min or 30 g / min, preferably 21 g / min; the feeding flow rate of solution B is 15 g / min - 30 g / min, for example, 15 g / min, 18 g / min, 21 g / min, 24 g / min, 27 g / min or 30 g / min, preferably 21 g / min.

[0024] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 3, the reaction temperature is 100°C - 160°C, for example, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C or 160°C, preferably 130°C.

[0025] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 3, the content of clindamycin hydrochloride in reaction solution C is 85% - 95%, preferably 92% - 95%.

[0026] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 4, the concentration of the sodium hydroxide aqueous solution is 10 - 15%.

[0027] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 4, the feeding flow rate of reaction solution C and the sodium hydroxide aqueous solution is 30 g / min.

[0028] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein in step 4, the reaction temperature is 20°C - 30°C, for example, 20°C, 23°C, 25°C, 28°C or 30°C, preferably 25°C.

[0029] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein, in step 5, the post-treatment includes chloroform extraction, combining the chloroform layers and concentrating, adding ethanol to dissolve after concentration to dryness, dropping hydrochloric acid for crystallization, filtering the obtained solid, and then adding acetone for crystallization to obtain clindamycin hydrochloride.

[0030] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein, in step 5, the concentration of hydrochloric acid is 10 - 15%.

[0031] The method for continuously producing clindamycin hydrochloride according to the present invention, wherein, in step 5, the HPLC purity of the obtained clindamycin hydrochloride is 96.8% - 99.3%, preferably 98.7% - 99.3%.

[0032] Beneficial effects

[0033] The method for continuously producing clindamycin hydrochloride provided by the present invention has a high reaction conversion rate, few side reaction impurities, safe production, and is suitable for industrial production. Through the continuous reaction process of the present invention, the reaction time can be shortened and the reaction concentration can be reduced, thereby reducing the danger and reducing the generation of by-product impurities, thus improving the yield and quality of the product. Brief description of the drawings

[0034] Figure 1 Shows the HPLC chromatogram of clindamycin hydrochloride prepared in Example 1 of the present invention.

[0035] Figure 2 Shows the HPLC chromatogram of clindamycin hydrochloride prepared in Example 2 of the present invention.

[0036] Figure 3 Shows the HPLC chromatogram of clindamycin hydrochloride prepared in Example 3 of the present invention.

[0037] Figure 4 Shows the HPLC chromatogram of clindamycin hydrochloride prepared in Example 4 of the present invention.

[0038] Figure 5 Shows the HPLC chromatogram of clindamycin hydrochloride prepared in Example 5 of the present invention. Detailed description of the invention

[0039] In the following examples, the reagents and raw materials not specifically described are commercially available products.

[0040] HPLC test instrument and test conditions:

[0041] Chromatographic conditions:

[0042] Instrument: High performance liquid chromatograph equipped with an ultraviolet detector;

[0043] Chromatographic column: Thermo Hypersil C18, 4.6 * 250 mm, 5 μm;

[0044] Detection wavelength: 210 nm;

[0045] Column temperature: 25 °C;

[0046] Sample injection volume: 20 μL;

[0047] Flow rate: 1.0 mL / min

[0048] Buffer solution: Dissolve 6.8 g of potassium dihydrogen phosphate in 1000 mL of water, and adjust the pH to 7.5 with 250 g / L potassium hydroxide solution

[0049] Mobile phase: Buffer solution: Acetonitrile = 55:45;

[0050] Running time: 20 min.

[0051] The continuous reaction production process of clindamycin hydrochloride of the present invention is illustrated by the following examples. In the examples, the concentration of the sodium hydroxide aqueous solution used in step 4 is 10 - 15%; the concentration of the hydrochloric acid used in step 5 is 10 - 15%. The reaction plate used in the examples is a Corning silicon carbide G1 microchannel device.

[0052] Example 1 Preparation of Clindamycin Hydrochloride

[0053] Step 1: Preparation of solution A: Put 50 g of triphosgene into 150 g of DMF, stir until dissolved and clarify for standby;

[0054] Step 2: Preparation of solution B: Put 50 g of lincomycin hydrochloride into 150 g of chloroform, stir until dissolved and clarify for standby;

[0055] Step 3: Feed with 4 reaction plates at 100 °C, solution A: 15 g / min, solution B: 15 g / min; Receive the reaction solution C with a 1 L bottle. The content of clindamycin hydrochloride in this reaction solution C is detected by liquid phase: 89.5%;

[0056] Step 4: Pump the above - collected reaction solution C and the sodium hydroxide aqueous solution into a 25 °C reaction plate through a pump, with a flow rate of 30 g / min, to obtain reaction solution D;

[0057] Step 5: The reaction solution D is layered. The water layer is extracted once again with chloroform. The chloroform layers are combined, concentrated to dryness. The concentrate is dissolved in ethanol until clear, hydrochloric acid is added for crystallization. The filtered solid is crystallized with acetone again to obtain 42 g of clindamycin hydrochloride, with a yield of 84% and a purity of 98.17%. The HPLC chromatogram is shown in Figure 1 .

[0058] Example 2 Preparation of Clindamycin Hydrochloride

[0059] Step 1: Preparation of Solution A: Put 50 g of triphosgene into 150 g of DMF, stir until dissolved and clarified for standby;

[0060] Step 2: Preparation of Solution B: Put 50 g of lincomycin hydrochloride into 150 g of chloroform, stir until dissolved and clarified for standby;

[0061] Step 3: Feed 4 reaction plates at 130 °C, Solution A: 15 g / min, Solution B: 15 g / min; Receive reaction solution C with a 1 L bottle. The content of clindamycin hydrochloride in this reaction solution C is detected by liquid phase: 93.8%;

[0062] Step 4: Pump the above-mentioned collected reaction solution C and aqueous sodium hydroxide solution into a 25 °C reaction plate at a flow rate of 30 g / min to obtain reaction solution D;

[0063] Step 5: The reaction solution D is layered. The aqueous layer is extracted once again with chloroform. The chloroform layers are combined, concentrated to dryness. The concentrate is dissolved in ethanol until clarified, hydrochloric acid is added for crystallization. The obtained solid is filtered and then crystallized with acetone to obtain 48.2 g of clindamycin hydrochloride, with a yield of 96.4%, a purity of 99.07%. The HPLC chromatogram is shown in Figure 2 。

[0064] Preparation of Clindamycin Hydrochloride in Example 3

[0065] Step 1: Preparation of Solution A: Put 50 g of triphosgene into 150 g of DMF, stir until dissolved and clarified for standby;

[0066] Step 2: Preparation of Solution B: Put 50 g of lincomycin hydrochloride into 150 g of chloroform, stir until dissolved and clarified for standby;

[0067] Step 3: Feed 4 reaction plates at 130 °C, Solution A: 21 g / min, Solution B: 21 g / min; Receive reaction solution C with a 1 L bottle. The content of clindamycin hydrochloride in this reaction solution C is detected by liquid phase: 94.1%;

[0068] Step 4: Pump the above-mentioned collected reaction solution C and aqueous sodium hydroxide solution into a 25 °C reaction plate at a flow rate of 30 g / min to obtain reaction solution D;

[0069] Step 5: The reaction solution D is layered. The aqueous layer is extracted once again with chloroform. The chloroform layers are combined, concentrated to dryness. The concentrate is dissolved in ethanol until clarified, hydrochloric acid is added for crystallization. The obtained solid is filtered and then crystallized with acetone to obtain 50.5 g of clindamycin hydrochloride, with a yield of 101%, a purity of 99.23%. The HPLC chromatogram is shown in Figure 3 。

[0070] Preparation of Clindamycin Hydrochloride in Example 4

[0071] Step 1: Preparation of Solution A: Add 50 g of triphosgene to 150 g of DMF, stir until dissolved and clear, and set aside for later use;

[0072] Step 2: Preparation of Solution B: Add 50 g of lincomycin hydrochloride to 150 g of chloroform, stir until dissolved and clear, and set aside for later use;

[0073] Step 3: Feed 4 reaction plates at 130 °C, with Solution A at 30 g / min and Solution B at 30 g / min; Receive reaction solution C in a 1 L bottle. By liquid phase detection of this reaction solution C, the content of clindamycin hydrochloride is 92.6%;

[0074] Step 4: Pump the above-collected reaction solution C and aqueous sodium hydroxide solution into a 25 °C reaction plate at a flow rate of 30 g / min to obtain reaction solution D;

[0075] Step 5: The reaction solution D is separated into layers. The aqueous layer is extracted once more with chloroform. The chloroform layers are combined, concentrated to dryness. The concentrate is dissolved in ethanol until clear, hydrochloric acid is added for crystallization. The solid obtained by filtration is then crystallized with acetone to obtain 47.1 g of clindamycin hydrochloride, with a yield of 94.2%, a purity of 98.74%. The HPLC chromatogram is shown in Figure 4 。

[0076] Preparation of Clindamycin Hydrochloride in Example 5

[0077] Step 1: Preparation of Solution A: Add 50 g of triphosgene to 150 g of DMF, stir until dissolved and clear, and set aside for later use;

[0078] Step 2: Preparation of Solution B: Add 50 g of lincomycin hydrochloride to 150 g of chloroform, stir until dissolved and clear, and set aside for later use;

[0079] Step 3: Feed 4 reaction plates at 160 °C, with Solution A at 30 g / min and Solution B at 30 g / min; Receive reaction solution C in a 1 L bottle. By liquid phase detection of this reaction solution C, the content of clindamycin hydrochloride is 85.7%;

[0080] Step 4: Pump the above-collected reaction solution C and aqueous sodium hydroxide solution into a 25 °C reaction plate at a flow rate of 30 g / min to obtain reaction solution D;

[0081] Step 5: The reaction solution D is separated into layers. The aqueous layer is extracted once more with chloroform. The chloroform layers are combined, concentrated to dryness. The concentrate is dissolved in ethanol until clear, hydrochloric acid is added for crystallization. The solid obtained by filtration is then crystallized with acetone to obtain 42.4 g of clindamycin hydrochloride, with a yield of 84.8%, a purity of 96.87%. The HPLC chromatogram is shown in Figure 5 。

Claims

1. A method for continuously producing clindamycin hydrochloride, comprising the following steps: Step 1: prepare a solution of triphosgene in DMF, referred to as solution A; Step 2: prepare a solution of lincomycin or its hydrochloride in chloroform, referred to as solution B; Step 3: pumping solution A and solution B into the reaction plate 1 at a certain flow rate to react, thereby obtaining a reaction solution C containing clindamycin hydrochloride; Step 4: pumping the reaction solution C and the sodium hydroxide aqueous solution into the reaction plate 2 at a certain flow rate to react, thereby obtaining a reaction solution D containing clindamycin free base; Step 5: The reaction solution D is post-treated to obtain clindamycin hydrochloride.

2. The method for continuously producing clindamycin hydrochloride according to claim 1, wherein: In step 1, the weight ratio of triphosgene to DMF is 1:2-1:4; in step 2, the weight ratio of lincomycin or its hydrochloride to chloroform is 1:2-1:4; the weight ratio of triphosgene to lincomycin is 1:

1.

3. The method for continuously producing clindamycin hydrochloride according to claim 1 or 2, wherein: In step 3, the feed flow rate of solution A is 15 g / min-30 g / min; the feed flow rate of solution B is 15 g / min-30 g / min.

4. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 3, wherein: In step 3, the reaction temperature is 100°C-160°C.

5. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 4, wherein: In step 3, the content of clindamycin hydrochloride in the reaction solution C is 85%-95%, preferably 92%-95%.

6. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 5, wherein: In step 4, the concentration of the sodium hydroxide aqueous solution is 10-15%; the feed flow rate of the reaction solution C and the sodium hydroxide aqueous solution is 30 g / min.

7. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 6, wherein: In step 4, the reaction temperature is 20°C-30°C.

8. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 7, wherein: In step 5, post-treatment includes chloroform extraction, combining the chloroform layers and concentrating, adding ethanol to dissolve after concentration to dryness, adding hydrochloric acid dropwise to crystallize, filtering the obtained solid, and then adding acetone to crystallize to obtain clindamycin hydrochloride.

9. The method for continuously producing clindamycin hydrochloride according to claim 8, wherein: In step 5, the concentration of hydrochloric acid is 10-15%.

10. The method for continuously producing clindamycin hydrochloride according to any one of claims 1 to 9, wherein: In step 5, the HPLC purity of the obtained clindamycin hydrochloride is 96.8%-99.3%, preferably 98.7%-99.3%.

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