Preparation process of clindamycin phosphate

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation process of clindamycin phosphate, which comprises the following preparation steps: chlorination reaction, alcoholization reaction, ketonization reaction and esterification reaction. Adding 50-55 parts by weight of phosphorus oxychloride, 340-380 parts by weight of a chelating agent and 60-70 parts by weight of triethylamine, and stirring until the materials are dissolved; the preparation method comprises the following steps: adding acetone into clindamycin propylidene until the acetone is completely dissolved, then adding the acetone into the clindamycin propylidene, keeping the temperature at 5-15 DEG C to react for 4-8 hours, and then hydrolyzing, removing a chelating agent, decolorizing, adsorbing, desorbing and crystallizing to obtain a clindamycin phosphate finished product, the method has the advantages of reducing emission of pyridine hydrochloride and reducing environmental pollution.

Description

Technical Field

[0001] The present application relates to the technical field of chemical synthesis, and in particular to a preparation process of clindamycin phosphate. Background Art

[0002] Clindamycin phosphate is a chemically semi-synthetic clindamycin derivative and an antibiotic drug. It has no antibacterial activity in vitro. After entering the body, it is rapidly hydrolyzed into clindamycin and exerts its pharmacological effects. Since its launch in my country in 1970, clindamycin phosphate has been widely used in clinical practice. Its antibacterial spectrum, antibacterial activity and therapeutic effect are the same as those of clindamycin, but its fat solubility and permeability are better than those of clindamycin. It can be taken orally, intramuscularly or intravenously. Compared with lincomycin, it has stronger antibacterial effect, better absorption, higher bone tissue concentration, and strong antibacterial activity against Gram-positive cocci and anaerobic bacteria. Its antibacterial spectrum is: Gram-positive cocci include penicillin G-resistant Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus (except Streptococcus phosphodiesterus), Streptococcus pneumoniae, Micrococcus, etc.; Gram-positive bacilli include Clostridium, Corynebacterium diphtheriae, etc.; anaerobic bacteria include Clostridium, Bacteroides, Fusobacterium, Propionibacterium, Eubacterium, anaerobic cocci, etc.

[0003] The existing synthesis process is to carry out chlorination reaction of lincomycin hydrochloride and phosphorus oxychloride in acetone or chloroform solvent, and then carry out alcoholization and ketonization to obtain clindamycin propylidene, and then carry out esterification reaction with phosphorus oxychloride in acetone solvent under the catalytic action of pyridine, and then carry out hydrolysis, macroporous resin adsorption, water washing, methanol analysis, concentration, crystallization and other steps to obtain clindamycin phosphate. In this synthesis process, after catalyzing the esterification reaction, pyridine is discharged in the form of pyridine hydrochloride through subsequent steps, which is highly polluting. Summary of the invention

[0004] In order to reduce the emission of pyridine hydrochloride and reduce environmental pollution, the present application provides a preparation process of clindamycin phosphate.

[0005] The present application provides a preparation process of clindamycin phosphate, which adopts the following technical scheme: A preparation process of clindamycin phosphate comprises the following preparation steps: chlorination reaction, alcoholization reaction, ketonization reaction and esterification reaction, wherein the specific contents of the ketonization reaction are as follows: Using acetone as solvent, adding 80-90 parts by weight of clindamycin hydrochloride alcoholate obtained by the alcoholization reaction and 50-55 parts by weight of phosphorus oxychloride, reacting at -13-0°C, and then hydrolyzing under alkaline conditions to obtain clindamycin propylidene; The specific contents of the esterification reaction are as follows: Using acetone as a solvent, adding 50-55 parts by weight of phosphorus oxychloride, 340-380 parts by weight of a chelating agent and 60-70 parts by weight of triethylamine, stirring until dissolved; adding acetone to the clindamycin propylidene obtained by the ketonization reaction until it is completely dissolved, then adding it, keeping warm at 5-15° C. for 4-8 hours, and then hydrolyzing, removing the chelating agent, decolorizing, adsorbing, desorbing and crystallizing to obtain a finished clindamycin phosphate; The preparation method of the chelating agent is as follows: S1. Using tetrahydrofuran as solvent, adding allylamine, raising the temperature to 45-55° C., dropping epichlorohydrin in an amount equimolar to allylamine, stirring to react, and obtaining a mixed solution A; adding an aqueous sodium hydroxide solution to the mixed solution A, wherein the amount of sodium hydroxide is 1.01-1.5 times the amount of epichlorohydrin added, stirring to react, adjusting the pH to neutral, obtaining a mixed solution B, and subjecting the mixed solution B to rotary evaporation to obtain a solid C; S2, dissolving solid C in tetrahydrofuran, stirring and heating to 50-70° C., then adding a mixture of iminodiacetonitrile and 4-aminopyridine, wherein the total molar amount of iminodiacetonitrile and 4-aminopyridine is the same as the molar amount of epichlorohydrin, stirring for reaction, and then removing the solvent by rotary evaporation to obtain monomer molecule D; S3. Under a nitrogen atmosphere, the monomer molecule D is dissolved in tetrahydrofuran, and the polymerization is initiated by a free radical initiator to obtain a chelating agent.

[0006] By adopting the above technical scheme, the chelate prepared in the present application contains a structure of multiple pyridyl groups, which can achieve the same reaction effect as pyridine, and even make the purity and yield of the reaction higher. It is speculated that it is due to the intermolecular hydrogen bonding between the chelate and the clindamycin propylidene, which makes it react more fully with the pyridine structure in the chelate; and the chelate of the present application can be separated from the reaction system by adding metal ions to chelate with it to form a precipitate, and the separation method is simple and effective, and easy to collect, and the formed chelate can be separated from the metal ions under acidic conditions, and the obtained chelate hydrochloride can be recovered and reused, which greatly reduces the environmental pressure; and the chelate hydrochloride of the present application can be hydrolyzed under acidic conditions to restore the carboxyl group, and then recovered according to the method of pyridine hydrochloride, so as to be reused.

[0007] Preferably, after the chelating agent participates in the reaction and before hydrolysis, copper ions are added dropwise to the reaction system to generate a precipitate, which is then removed by filtration.

[0008] By adopting the above technical solution, copper ions are non-ferrous metals, which are used to remove chelating agents, making their precipitation easier to observe, and have a good chelating effect and are relatively cheap.

[0009] Preferably, the added amount of the allylamine is 0.5-0.7 parts by weight, and the added amount of the free radical initiator is 0.028-0.034 parts by weight.

[0010] By adopting the above technical solution, the chelating agent prepared by this addition ratio has a better precipitation effect and is easy to remove.

[0011] Preferably, the free radical initiator is one or both of azobisisobutyronitrile and azobisisoheptanenitrile.

[0012] Preferably, the molar ratio of the iminodiacetonitrile to the 4-aminopyridine is 1:(0.5-2).

[0013] By adopting the above technical solution, when the addition amount of the chelating agent is the same, as the addition ratio of 4-aminopyridine gradually increases, the yield and purity of the reaction both show a trend of first increasing and then decreasing. It is speculated that when the addition ratio of 4-aminopyridine is too small, its reaction is insufficient, resulting in a decrease in yield and, at the same time, a decrease in purity; and when the addition ratio of 4-aminopyridine is too large, the molecules after the reaction are insufficient in carboxyl content, and the chelate is not completely precipitated and mixed into the product, resulting in a decrease in product purity.

[0014] Preferably, the molar ratio of the iminodiacetonitrile to the 4-aminopyridine is 1:1.

[0015] By adopting the above technical solution, through experiments, when the molar ratio of iminodiacetonitrile and 4-aminopyridine added during the preparation of the chelating agent is 1:1, the reaction yield and the purity of the product are both optimal.

[0016] Preferably, the added amount of the chelating agent is 360 parts by weight.

[0017] By adopting the above technical solution, the optimal addition amount of the chelating agent is 360 parts by weight. Adding too much will easily cause waste and also reduce the purity of the product.

[0018] Preferably, the amount of triethylamine added is 65 parts by weight.

[0019] By adopting the above technical scheme, the addition of triethylamine helps to reduce the amount of chelating agent used and reduce the cost of the reaction. In addition, triethylamine is highly volatile and easy to remove, and is not easily mixed in the product. In addition to replacing part of the chelate, triethylamine can also polymerize the cations in the reaction product and promote the reaction to proceed in the forward direction.

[0020] As a preference: the esterification reaction further comprises a refining step: The finished clindamycin phosphate is dissolved in 8-10 times of a mixed solution of ethanol / water with a volume ratio of 1:1, heated to 45-55°C, stirred until dissolved, and then medicinal charcoal is added, stirred for decolorization, filtered, and the filtrate is concentrated to a volume of two-fifths to one-half of the original volume, and then cooled for crystallization, centrifuged, and the precipitate is washed with ethanol and dried to obtain refined clindamycin phosphate.

[0021] By adopting the above technical solution, the purity of the product can be further improved through refining, so that the product has higher quality.

[0022] In summary, the present application includes at least one of the following beneficial technical effects: 1. The chelate prepared in the present application contains a structure of multiple pyridyl groups, which can achieve the same reaction effect as pyridine, and even make the reaction purity and yield higher. It is speculated that it is due to the intermolecular hydrogen bonding between the chelate and the clindamycin propylidene, which makes it react more fully with the pyridine structure in the chelate; and the chelate of the present application can be separated from the reaction system by adding metal ions to chelate with it to form a precipitate, and the separation method is simple and effective, easy to collect, and the formed chelate can be separated from the metal ions under acidic conditions, and the obtained chelate hydrochloride can be recycled and reused, which greatly reduces the environmental pressure.

[0023] 2. The present application prepares a chelating agent with a pyridine structure in its molecular structure and uses it to replace pyridine. It is found that the yield and purity of the product are good, and the prepared chelating agent can be removed well by chelating with metal ions to form a precipitate, so that the purity of the product will not be low due to the difficulty in removing the polymer added; through experimental exploration, the yield of clindamycin phosphate obtained by the preparation process of clindamycin phosphate of the present application is between 84.2-92.4%, and the purity is between 90.2-97.3%. After refining, the purity can reach 99.5%. DETAILED DESCRIPTION

[0024] The present application is further described in detail below in conjunction with the specific contents.

[0025] raw material The raw materials in the preparation examples and embodiments of the present application were all purchased from commercial sources and were all analytically pure.

[0026] Preparation Example 1 A chelating agent, the preparation method of which is as follows: S1. Add 0.6 kg of allylamine to 2.5 kg of tetrahydrofuran and stir evenly. After heating to 50°C, drip epichlorohydrin in an amount equimolar to allylamine at a dripping speed of 1 mL / min. Stir while dripping. After the dripping is complete, stir and react for 4 hours to obtain a mixed solution A. Add a 35% mass percentage concentration of sodium hydroxide aqueous solution to the mixed solution A, wherein the amount of sodium hydroxide is 1.1 times the amount of epichlorohydrin added, and stir and react for 1 hour. Then adjust the pH to neutral with a 0.1 mol / L hydrochloric acid solution to obtain a mixed solution B. Rotary evaporate the mixed solution B to obtain a solid C. S2, adding solid C to 2.5 kg of tetrahydrofuran, stirring and heating to 60 ° C, then adding a mixture of iminodiacetonitrile and 4-aminopyridine, the total molar amount of iminodiacetonitrile and 4-aminopyridine is the same as the molar amount of epichlorohydrin, the molar ratio of iminodiacetonitrile to 4-aminopyridine is 1:1, iminodiacetonitrile and 4-aminopyridine are added in 5 times, the time interval between two adjacent additions is 20 minutes, after the addition is completed, continue to stir the reaction for 4 hours, and then remove the solvent by rotary evaporation to obtain monomer molecule D; S3. Under a nitrogen atmosphere, the monomer molecule D is dissolved in 1.5 kg of tetrahydrofuran and stirred until dissolved. Then, 0.032 kg of azobisisobutyronitrile is added and the temperature is raised to 65° C. and stirred while the temperature is raised. After stirring and reacting for 12 hours, the solvent is evaporated and concentrated to obtain a chelating agent.

[0027] Preparation Example 2 A chelating agent, which is different from Preparation Example 1 in that the molar ratio of iminodiacetonitrile to 4-aminopyridine is 1:2, and the remaining steps are the same as Preparation Example 1.

[0028] Preparation Example 3 A chelating agent, which is different from Preparation Example 1 in that the molar ratio of iminodiacetonitrile to 4-aminopyridine is 1:0.5, and the remaining steps are the same as Preparation Example 1.

[0029] Example 1 A preparation process of clindamycin phosphate comprises the following preparation steps: S1. Chlorination reaction: add 210 kg of solid light into the batching tank, and then add chloroform until the solid light is completely dissolved to obtain a solid light solution; Add 1350kg of chloroform and 95kg of DMF into the chlorination tank, then add the prepared light-fixing solution, stir until dissolved, add 95kg of lincomycin hydrochloride, heat to 70℃, and keep warm for 15h; S2, alcoholization reaction: the temperature of the reaction liquid obtained in S1 is adjusted to 55°C, and then 750kg of water and 350kg of 30% by mass sodium hydroxide aqueous solution are added, stirred for hydrolysis reaction, and then separated into layers, the organic phase is taken, washed with water, and then transferred to a concentration tank, the chloroform is concentrated to dryness and then the concentration is stopped, 180kg of ethanol is added, the temperature is lowered to 0°C for crystallization, the material is discharged and centrifuged after crystallization, and then washed with ethanol, and the material is dried and the wet product of clindamycin hydrochloride alcoholate is transferred to a desiccant for drying to obtain clindamycin hydrochloride alcoholate, and the purity thereof is 99% after testing; S3, ketonization reaction: add 85 kg of clindamycin hydrochloride alcoholate prepared in S2, 270 kg of acetone and 52 kg of phosphorus oxychloride into the ketonization tank, and keep the reaction at -10°C for 6 hours; Then, 500 kg of water and 200 kg of 30% sodium hydroxide solution by mass fraction are placed in a hydrolysis crystallization tank, the feed liquid in the ketoneization tank is transferred to the hydrolysis crystallization tank, a hydrolysis reaction is carried out at 60° C., and then the temperature is lowered to 5° C., a 30% sodium hydroxide solution by mass fraction is added dropwise until crystals are precipitated, and the crystals are kept warm and crystallized until the number of crystals no longer increases, the material is discharged and centrifuged, and after adsorption washing with water, it is dried, and the material is dried to obtain clindamycin propyl; S4, esterification reaction: add 500 kg of acetone, 52 kg of phosphorus oxychloride, 360 kg of chelating agent and 65 kg of triethylamine into an esterification tank, and stir until dissolved; add acetone to the clindamycin propylidene in S3 until it is completely dissolved, and then add it into the esterification tank, and keep the reaction at 10°C for 5 hours; wherein the chelating agent is from Preparation Example 1; 500 kg of water was added to the hydrolysis tank, and the reaction liquid in the esterification tank was transferred to the hydrolysis tank for hydrolysis reaction. After the hydrolysis reaction was completed, a copper chloride solution with a mass fraction of 10% was dripped into the reaction liquid until the precipitation no longer increased, and the filtrate was filtered and concentrated at 75°C until there was no obvious fraction, and the circulating water was opened for cooling, and 800 kg of water was added to the concentration tank, and then medicinal carbon was added for decolorization, and the filter was pressed to the high-level tank, and then water was added, and the feed liquid in the high-level tank was placed in a resin adsorption column for adsorption. After the adsorption was completed, water was added to the top of the resin adsorption column for washing; then methanol was used for desorption, and the desorption liquid was concentrated at 75°C. When it was concentrated to a paste, the concentration was considered to be completed, and then 800 kg of ethanol was added for crystallization, and dried to obtain the clindamycin phosphate finished product.

[0030] Example 2 A preparation process of clindamycin phosphate, which is different from Example 1 in that the chelating agent is from Preparation Example 2, and the remaining steps are the same as those of Example 1.

[0031] Example 3 A preparation process of clindamycin phosphate, which is different from Example 1 in that the chelating agent is from Preparation Example 3, and the remaining steps are the same as those of Example 1.

[0032] Example 4 A process for preparing clindamycin phosphate, which is different from that in Example 1 in that the amount of chelating agent added in S4 is 340 kg, and the remaining steps are the same as those in Example 1.

[0033] Example 5 A process for preparing clindamycin phosphate is different from that in Example 1 in that the amount of chelating agent added in S4 is 380 kg, and the remaining steps are the same as those in Example 1.

[0034] Example 6 A preparation process of clindamycin phosphate, which is different from that of Example 1 in that the amount of triethylamine added in S4 is 60 kg, and the remaining steps are the same as those of Example 1.

[0035] Example 7 A preparation process of clindamycin phosphate, which is different from that of Example 1 in that the amount of triethylamine added in S4 is 70 kg, and the remaining steps are the same as those of Example 1.

[0036] Example 8 A preparation process of clindamycin phosphate, which is different from that of Example 1 in that S4 further comprises a refining step, the specific contents of which are as follows: The prepared clindamycin phosphate finished product is dissolved in 9 times of a mixed solution of ethanol / water with a volume ratio of 1:1, the temperature is raised to 50°C, stirred until dissolved, and then medicinal charcoal is added, stirred for decolorization, filtered, and the filtrate is concentrated at 75°C to one third of the original volume, and then cooled for crystallization, centrifuged, and the precipitate is washed with ethanol and dried to obtain refined clindamycin phosphate.

[0037] Comparative Example 1 A process for preparing clindamycin phosphate, which is different from that in Example 1 in that the chelating agent in S4 is replaced by 64 kg of pyridine, and the remaining steps are the same as those in Example 1.

[0038] Performance testing Detection method / test method Clindamycin phosphate was prepared according to the preparation processes of Examples 1-8 and Comparative Example 1, and then its purity and yield were tested. The test results are shown in Table 1; wherein the yield is calculated based on the actual amount of clindamycin hydrochloride alcoholate added to S3.

[0039] Table 1 Test results of Examples 1-8 and Comparative Example 1

[0040] It can be seen from Examples 1-8 and Comparative Example 1, as well as the test results of Table 1, that the present application prepares a chelating agent with a pyridine structure in the molecular structure, and uses it to replace pyridine, and it is found that the yield and purity of the product are good, and the prepared chelating agent can be removed well by chelating with metal ions to form a precipitate, so that the purity of the product will not be low due to the difficulty in removing the polymer added; through experimental exploration, the yield of clindamycin phosphate prepared by the preparation process of clindamycin phosphate of the present application is between 84.2-92.4%, and the purity is between 90.2-97.3%. After refining, the purity can reach 99.5%.

[0041] It can be seen from the test data of Example 1 and Comparative Example 1 that the chelate prepared in the present application can achieve the same reaction effect as pyridine, and even make the purity and yield of the reaction higher; and the chelate of the present application can be separated from the reaction system by adding copper ions and chelating with them to form a precipitate, and the separation method is simple and effective, easy to collect, and the formed chelate can be separated from the metal ions under acidic conditions, and the obtained chelate hydrochloride can be recovered and reused, which greatly reduces the environmental pressure.

[0042] It can be seen from the detection data of Example 1-3 that when the addition amount of chelating agent is the same, as the addition ratio of 4-aminopyridine gradually increases, the yield and purity of its reaction both show a trend of first increasing and then decreasing, and it is speculated that when the addition ratio of 4-aminopyridine is too small, its reaction is insufficient, resulting in a reduction in yield, and at the same time, purity is also reduced; and when the addition ratio of 4-aminopyridine is too large, its reacted molecule is insufficient due to carboxyl content, and chelate is not enough to precipitate completely and mixes into the product, resulting in a reduction in product purity. By experiment, when the molar ratio of iminodiacetonitrile and 4-aminopyridine added by chelating agent during preparation is 1: 1, the yield of reaction and the purity of product are both optimal. On this basis, in conjunction with Example 8, by refining, the purity of the product can be further improved so that the product has higher quality.

[0043] It can be seen from the test data of Example 1 and Examples 4-5 that the optimal addition amount of the chelating agent is 360 kg, and adding too much is likely to cause waste and also reduce the purity of the product. In conjunction with Examples 6-7, the addition of triethylamine helps to reduce the amount of the chelating agent, reduce the cost of the reaction, and triethylamine is highly volatile and easy to remove, and is not easily mixed in the product.

[0044] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A process for preparing clindamycin phosphate, characterized in that: The method comprises the following preparation steps: chlorination reaction, alcoholization reaction, ketonization reaction and esterification reaction. The specific contents of the ketonization reaction are as follows: Using acetone as solvent, adding 80-90 parts by weight of clindamycin hydrochloride alcoholate obtained by the alcoholization reaction and 50-55 parts by weight of phosphorus oxychloride, reacting at -13-0°C, and then hydrolyzing under alkaline conditions to obtain clindamycin propylidene; The specific contents of the esterification reaction are as follows: Using acetone as a solvent, adding 50-55 parts by weight of phosphorus oxychloride, 340-380 parts by weight of a chelating agent and 60-70 parts by weight of triethylamine, stirring until dissolved; adding acetone to the clindamycin propylidene obtained by the ketonization reaction until it is completely dissolved, then adding it, keeping warm at 5-15° C. for 4-8 hours, and then hydrolyzing, removing the chelating agent, decolorizing, adsorbing, desorbing and crystallizing to obtain a finished clindamycin phosphate; The preparation method of the chelating agent is as follows: S1. Using tetrahydrofuran as solvent, adding allylamine, raising the temperature to 45-55° C., dropping epichlorohydrin in an amount equimolar to allylamine, stirring to react, and obtaining a mixed solution A; adding an aqueous sodium hydroxide solution to the mixed solution A, wherein the amount of sodium hydroxide is 1.01-1.5 times the amount of epichlorohydrin added, stirring to react, adjusting the pH to neutral, obtaining a mixed solution B, and subjecting the mixed solution B to rotary evaporation to obtain a solid C; S2, dissolving solid C in tetrahydrofuran, stirring and heating to 50-70° C., then adding a mixture of iminodiacetonitrile and 4-aminopyridine, wherein the total molar amount of iminodiacetonitrile and 4-aminopyridine is the same as the molar amount of epichlorohydrin, stirring for reaction, and then removing the solvent by rotary evaporation to obtain monomer molecule D; S3. Under a nitrogen atmosphere, the monomer molecule D is dissolved in tetrahydrofuran, and the polymerization is initiated by a free radical initiator to obtain a chelating agent.

2. A process for preparing clindamycin phosphate according to claim 1, characterized in that: After the chelating agent participates in the reaction and before hydrolysis, copper ions are added dropwise to the reaction system to generate precipitation, which is then removed by filtration.

3. A process for preparing clindamycin phosphate according to claim 1, characterized in that: The added amount of the allylamine is 0.5-0.7 parts by weight, and the added amount of the free radical initiator is 0.028-0.034 parts by weight.

4. A process for preparing clindamycin phosphate according to claim 1, characterized in that: The free radical initiator is one or both of azobisisobutyronitrile and azobisisoheptanenitrile.

5. A process for preparing clindamycin phosphate according to claim 1, characterized in that: The molar ratio of the iminodiacetonitrile to the 4-aminopyridine is 1:(0.5-2).

6. A process for preparing clindamycin phosphate according to claim 1, characterized in that: The molar ratio of the iminodiacetonitrile to the 4-aminopyridine is 1:

1.

7. A process for preparing clindamycin phosphate according to claim 6, characterized in that: The added amount of the chelating agent is 360 parts by weight.

8. A process for preparing clindamycin phosphate according to claim 7, characterized in that: The added amount of the triethylamine is 65 parts by weight.

9. A process for preparing clindamycin phosphate according to claim 1, characterized in that: The esterification reaction further comprises a refining step: The finished clindamycin phosphate is dissolved in 8-10 times of a mixed solution of ethanol / water with a volume ratio of 1:1, heated to 45-55°C, stirred until dissolved, and then medicinal charcoal is added, stirred for decolorization, filtered, and the filtrate is concentrated to a volume of two-fifths to one-half of the original volume, and then cooled for crystallization, centrifuged, and the precipitate is washed with ethanol and dried to obtain refined clindamycin phosphate.

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