Preparation method of ciprofloxacin lactate

Abstract

The invention provides a preparation method of ciprofloxacin lactate, and belongs to the technical field of heterocyclic compounds. Adding water to dissolve ciprofloxacin hydrochloride, and dropwise adding alkali liquor into the obtained dissolved solution until ciprofloxacin crystals are separated out; filtering out and separating out crystals, and washing to obtain ciprofloxacin tide blocks; the preparation method comprises the following steps: adding a ciprofloxacin tide block into a solvent, stirring and heating to 60-80 DEG C, adding a salt-forming agent lactic acid, and cooling to 15-20 DEG C to crystallize after a heat preservation reaction is finished; and washing the obtained crystal, and carrying out vacuum drying to obtain the finished product ciprofloxacin lactate. According to the scheme, the consumption of lactic acid in the ciprofloxacin synthesis step is obviously reduced, three wastes are reduced, the cost is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present application relates to a method for preparing ciprofloxacin lactate, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] Ciprofloxacin lactate is a broad-spectrum antibiotic, belonging to quinolone antibiotics, and its main mechanism of action is to inhibit the DNA gyrase involved in nucleic acid synthesis, and to prevent cell division and sterilization by destroying the bacterial DNA structure. It is generally prepared by ciprofloxacin hydrochloride, such as CN106632036A, ciprofloxacin hydrochloride is dissolved in purified water, alkali adjusted with ammonia or sodium hydroxide, ciprofloxacin is obtained, and dried after filtering. In acetone or ethanol solvent system, ciprofloxacin and lactic acid are reacted to form salt, and the crystallization is cooled and dried. Ciprofloxacin in this method needs to be taken out and dried midway, and energy consumption is high. And the lactic acid weight used for salt formation is 0.45~1.1 times of the weight of ciprofloxacin, which is converted into a molar equivalent of 1.6~4.5 times of ciprofloxacin, and the lactic acid consumption is very large. Summary of the invention

[0003] In view of this, the present application provides a method for preparing ciprofloxacin lactate, which significantly reduces the consumption of lactic acid in the synthesis step of ciprofloxacin lactate by depolymerizing lactic acid, reduces three wastes, reduces costs, and is suitable for industrial production.

[0004] Specifically, the present application is implemented through the following scheme: A preparation method of ciprofloxacin lactate, comprising the following steps: Step 1, dissolving ciprofloxacin hydrochloride in water, and adding alkali solution dropwise to the obtained solution until ciprofloxacin crystals are precipitated; Step 2, filtering out the precipitated crystals, washing, and obtaining a ciprofloxacin tidal block; Step 3, adding the ciprofloxacin block to the solvent, stirring and heating to 60-80°C, adding depolymerized lactic acid with a polymer peak of ≤3%, keeping the reaction warm until the reaction is complete, and cooling to 15-20°C for crystallization; Step 4: washing the obtained crystals, and vacuum drying to obtain the finished product of ciprofloxacin lactate.

[0005] Further, as a preference: In step 1, the added mass ratio of ciprofloxacin hydrochloride to water is 1:10-20.

[0006] In step 2, the water content of the ciprofloxacin tidal block is 15-20%.

[0007] In step three, The solvent is ethanol with a volume concentration of ≥85%.

[0008] The mass ratio of ciprofloxacin tidal block to solvent is 9~13:1.

[0009] The depolymerized lactic acid is obtained by depolymerizing lactic acid. The depolymerization process is as follows: after adding lactic acid to water and mixing, the temperature is raised to 70-100°C, and the reaction is kept warm. The related substances of lactic acid are detected, and the polymer peak decreases from more than 30% to less than 3%, thereby obtaining the salt-forming agent lactic acid. The added mass ratio of lactic acid to water is 1:1-5, and the heat preservation reaction time is 24-72 hours.

[0010] The molar ratio of the ciprofloxacin mass to the depolymerized lactic acid is 1:1.1-1.4 (the molar ratio is calculated by measuring the ciprofloxacin content and the lactic acid content in step three), and preferably 1:1.25-1.37.

[0011] Activated carbon is also added to the heat preservation reaction, and after stirring and decolorizing for 0.5 to 3.5 hours, it is filtered and the filtrate is cooled and crystallized.

[0012] The above scheme not only greatly reduces the energy consumption in the preparation process of ciprofloxacin lactate, but also greatly reduces the lactic acid consumption in the salt formation process of ciprofloxacin lactate. DETAILED DESCRIPTION

[0013] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below in combination with the specific cases in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application. Example

[0014] The preparation of ciprofloxacin lactate in this embodiment, the steps are as follows: (1) Lactic acid depolymerization: 30 g of 85% lactic acid and 30 g of purified water were added to a 500 ml four-necked bottle equipped with a stirrer and a thermometer, and the temperature was raised to 80°C and kept warm for 24 hours. The related substances of lactic acid were detected, and the polymer peak decreased from 32.13% to 2.66%, and the depolymerization was terminated to obtain depolymerized lactic acid.

[0015] (2) Add 50 g of ciprofloxacin hydrochloride and 500 g of purified water into a 500 ml four-necked flask equipped with a stirrer and a thermometer, and heat to 52°C until all ciprofloxacin is dissolved.

[0016] (3) At 60° C., a 10% aqueous solution of sodium hydroxide was added dropwise to the solution obtained by the complete dissolution in step (2), and the pH was adjusted to neutral. The precipitate was filtered and rinsed to obtain a ciprofloxacin tide block. The water content of the tide block was detected to be 31%.

[0017] (4) Take 60.37 g of the ciprofloxacin block obtained in step (3), add 450 g of 90% ethanol, stir and heat to 70°C.

[0018] (5) The depolymerized lactic acid obtained in step (1) was added dropwise to form salt. The amount of depolymerized lactic acid added was 33 g (the mass concentration of lactic acid before depolymerization was 85%, and water was added in a 1:1 ratio for depolymerization. The effective content of lactic acid in 33 g of depolymerized lactic acid = 33*0.85*0.5 = 14.025 g. The number of moles of lactic acid = 14.025 / 90.08 = 0.1557 mol, the molar amount of ciprofloxacin = 60.37*(1-31%) / 331.35 = 0.1257 mol, and the molar ratio of lactic acid to ciprofloxacin = 0.1557 / 0.1257 = 1.24 molar equivalents). After the salt formation reaction was carried out by heat preservation for 1 hour, the temperature was lowered to below 10° C. for crystallization.

[0019] (6) The crystallized product was filtered, rinsed and dried under reduced pressure to obtain 51.91 g of finished ciprofloxacin lactate. The mass yield based on ciprofloxacin hydrochloride was 51.91 / 50*100%=104%, and the main peak of the liquid phase was 99.83%. Example

[0020] The preparation of ciprofloxacin lactate in this embodiment, the steps are as follows: (1) Lactic acid depolymerization: 30 g of 85% lactic acid and 30 g of purified water were added to a 500 ml four-necked bottle equipped with a stirrer and a thermometer, and the temperature was raised to 80°C and kept warm for 24 hours. The related substances of lactic acid were detected, and the polymer peak decreased from 31.37% to 2.48%, and the depolymerization was terminated to obtain depolymerized lactic acid.

[0021] (2) Add 50 g of ciprofloxacin hydrochloride and 500 g of purified water into a 500 ml four-necked flask equipped with a stirrer and a thermometer, and heat to 53°C until all ciprofloxacin is dissolved.

[0022] (3) At 60° C., a 10% aqueous solution of sodium hydroxide was added dropwise to the solution obtained by the complete dissolution in step (2), and the pH was adjusted to neutral. The precipitate was filtered and rinsed to obtain a ciprofloxacin tide block. The water content of the tide block was detected to be 34%.

[0023] (4) Take 63.11 g of the ciprofloxacin block obtained in step (3), add 450 g of 90% ethanol, stir and heat to 70°C.

[0024] (5) The depolymerized lactic acid obtained in step (1) was added dropwise to form salt. The amount of depolymerized lactic acid added was 36 g (the mass concentration of lactic acid before depolymerization was 85%, and water was added in a 1:1 ratio for depolymerization. The effective content of lactic acid in 36 g of depolymerized lactic acid = 36*0.85*0.5 = 15.3 g. The molar number of lactic acid = 15.3 / 90.08 = 0.1698 mol, the molar amount of ciprofloxacin = 63.11*(1-34%) / 331.35 = 0.1257 mol, and the molar ratio of lactic acid to ciprofloxacin = 0.1698 / 0.1257 = 1.35 molar equivalents). After the salt formation reaction was carried out by heat preservation for 1 hour, the temperature was lowered to below 10° C. for crystallization.

[0025] (6) The crystallized product was filtered, rinsed and dried under reduced pressure to obtain 52.44 g of finished ciprofloxacin lactate. The mass yield based on ciprofloxacin hydrochloride was 52.44 / 50*100%=105%, and the main peak of the liquid phase was 99.84%. Example

[0026] The preparation of ciprofloxacin lactate in this embodiment, the steps are as follows: (1) Lactic acid depolymerization: 30 g of lactic acid with a mass fraction of 85% and 90 g of purified water were added to a 500 ml four-necked bottle equipped with a stirrer and a thermometer, and the temperature was raised to 80°C and kept warm for 24 hours. The related substances of lactic acid were detected, and the polymer peak decreased from 36.13% to 2.42% (falling within 2.5%), and the depolymerization was terminated to obtain depolymerized lactic acid.

[0027] (2) Add 50 g of ciprofloxacin hydrochloride and 500 g of purified water into a 500 ml four-necked flask equipped with a stirrer and a thermometer, and heat to 55°C until all ciprofloxacin is dissolved.

[0028] (3) At 60° C., a 10% aqueous solution of sodium hydroxide was added dropwise to the solution obtained by the complete dissolution in step (2), and the pH was adjusted to neutral. The precipitate was filtered and rinsed to obtain a ciprofloxacin tide block. The water content of the tide block was detected to be 36%.

[0029] (4) Take 65.08 g of the ciprofloxacin tidal block obtained in step (3), add 450 g of 90% ethanol, stir and heat to 70°C.

[0030] (5) The depolymerized lactic acid obtained in step (1) was added dropwise to form salt. The amount of depolymerized lactic acid added was 72 g (the mass concentration of lactic acid before depolymerization was 85%, and water was added in a ratio of 1:3 for depolymerization. The effective content of lactic acid in 36 g of depolymerized lactic acid = 72*0.85*0.25 = 15.3 g. The molar number of lactic acid = 15.3 / 90.08 = 0.1698 mol, the molar amount of ciprofloxacin = 65.08*(1-36%) / 331.35 = 0.1257 mol, and the molar ratio of lactic acid to ciprofloxacin = 0.1698 / 0.1257 = 1.35 molar equivalents). After the salt formation reaction was carried out by heat preservation for 1 hour, the temperature was lowered to below 10° C. for crystallization.

[0031] (6) The crystallized product was filtered, rinsed and dried under reduced pressure to obtain 52.61 g of finished ciprofloxacin lactate. The mass yield based on ciprofloxacin hydrochloride was 52.63 / 50*100%=105%, and the main peak of the liquid phase was 99.84%.

[0032] Embodiments 1, 2, and 3 use depolymerized lactic acid as the reaction material, and the molar equivalent of lactic acid relative to ciprofloxacin is maintained at a relatively low level of 1:1.25-1.37. It can be seen from each embodiment that by increasing the proportion of water in the depolymerized lactic acid process, the lactic acid depolymerization can be made more thorough at the same time and temperature. The mass yields of the lactic acid rings made with different lactic acid effective contents are close, and by comparison, the lactic acid amount can be reduced.

[0033] This comparative example uses lactic acid and ciprofloxacin hydrochloride to prepare ciprofloxacin lactate, and the process is as follows: (1) Place 50 g of ciprofloxacin hydrochloride and 500 g of purified water into a 500 ml four-necked flask equipped with a stirrer and a thermometer, and heat to 52°C until all ciprofloxacin is dissolved.

[0034] (2) At 60° C., a 10% aqueous solution of sodium hydroxide was added dropwise to the solution obtained by the complete dissolution in step (1), and the pH was adjusted to neutral. The precipitate was filtered and rinsed to obtain a ciprofloxacin tide block. The water content of the tide block was detected to be 34%.

[0035] (3) Take 63.11 g of the ciprofloxacin tidal block obtained in step (2), add 450 g of 90% ethanol, stir and heat to 70°C.

[0036] (4) Add 85% lactic acid to form salt. The amount of lactic acid used is 33 g (the mass concentration of lactic acid before depolymerization is 85%, and water is added in a 1:1 ratio for depolymerization. The effective content of 30 g lactic acid = 33*0.85 = 28.05 g. The number of moles of lactic acid = 28.05 / 90.08 = 0.3114 mol, the molar amount of ciprofloxacin = 63.11*(1-34%) / 331.35 = 0.1257 mol, and the molar ratio of lactic acid to ciprofloxacin = 0.3114 / 0.1257 = 2.48 molar equivalents). After the salt is formed and kept warm for 1 hour, the temperature is lowered to below 10°C for crystallization.

[0037] (5) The crystallized product was filtered, rinsed and dried under reduced pressure to obtain 52.64 g of finished ciprofloxacin lactate. The mass yield based on ciprofloxacin hydrochloride was 52.64 / 50*100%=105%, and the main peak of the liquid phase was 99.84%.

[0038] This comparative example directly uses lactic acid as the reaction raw material. Compared with the depolymerized lactic acid used as the raw material in Examples 1, 2, and 3, the equivalent of lactic acid relative to ciprofloxacin is 2.48, nearly twice that of Examples 1, 2, and 3, which shows that the consumption of lactic acid is large.

[0039] Compared with CN106632036A, the present invention can continuously carry out the depolymerization of lactic acid, the acquisition of tidal blocks and the salt formation, without taking out the product or intermediate for drying and other treatments.

[0040] 1) Lactic acid consumption was calculated based on the effective content of lactic acid and the molar equivalent of lactic acid to ciprofloxacin.

[0041] 2) Energy consumption: Only the steam consumption of the ciprofloxacin baking step is calculated. The embodiment and the comparative example do not perform baking of ciprofloxacin, i.e., the energy consumption of this step is 0; when evaporating the moisture of the ciprofloxacin tidal block, the electricity consumption is not calculated, and only the steam energy consumption of this step is calculated. The comprehensive thermal efficiency is 20%, and the moisture content of the ciprofloxacin tidal block is 35%. The steam energy consumption reduced per kilogram of product = (1*0.35*4.18*(100-25)+1*0.35*2256+(1-0.35)*15*(120-25)) / 2256 / 20%=4.05kg steam.

[0042] 3) Compared with the lactic acid content in the mother liquor of the three waste discharge, after the solvent is recovered, the lactic acid that has not formed into a salt remains in the water system, which will increase the cost of wastewater treatment.

[0043] It can be seen that the use of this solution can achieve a significant reduction in lactic acid consumption and preparation energy consumption.

[0044] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing ciprofloxacin lactate, characterized in that: Here are the steps: Step 1, dissolving ciprofloxacin hydrochloride in water, and adding alkali solution dropwise to the obtained solution until ciprofloxacin crystals are precipitated; Step 2, filtering out the precipitated crystals, washing, and obtaining a ciprofloxacin tidal block; Step 3, adding the ciprofloxacin block to the solvent, stirring and heating to 60-80°C, adding depolymerized lactic acid with a polymer peak of ≤3%, keeping the reaction warm until the reaction is complete, and cooling to 15-20°C for crystallization; Step 4: washing the obtained crystals, and vacuum drying to obtain the finished product of ciprofloxacin lactate.

2. A method for preparing ciprofloxacin lactate according to claim 1, characterized in that: In step 1, the added mass ratio of ciprofloxacin hydrochloride to water is 1:10-20.

3. A method for preparing ciprofloxacin lactate according to claim 1, characterized in that: The water content of the ciprofloxacin tide block is 15-20%.

4. A method for preparing ciprofloxacin lactate according to claim 1, characterized in that: The solvent is ethanol with a volume concentration of ≥85%.

5. A method for preparing ciprofloxacin lactate according to claim 1, characterized in that: In step 3, the mass ratio of ciprofloxacin tidal block to solvent is 9-13:

1.

6. The method for preparing ciprofloxacin lactate according to claim 1, characterized in that: The preparation process of the depolymerized lactic acid is as follows: lactic acid is mixed with water, the mixture is heated to 70-100° C., and the mixture is kept warm for reaction.

7. The method for preparing ciprofloxacin lactate according to claim 6, characterized in that: The insulation reaction time is 24 to 72 hours, and the added mass ratio of lactic acid to water is 1:1 to 5.

8. The method for preparing ciprofloxacin lactate according to claim 1, characterized in that: In step 3, activated carbon is added to the heat preservation reaction, and after stirring and decolorizing for 0.5 to 3.5 hours, the mixture is filtered, and the obtained filtrate is cooled and crystallized.

9. The method for preparing ciprofloxacin lactate according to claim 1, characterized in that: The molar ratio of ciprofloxacin to depolymerized lactic acid is 1:1.1-1.

4.

10. The method for preparing ciprofloxacin lactate according to claim 9, characterized in that: The molar ratio of ciprofloxacin to depolymerized lactic acid is 1:1.25-1.37.