A method for removing boron from moxifloxacin hydrochloride and a method for preparing pure moxifloxacin hydrochloride

Abstract

The application provides a boron removal method of moxifloxacin hydrochloride and a preparation method of pure moxifloxacin hydrochloride, and belongs to the technical field of medicine preparation. In the application, LSC-800 resin is used for adsorbing and removing boric acid under the condition that the pH value is 8-9. The LSC-800 resin is a macroporous structure chelating resin which is crosslinked by styrene and divinylbenzene and has N-methylglucosamine groups. The polyol group part of the LSC-800 resin can generate complex anions with boric acid groups, and the amine group part of the LSC-800 resin can capture the generated complex anions as anion exchange groups, so that the boric acid ions in the boric acid-containing moxifloxacin hydrochloride can be selectively adsorbed, and the boric acid ions can be effectively removed. The results of the examples show that no boric acid is detected in the obtained moxifloxacin hydrochloride by using the boron removal method.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine preparation, in particular to a method for removing boron from moxifloxacin hydrochloride and a method for preparing pure moxifloxacin hydrochloride. BACKGROUND

[0002] Moxifloxacin hydrochloride is an 8-methoxy fluoroquinolone antibacterial drug with broad-spectrum and antibacterial activity. Moxifloxacin hydrochloride shows broad-spectrum antibacterial activity in vitro against gram-positive bacteria, gram-negative bacteria, anaerobes, acid-fast bacteria and atypical microorganisms such as mycoplasma, chlamydia and legionella. The antibacterial mechanism of moxifloxacin hydrochloride is to interfere with topoisomerase II and IV. Topoisomerase is a key enzyme for controlling DNA topology and in DNA replication, repair and transcription. The bactericidal curve shows that moxifloxacin has concentration-dependent bactericidal activity. As a new generation of fluoroquinolone drug, moxifloxacin hydrochloride has good development prospects due to its advantages of broad-spectrum, high efficiency, strong resistance to drug resistance and less side effects.

[0003] At present, the requirements for genetic toxic impurities of drugs are becoming more and more strict. Boric acid is used in the preparation process of moxifloxacin hydrochloride. Recent studies have shown that boric acid and its esters have certain mutagenicity, and the potential genotoxicity of boric acid as a warning structure is worthy of further study. However, the preparation process of moxifloxacin hydrochloride reported in the literature does not remove boric acid, and boric acid may remain in the product. For example, the residual amount of boric acid in moxifloxacin hydrochloride obtained by the method of the prior art patent CN201410405137.5 A method for synthesizing moxifloxacin hydrochloride is 114 ppm. SUMMARY

[0004] Therefore, the present application aims to provide a method for removing boron from moxifloxacin hydrochloride and a method for preparing pure moxifloxacin hydrochloride. The method provided by the present application can effectively remove boric acid ions in moxifloxacin hydrochloride.

[0005] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0006] The present application provides a method for removing boron from moxifloxacin hydrochloride, comprising the following steps:

[0007] (2) mixing moxifloxacin hydrochloride crude product with water, adjusting the pH value of the mixed solution to 8-10, adding LSC-800 resin for boron removal reaction to obtain a boron removal reaction solution, and the moxifloxacin hydrochloride crude product contains impurity boric acid;

[0008] (2) mixing the boron removal reaction solution with hydrochloric acid for salt formation reaction to obtain pure moxifloxacin hydrochloride.

[0009] Preferably, the mass ratio of the crude moxifloxacin hydrochloride to water is 1:6-10.

[0010] Preferably, the mass ratio of the crude moxifloxacin hydrochloride to LSC-800 resin is 1:0.01-0.05.

[0011] Preferably, the temperature of the boron removal reaction is 10-40℃, and the time is 1-4h.

[0012] The present application provides a preparation method of pure moxifloxacin hydrochloride, comprising the following steps:

[0013] (a) mixing boric acid and acetic anhydride with acetic acid as the solvent at 90-110℃, and then mixing the obtained mixture with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester to perform chelation reaction, thereby obtaining an intermediate chelate;

[0014] (b) mixing the intermediate chelate with (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine with methanol as the solvent to perform condensation reaction, thereby obtaining a moxifloxacin chelate-methanol solution;

[0015] (c) mixing the moxifloxacin chelate-methanol solution with concentrated hydrochloric acid, and then performing cooling crystallization, thereby obtaining crude moxifloxacin hydrochloride;

[0016] (d) performing boron removal reaction according to the above boron removal method of moxifloxacin hydrochloride, thereby obtaining a salt formation reaction liquid;

[0017] (e) first cooling the salt formation reaction liquid to 60-80℃ to perform first stirring crystallization, and then second cooling the solid-liquid mixture after the first stirring crystallization to 0-10℃ to perform second stirring crystallization, thereby obtaining pure moxifloxacin hydrochloride.

[0018] Preferably, the temperature of the chelation reaction in step (a) is 90-100℃, and the time is 2-3h.

[0019] Preferably, the mass ratio of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester to boric acid and acetic anhydride in step (a) is 1:(0.25-0.35):(1.7-1.8).

[0020] Preferably, the temperature of the condensation reaction in step (b) is 50-60℃, and the time is 6-8h.

[0021] Preferably, the mass ratio of the intermediate chelate to (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine in step (b) is 1:0.3-0.4.

[0022] Preferably, the temperature of mixing the moxifloxacin complex-methanol solution with concentrated hydrochloric acid in step (c) is 20-30℃.

[0023] The application provides a method for removing boron from moxifloxacin hydrochloride, comprising the following steps: (1) mixing moxifloxacin hydrochloride crude product with water, adjusting the pH value of the mixed solution to 8-10, adding LSC-800 resin to carry out boron removal reaction to obtain a boron removal reaction solution, wherein the moxifloxacin hydrochloride crude product contains impurity boric acid; (2) mixing the boron removal reaction solution with hydrochloric acid to carry out salting reaction to obtain moxifloxacin hydrochloride pure product. The application uses LSC-800 resin to carry out adsorption boron removal under the condition of pH value of 8-10, and the LSC-800 resin is a macroporous chelating resin with N-methyl glucosamine group and cross-linked by styrene and divinylbenzene. The polyol group of the LSC-800 resin can generate complex anions with boric acid radicals, and the amine group of the LSC-800 resin can capture the generated complex anions as anion exchange group, so as to realize selective adsorption of boric acid radicals in boric acid moxifloxacin hydrochloride and effective removal of the boric acid radicals. Further, the LSC-800 resin can be regenerated, and the cost of boron removal can be reduced. The results of examples show that no boric acid is detected in the obtained moxifloxacin hydrochloride by using the boron removal method provided by the application.

[0024] This invention provides a method for preparing pure moxifloxacin hydrochloride, comprising the following steps: (a) using acetic acid as a solvent, mixing boric acid and acetic anhydride at 90–110 °C, and then performing a chelation reaction with ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate to obtain an intermediate chelate; (b) using methanol as a solvent, mixing the intermediate chelate with (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine. (c) A condensation reaction is performed to obtain a moxifloxacin chelate-methanol solution; (d) the moxifloxacin chelate-methanol solution is mixed with concentrated hydrochloric acid and cooled to crystallize, yielding crude moxifloxacin hydrochloride; (e) a boron removal reaction is performed according to the above-described method for removing boron from moxifloxacin hydrochloride to obtain a salt-forming reaction solution; (f) the salt-forming reaction solution is first cooled to 60-80°C and subjected to first stirring to crystallize; then the solid-liquid mixture after the first stirring and crystallization is second cooled to 0-10°C and subjected to second stirring to crystallize, yielding pure moxifloxacin hydrochloride. The preparation method provided by this invention is mild, environmentally friendly, and low-cost, and can obtain high-purity moxifloxacin hydrochloride without boric acid residue. Specifically, this invention involves mixing boric acid and acetic anhydride at 90–110°C, resulting in a mild reaction. It uses acetic acid and methanol as solvents, making it environmentally friendly. Furthermore, the invention eliminates the need for catalysts and acid-binding agents during preparation, reducing the cost of raw materials. By controlling the temperatures of the first and second stirring crystallization processes in the salt-forming reaction solution, this invention can obtain high-purity moxifloxacin hydrochloride crystals in columnar form. The results of the examples show that the purity of the moxifloxacin hydrochloride obtained by this invention is 99.92%, and no boric acid was detected. Attached Figure Description

[0025] Figure 1 This is a flowchart illustrating the preparation process of pure moxifloxacin hydrochloride according to the present invention.

[0026] Figure 2 The product obtained in Example 1 of this invention 1 H-NMR spectrum;

[0027] Figure 3 The product obtained in Example 1 of this invention 13 C-NMR spectrum. Detailed Implementation

[0028] This invention provides a method for removing boron from moxifloxacin hydrochloride, comprising the following steps:

[0029] (1) Mix crude moxifloxacin hydrochloride with water, adjust the pH of the mixture to 8-10, add LSC-800 resin to carry out boron removal reaction, and obtain boron removal reaction solution. The crude moxifloxacin hydrochloride contains boric acid impurity.

[0030] (2) mixing the boron-removing reaction solution with hydrochloric acid to perform a salting reaction, so as to obtain pure moxifloxacin hydrochloride.

[0031] In the present application, the crude moxifloxacin hydrochloride is mixed with water, the pH value of the mixed solution is adjusted to 8-10, and LSC-800 resin is added to perform a boron-removing reaction, so as to obtain a boron-removing reaction solution. In the present application, the crude moxifloxacin hydrochloride is prepared by using boric acid as a chelating agent, and contains impurity boron. In the present application, the water is preferably purified water; and the mass ratio of the moxifloxacin hydrochloride containing boron acid to water is preferably 1:6-10, and more preferably 1:8-9.

[0032] In the present application, the pH value of the mixed solution is adjusted to 8-10, and preferably to 9. In the present application, the alkaline reagent for adjusting the pH value of the mixed solution is preferably sodium hydroxide solution, and the mass concentration of the sodium hydroxide solution is preferably 10-30%, and more preferably 15-20%.

[0033] In the present application, the mass ratio of the moxifloxacin hydrochloride containing boron acid to LSC-800 resin is preferably 1:0.01-0.05, and more preferably 1:0.01-0.02. In the present application, the source of the LSC-800 resin is preferably commercially available; and as a specific embodiment of the present application, the LSC-800 resin is purchased from Xi'an Lanxiao Science and Technology New Material Co., Ltd.

[0034] In the present application, the temperature of the boron-removing reaction is preferably 10-40°C, and more preferably 20-30h; and the time is preferably 1-4h, and more preferably 2-3h. The boron-removing reaction is preferably performed under stirring in the present application, and the stirring speed is preferably 100-300rpm, and more preferably 200rpm.

[0035] After obtaining the boron-removing reaction solution, the boron-removing reaction solution is mixed with hydrochloric acid to perform a salting reaction, so as to obtain pure moxifloxacin hydrochloride. In the present application, the hydrochloric acid is preferably concentrated hydrochloric acid, and the mass concentration of the concentrated hydrochloric acid is preferably 36-38%, and more preferably 37%. In the present application, after the boron-removing reaction solution is mixed with hydrochloric acid, the pH value of the obtained mixed solution is preferably 1-2.

[0036] In the present application, the temperature of the salting reaction is preferably 90-100°C, and more preferably 95°C. The salting reaction is performed in the present application, so as to obtain moxifloxacin hydrochloride after removing boron acid.

[0037] After the salting reaction, the salting reaction solution is preferably subjected to post-treatment in the present application, and the post-treatment preferably comprises the following steps:

[0038] The aqueous salting solution is subjected to solid-liquid separation, and the obtained liquid is sequentially subjected to first and second cooling crystallization, so as to obtain a solid product.

[0039] The solid product is sequentially washed and dried to obtain pure moxifloxacin hydrochloride.

[0040] The present application does not have special requirements for the solid-liquid separation method, and the solid-liquid separation method known to those skilled in the art can be used, for example, filtration.

[0041] In the present application, the temperature of the first cooling crystallization is preferably 60-80℃, and more preferably 70℃; the time is preferably 0.5-1h, and more preferably 0.6-0.8h. The temperature of the second cooling crystallization is preferably 0-10℃, and more preferably 0-5℃; the time is preferably 2-3h, and more preferably 2.5h. In the present application, the first cooling crystallization and the second cooling crystallization are preferably carried out under stirring, and the stirring speed is preferably independently 100-300rpm, and more preferably 200rpm.

[0042] In the present application, after the second cooling crystallization, the present application preferably centrifuges the liquid after crystallization to obtain a solid product.

[0043] The present application does not have special requirements for the washing and drying method of the solid product, and the washing and drying method known to those skilled in the art can be used.

[0044] In the present application, the LSC-800 resin can be regenerated after the boron removal reaction, and in the present application, the regeneration method preferably comprises the following steps:

[0045] The hydrochloric acid solution is mixed with the used LSC-800 resin, and stirring and standing are sequentially carried out, then the hydrochloric acid solution is poured out, the above operation is repeated 2 times, and the LSC-800 resin after standing is washed with pure water to obtain regenerated LSC-800 resin.

[0046] In the present application, the mass concentration of the hydrochloric acid solution is preferably 4%; the volume of the hydrochloric acid solution is preferably 1-2 times the volume of the LSC-800 resin. In the present application, the temperature of the stirring and standing is preferably room temperature; the time of single stirring is preferably 15-30min, and more preferably 20-25min; the time of single standing is preferably 15-30min, and more preferably 20-25min. The present application does not have special requirements for the washing method, and the washing method known to those skilled in the art can be used. In the present application, the pH value of the washing liquid obtained after washing is preferably 5-7.

[0047] Alternatively, the regeneration method preferably comprises the following steps:

[0048] The sodium hydroxide solution is mixed with the LSC-800 resin, and stirring and standing are carried out in sequence, after which the sodium hydroxide solution is poured out, and the above operation is repeated twice, and the LSC-800 resin after standing is washed with pure water to obtain regenerated LSC-800 resin.

[0049] In the present application, the mass concentration of the sodium hydroxide solution is preferably 4%, and the volume of the sodium hydroxide solution is preferably 1-2 times the volume of the LSC-800 resin. In the present application, the temperature of the stirring and standing is preferably room temperature, the time of single stirring is preferably 15-30 min, more preferably 20-25 min, and the time of single standing is preferably 15-30 min, more preferably 20-25 min. The present application does not have special requirements for the washing mode, and a washing mode well known to those skilled in the art can be used. In the present application, the pH value of the washing liquid obtained after washing is preferably 7-8.

[0050] The present application provides a preparation method of pure moxifloxacin hydrochloride, comprising the following steps:

[0051] (a) mixing boric acid and acetic anhydride with acetic acid as a solvent at 90-110℃, and mixing the obtained mixture with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester to carry out chelation reaction, to obtain an intermediate chelate;

[0052] (b) mixing the intermediate chelate with (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine with methanol as a solvent to carry out condensation reaction, to obtain a moxifloxacin chelate-methanol solution;

[0053] (c) mixing the moxifloxacin chelate-methanol solution with concentrated hydrochloric acid, and carrying out cooling crystallization, to obtain crude moxifloxacin hydrochloride;

[0054] (d) carrying out boron removal reaction according to the above boron removal method of moxifloxacin hydrochloride, to obtain a salting reaction liquid;

[0055] (e) first cooling the salting reaction liquid to 60-80℃, and carrying out first stirring crystallization, and then second cooling the solid-liquid mixture after the first stirring crystallization to 0-10℃, and carrying out second stirring crystallization, to obtain pure moxifloxacin hydrochloride.

[0056] The present application uses acetic acid as solvent, and the obtained mixture is mixed with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (referred to as ring-closed ester) at 90-110°C, preferably at 95-10°C, to carry out chelation reaction, and obtain intermediate chelate. In the present application, the mixing method is preferably as follows: under stirring, boric acid is added into acetic acid, and the temperature is controlled at 90-110°C, acetic anhydride is added dropwise, and then ring-closed ester is added to carry out chelation reaction.

[0057] In the present application, the mass ratio of ring-closed ester to boric acid and acetic anhydride is preferably 1:(0.25-0.35):(1.7-1.8), and more preferably 1:0.29:1.74. In the present application, the mass ratio of ring-closed ester to acetic acid is preferably 1:0.6-0.7, and more preferably 1:0.65. In the present application, the temperature of chelation reaction is preferably 90-100°C, and more preferably 95°C, and the time is 2-3h, and more preferably 2.5h.

[0058] After the chelation reaction, the present application preferably carries out post-treatment on the obtained chelation reaction liquid, and the post-treatment preferably comprises the following steps:

[0059] After the chelation reaction liquid is cooled to 40-50°C, it is mixed with ice water to carry out crystallization, and obtain solid product;

[0060] The solid product is sequentially washed and dried to obtain pure intermediate chelate.

[0061] In the present application, the mass of ice water is 5-8 times, preferably 6-7 times the mass of ring-closed ester. In the present application, the temperature of crystallization is preferably 0-5°C, and more preferably 2-4°C, and the time is preferably 1-2h, and more preferably 1.5h. After the crystallization, the present application preferably carries out centrifugation on the liquid after crystallization to obtain solid product.

[0062] In the present application, the washing agent for washing is preferably cold water at 0-5°C. The present application washes the solid product to neutral by the washing. In the present application, the drying is preferably air-drying at 70°C, and the water content of the obtained intermediate chelate after drying is preferably ≤5%.

[0063] After obtaining the intermediate chelate, the present application mixes the intermediate chelate with (4aS,7aS)-octahydro-lH-pyrrolo[3,4-b]pyridine (abbreviated as moxy small ring) in methanol to perform condensation reaction, obtaining moxy chelate-methanol solution. In the present application, the mixing method is preferably adding the intermediate chelate into methanol and adding the moxy small ring dropwise. In the present application, the mass ratio of the intermediate chelate to the moxy small ring is preferably 1:0.3-0.4, more preferably 1:0.3-0.35; the mass ratio of the intermediate chelate to methanol is preferably 1:3-5, more preferably 1:3-4.

[0064] In the present application, the condensation reaction is preferably performed at a temperature of 50-60°C, more preferably 55°C, for 6-8h, more preferably 7h.

[0065] After the condensation reaction, the obtained condensation reaction solution is a methanol solution of moxy chelate. The present application does not perform post-treatment on the obtained condensation reaction solution, and directly performs the next step.

[0066] After obtaining the moxy chelate-methanol solution, the present application mixes the moxy chelate-methanol solution with concentrated hydrochloric acid to perform cooling crystallization, obtaining crude moxifloxacin hydrochloride, i.e. borate-containing moxifloxacin hydrochloride. In the present application, the mass concentration of the concentrated hydrochloric acid is preferably 36-38%, more preferably 37%. In the present application, the mixing method is preferably stirring mixing, and the temperature of the moxy chelate-methanol solution during the mixing is preferably 20-30°C, more preferably 25°C. In the present application, the pH value of the mixture of the moxy chelate-methanol solution and the concentrated hydrochloric acid is preferably 1-2.

[0067] In the present application, the cooling crystallization is preferably performed at a temperature of 0-10°C, more preferably 2-8°C, for 2-4h, more preferably 3h. In the present application, the cooling crystallization is preferably performed under stirring, and the stirring speed is preferably 100-300rpm, more preferably 200rpm. After cooling, the present application preferably performs centrifugation on the liquid after the cooling crystallization to obtain borate-containing moxifloxacin hydrochloride solid.

[0068] After obtaining the crude moxifloxacin hydrochloride, the present application performs boron removal reaction according to the above boron removal method to obtain a salting reaction solution, and then performs first stirring crystallization by first cooling the salting reaction solution to 60-80°C; and then performs second stirring crystallization by second cooling to 0-10°C, obtaining pure moxifloxacin hydrochloride. Since the boron removal method is the same, it will not be described here.

[0069] The first cooling of the salt formation reaction liquid is to 60-80°C, preferably to 70°C, and the first stirring crystallization is performed. In the present application, the time of the first stirring crystallization is preferably 0.5-1h, more preferably 0.6-0.8h, and the stirring speed is preferably 100-300rpm, more preferably 200rpm.

[0070] The liquid after the first stirring crystallization is cooled to 0-10°C, more preferably 2-8h, and the second stirring crystallization is performed. In the present application, the time of the second stirring crystallization is preferably 2-3h, more preferably 2.5h, and the stirring speed is preferably 100-300rpm, more preferably 200rpm.

[0071] After the second stirring crystallization, the second stirring crystallization liquid obtained is preferably subjected to post-treatment, and the post-treatment preferably comprises the following steps:

[0072] The second stirring crystallization liquid is subjected to centrifugation, washing of the obtained solid, and drying in sequence, and the pure moxifloxacin hydrochloride is obtained. The mode of centrifugation is not particularly required in the present application, and the mode of centrifugation well known to those skilled in the art can be used. In the present application, the washing agent is preferably purified water; in the present application, the drying mode is preferably air drying, and the drying temperature is preferably 50-60°C, more preferably 55°C; and the time is preferably 6-8h, more preferably 7h.

[0073] In the present application, the preparation flow chart of the moxifloxacin hydrochloride is as shown in Figure 1 .

[0074] The boron removal method of moxifloxacin hydrochloride and the preparation method of the pure moxifloxacin hydrochloride provided by the present application are described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0075] Example 1

[0076] Step one: preparation of chelate

[0077] Into a reaction kettle, 5.20kg of acetic acid was added, and 2.32kg of boric acid was added under stirring. The temperature was increased to 90°C under stirring, and 13.92kg of acetic anhydride was added dropwise to the system while controlling the temperature at 90°C. After the addition was completed, the system was stirred at 110°C for 0.5h, and then the temperature was decreased to 95°C. 8.00kg of cyclic ester was added, and the chelation reaction was performed at 90°C for 2h. After the chelation reaction was completed, the temperature of the system was decreased to 40°C, and the reaction liquid was poured into 48.00kg of ice water. A large amount of solid was precipitated, and the temperature was controlled at 0-5°C. Crystallization was performed for 1h, and then the solid was separated by centrifugation and filtration. The filter cake was washed with 0°C cold water until it was neutral, and then air-dried at 70°C until the water content was less than 5.0%. Thus, 10.35kg of intermediate chelate was obtained, and the yield was 98.8%.

[0078] Step two: preparation of moxifloxacin chelate

[0079] Into the reactor, 40.00 kg of methanol was added, and then 10.00 kg of the intermediate chelate was added under stirring. 3.00 kg of moxifloxacin was added dropwise, and the temperature was controlled not to exceed 60°C. After the dropwise addition was completed, the temperature was controlled at 60°C for 6 h of condensation reaction. The temperature was then lowered to 20°C, and a methanol solution of moxifloxacin chelate was obtained, which was directly used in the next step.

[0080] Step three: preparation of pure moxifloxacin hydrochloride

[0081] The methanol solution of moxifloxacin chelate was controlled at a temperature of 20°C, and concentrated hydrochloric acid was added dropwise under stirring. The pH was adjusted to 1, and then the temperature was lowered to 5°C. The product was stirred for 3 h of crystallization. The product was centrifuged and filtered. The filter cake was added to the reactor, and 80.00 kg of purified water was added. Under stirring, 20% sodium hydroxide aqueous solution was added dropwise, and the pH was adjusted to 8. 0.10 kg of LSC-800 resin was added, and the temperature was controlled at 20°C. The product was stirred for 1 h of adsorption to remove boric acid. The product was filtered, and the filtrate was adjusted to pH 1 with concentrated hydrochloric acid. The temperature was raised to 90°C to obtain a water solution of moxifloxacin hydrochloride. The product was filtered, and the filtrate was first cooled to 70°C, and then stirred for 0.5 h of crystallization. The temperature was then lowered to 5°C, and the product was stirred for 2.5 h of crystallization. The product was centrifuged and filtered. Purified water was used for washing, and the filter cake was dried at 50°C for 6 h of air blowing. 7.24 kg of pure moxifloxacin hydrochloride was obtained, with a total yield of 69.1% and a purity of 99.95%.

[0082] The obtained product was moxifloxacin hydrochloride. 1 The H-NMR spectrum of the obtained product is shown in Figure 2 As can be seen, the obtained product was moxifloxacin hydrochloride. Figure 2

[0083] The obtained product was moxifloxacin hydrochloride. 13 The C-NMR spectrum of the obtained product is shown in Figure 3 As can be seen, the obtained product was moxifloxacin hydrochloride. Figure 3

[0084] The content of boric acid in the obtained product was detected by ICP-MS. No boric acid was detected in the product.

[0085] Example 2

[0086] Step one: preparation of chelate

[0087] ​​Into a reactor, add acetic acid 4.80 kg, add boric acid 2.00 kg under stirring, heat up to 90 °C under stirring, and control the temperature at 100 °C. Add acetic anhydride 13.60 kg dropwise into the system. After the addition, keep the temperature at 115 °C and stir for 0.5 h. Then, cool down to 95 °C, add the cyclization ester 8.00 kg, and keep the temperature at 95 °C for 2.5 h. After the reaction is completed, cool down the liquid to 45 °C, pour the reaction liquid into 40.00 kg of ice water, and precipitate a large amount of solid. Control the temperature at 2 °C, and crystallize for 1.5 h. Centrifugal filtration, and wash the filter cake with cold water at 2 °C until neutral. Dry at 70 °C to obtain the intermediate chelate 10.20 kg, with a yield of 97.4%.

[0088] Step two: preparation of moxifloxacin chelate

[0089] Into a reactor, add methanol 30.00 kg, and add the intermediate chelate 10.00 kg under stirring. Add moxifloxacin small ring 4.00 kg dropwise, control the temperature at no more than 60 °C, and after the dropwise addition, control the temperature at 55 °C for 7 h. Cool down to 25 °C to obtain a methanol solution of moxifloxacin chelate, which is directly used in the next step.

[0090] Step three: preparation of moxifloxacin hydrochloride

[0091] Add concentrated hydrochloric acid dropwise into the methanol solution of moxifloxacin chelate under stirring, control the temperature at 25 °C, and adjust the pH to 1.5. Then, cool down to 5 °C, and stir for 3 h. Centrifugal filtration. Add the filter cake into a reactor, and add purified water 60.00 kg. Add 10% sodium hydroxide aqueous solution dropwise under stirring, adjust the pH to 9, add LSC-800 resin 0.10 kg, control the temperature at 25 °C, and adsorb the boric acid for 2 h. Filter, and adjust the pH of the filtrate to 1.5 with concentrated hydrochloric acid. Heat up to 95 °C to obtain a moxifloxacin hydrochloride aqueous solution. Filter, cool down to 70 °C first, stir for 0.8 h, then cool down to 5 °C, stir for 2.5 h, centrifugal filtration, and wash with purified water. Dry the filter cake at 55 °C for 7 h to obtain moxifloxacin hydrochloride 7.19 kg, with a total yield of 67.7% and a purity of 99.92%.

[0092] The boric acid content in the obtained product is detected. The product is detected to be free of boric acid.

[0093] Example 3

[0094] Step one: preparation of chelate

[0095] Into a reactor, add acetic acid 5.60 kg, add boric acid 2.80 kg under stirring, heat to 90℃ under stirring, and control the temperature at 110℃. Add acetic anhydride 14.40 kg dropwise into the system, after completion of the addition, keep the temperature at 120℃ and stir for 0.5 h, then cool to 95℃, add the cyclization ester 8.00 kg, keep the temperature at 100℃ and react for 3 h. After completion of the reaction, cool the reaction liquid to 50℃, pour the reaction liquid into 64.00 kg of ice water, a large amount of solid is precipitated, control the temperature at 5℃, and crystallize for 2 h. Centrifugal filtration is performed, the filter cake is washed with cold water at 5℃ until neutral, and then dried at 70℃ to obtain 10.22 kg of intermediate chelate, with a yield of 97.6%.

[0096] Step two: preparation of moxifloxacin chelate

[0097] Into a reactor, add methanol 50.00 kg, add the intermediate chelate 10.00 kg under stirring, and add moxifloxacin small ring 3.00 kg dropwise, control the temperature at not more than 60℃, after completion of the addition, control the temperature at 60℃ and react for 8 h, and then cool to 30℃ to obtain a methanol solution of moxifloxacin chelate, which is directly used in the next step.

[0098] Step three: preparation of moxifloxacin hydrochloride

[0099] The methanol solution of moxifloxacin chelate is controlled at 30℃, and concentrated hydrochloric acid is added dropwise under stirring to adjust the pH to 2, and then cooled to 10℃, and stirred for crystallization for 4 h. Centrifugal filtration is performed. The filter cake is added into a reactor, and then purified water 100.00 kg is added, and 30% sodium hydroxide aqueous solution is added dropwise under stirring to adjust the pH to 10, and LSC-800 resin 0.50 kg is added, and the temperature is controlled at 20℃, and stirring adsorption is performed for 4 h to remove boric acid, and then filtered, and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid, and then heated to 100℃ to obtain a moxifloxacin hydrochloride aqueous solution, which is filtered, and then cooled to 80℃, and stirred for crystallization for 1 h, and then cooled to 10℃, and stirred for crystallization for 3 h, and then centrifugal filtration is performed, and the filter cake is washed with purified water, and then dried at 60℃ for 8 h to obtain 7.21 kg of pure moxifloxacin hydrochloride, with a total yield of 68.0%, and a purity of 99.93%.

[0100] The boric acid content in the obtained product is detected, and no boric acid is detected in the product.

[0101] Comparative example 1

[0102] Moxifloxacin hydrochloride is prepared by the method of patent CN201410405137.5, as follows:

[0103] In a reactor, 16.00 kg of acetic anhydride was heated to 70°C, 2.40 kg of boric acid was slowly added between 70-90°C, and then the temperature was raised to reflux for 1 h, and then cooled to 70°C, 8.00 kg of cyclic ester was added under stirring, and then the temperature was raised to 100-105°C for 1 h, and then cooled to 0°C, 32 L of ice water was slowly added, and then 48 L of cold water at 0-5°C was added, and then the temperature was kept at 0-5°C for 2 h, and then the product was precipitated, filtered, washed with 40 L of water, and then vacuum dried at 40°C until the moisture was 2%, and then 10.05 kg of intermediate chelate was obtained.

[0104] In a reactor, 10.00 kg of intermediate chelate, 39.6 kg of acetonitrile, 3.14 kg of moxifloxacin small ring, and 2.40 kg of triethylamine were added, and then the temperature was controlled at 50°C for 4 h; after the reaction was completed, the temperature was kept at 50°C, and then vacuum reduced pressure concentration was performed, and then acetonitrile was recovered; after the concentration was completed, 40.00 kg of anhydrous ethanol was added to the concentrated residue, and then stirred and dissolved, and then 12 mol / L of hydrochloric acid was added dropwise to the solution at 25°C, and then the pH was adjusted to 1 while stirring, and then the temperature was kept at 1 h; the temperature was lowered to 5°C, and then the crystal was maintained for 2 h; after the crystal was maintained, it was filtered, and then washed twice with 10.00 kg of 95% ethanol; and then vacuum dried at 60°C until the moisture was 2.6%, and then 8.15 kg of moxifloxacin hydrochloride was obtained; after refined with 10 times of 80% ethanol aqueous solution, 6.92 kg of moxifloxacin hydrochloride was obtained, the total yield was 63.8%, and the purity was 99.80%.

[0105] The boric acid content in the obtained product was detected, and the detection showed that the boric acid content in the product was 114 ppm.

[0106] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for removing boron from moxifloxacin hydrochloride, comprising the following steps: (1) mixing moxifloxacin hydrochloride crude product with water, adjusting the pH value of the mixture to 8-10, adding LSC-800 resin to remove boron, and obtaining a boron removal reaction solution, wherein the moxifloxacin hydrochloride crude product contains impurity boric acid; (2) mixing the boron removal reaction solution with hydrochloric acid to perform a salting reaction, and obtaining moxifloxacin hydrochloride pure product. The mass ratio of the moxifloxacin hydrochloride crude product to water is 1: 6-10. The mass ratio of the moxifloxacin hydrochloride crude product to LSC-800 resin is 1: 0.01-0.

05.

2. The method of claim 1, wherein, The temperature of the boron removal reaction is 10-40℃, and the time is 1-4h.

3. The method of claim 1, wherein the boron removal is characterized by, 5.A method for preparing moxifloxacin hydrochloride pure product, comprising the following steps: (a) mixing boric acid and acetic anhydride in acetic acid as a solvent at 90-110℃, mixing the obtained mixture with 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester to perform a chelation reaction, and obtaining an intermediate chelate; (b) mixing the intermediate chelate with (4aS, 7aS) -octahydro-1H-pyrrolo [3, 4-b] pyridine in methanol as a solvent to perform a condensation reaction, and obtaining moxifloxacin chelate-methanol solution; (c) mixing the moxifloxacin chelate-methanol solution with concentrated hydrochloric acid, and performing cooling crystallization to obtain moxifloxacin hydrochloride crude product; (d) performing boron removal reaction according to the method for removing boron from moxifloxacin hydrochloride according to any one of claims 1-4 to obtain a salting reaction solution; (e) cooling the salting reaction solution to 60-80℃ for the first time to perform the first stirring crystallization, and then cooling the solid-liquid mixture after the first stirring crystallization to 0-10℃ for the second time to perform the second stirring crystallization, and obtaining moxifloxacin hydrochloride pure product; wherein, the specific structural formula is as follows:

4. The method of claim 1 or 3, wherein the boron removal method is characterized by, ​ ​ ​ ​ ​ ​ ​ ​

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