CN111233858B - Preparation method of moxifloxacin hydrochloride - Google Patents
Preparation method of moxifloxacin hydrochloride Download PDFInfo
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- CN111233858B CN111233858B CN202010209796.7A CN202010209796A CN111233858B CN 111233858 B CN111233858 B CN 111233858B CN 202010209796 A CN202010209796 A CN 202010209796A CN 111233858 B CN111233858 B CN 111233858B
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Abstract
The invention discloses a preparation method of moxifloxacin hydrochloride, which comprises the following steps: preparing 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4-boron diacetate; ② 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate ester with (S, S) -2, 8-diazabicyclo [4.3.0]]Condensing nonane in a solvent in the presence of an acid-binding agent to obtain a borane condensate, removing the solvent, dissolving the borane condensate in water, adding hydrochloric acid to form a salt, and crystallizing to obtain moxifloxacin hydrochloride. According to the preparation method, the borane condensation compound is dissolved in water and hydrochloric acid is added to form salt and crystallize, genotoxic impurities of methyl chloride and ethyl chloride are not generated, and an impurity C is not generated, so that the moxifloxacin hydrochloride prepared by the method is high in purity and low in risk.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of moxifloxacin hydrochloride.
Background
Moxifloxacin hydrochloride (Moxifloxacin hydrochloride) is a fourth generation fluoroquinolone antibiotic developed by bayer company, germany, with the chemical name 1-cyclopropyl-6-fluoro-7- ([ S, S ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl) -8-methoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, trade name: avelox.
The moxifloxacin hydrochloride is a broad-spectrum antibiotic, has antibacterial activity on gram-negative bacteria, gram-positive cocci, mycoplasma, chlamydia, anaerobe and the like, and is clinically applied to treating socially acquired pneumonia, acute attack of chronic bronchitis, acute sinusitis and the like caused by staphylococcus aureus, influenza bacillus, pneumococcus, mucositis moraxella, pneumonia bacillus and the like. The moxifloxacin hydrochloride has the advantages of high efficiency, low toxicity, low-level drug resistance, almost no obvious phototoxicity and the like, and is one of fluoroquinolone antibiotics with more clinical applications.
The synthesis methods of moxifloxacin hydrochloride reported in the existing literature mainly comprise the following steps:
the european patent EP0550903 discloses a synthetic route:
the route is straightforward, but competitive substitution of C6-F with C7-F tends to produce C6-F substituted by-products, affecting product yield and purity.
The patent WO2005012285 discloses a synthetic route as follows:
chinese patents CN103012452, CN102276603, CN102952131, CN104230924 and CN102731496 are all schemes obtained by improvement on the basis of WO 2005012285.
CN103012452 mentions that the borane condensation compound is deprotected by inorganic alkaline water, then extracted by toluene, the pH of the water phase is adjusted to 7.0-8.5 by hydrochloric acid, then extracted by halogenated alkane, and the halogenated alkane is recovered to obtain free base moxifloxacin. The method has more complicated steps, and toluene is used for extraction, and the toluene belongs to 3 kinds of carcinogens, has higher risk and is not beneficial to environmental protection.
CN102276603, CN102952131, CN104230924, CN102731496 and WO2005012285 dissolve borane condensates with methanol or ethanol and then concentrate HCl to form salts, which runs the risk of generating genotoxic impurities methyl chloride, ethyl chloride, which are mutagenic impurities of class 1 with positive carcinogenic data, and are explicitly indicated and specified in the ICH M7 appendix for their specific acceptable uptake. In addition, direct crystallization in ethanol may also produce impurity C.
Disclosure of Invention
The invention aims to solve the technical problems that the existing preparation process of moxifloxacin hydrochloride can generate genotoxic impurities, has multiple steps and is low in purity, and provides the preparation method of moxifloxacin hydrochloride with simple steps and high product purity.
The technical scheme for realizing the aim of the invention is a preparation method of moxifloxacin hydrochloride, which comprises the following steps:
preparation of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate.
② 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate ester with (S, S) -2, 8-diazabicyclo [4.3.0 ] ]Condensation reaction of nonane in solvent in the presence of acid binding agent to obtain borane condensate, removing solvent, dissolving borane condensate in water, adding hydrochloric acid to form salt, and crystallizing to obtain moxifloxacin hydrochloride.
Step I, preparing 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4When boron diacetate is used, firstly, reacting acetic anhydride with boric acid at the temperature of 80-90 ℃ for 1-2 h in a heat preservation way, then adding 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester under stirring, and reacting for 1-2 h at the temperature of 100-110 ℃; cooling the reacted materials to 10-20 ℃, precipitating crystals, adding water with the temperature of 10-20 ℃ for pulping for 1h, then filtering, washing the crystals, and drying in vacuum to obtain 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4-boron diacetate crystals.
Boric acid, acetic anhydride and 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester, wherein the weight ratio of (0.2-0.25) to (1.5-2.0) is 1.
In the step (II), the solvent is acetonitrile or dichloromethane.
In the step (II), the acid-binding agent is one or a composition of more than one of triethylamine, N-methylimidazole, pyridine, sodium carbonate and N, N-diisopropylethylamine.
Step (c), 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate: (S, S) -2, 8-diazabicyclo [4.3.0]Nonane: the molar ratio of the acid-binding agent is 1 (1.0-1.3): (0.9-1.3).
In the second step, the condensation reaction temperature is 25-50 ℃.
Preferably, in the step (II), the condensation reaction temperature is 38 to 42 ℃.
Dissolving a borane condensation compound in water, adding hydrochloric acid to form salt and crystallize, dissolving the borane condensation compound in water, adding hydrochloric acid to adjust the pH value to 2.0-3.0, stirring and crystallizing at 0-30 ℃ for 0.5-1.5 h, and deprotecting; then adding hydrochloric acid to adjust the pH value to 1.0-2.0, and crystallizing at 0-30 ℃ for 0.5-1.5 h to form salt.
In the second step, when the borane condensation compound is dissolved in water, the mass ratio of the water to the borane condensation compound is (5-10): 1.
The invention has the positive effects that:
(1) according to the preparation method, the borane condensation compound is dissolved in water and hydrochloric acid is added to form salt and crystallize, genotoxic impurities of methyl chloride and ethyl chloride cannot be generated, and due to the fact that salt and crystallization are not carried out in ethanol, impurity C cannot be generated, the moxifloxacin hydrochloride prepared by the method is high in purity and low in risk, and the purity of the moxifloxacin hydrochloride detected by HPLC reaches 99.97%.
(2) The preparation method has simple route, simplifies the refining and purifying process, and does not need recrystallization; and the clarity of the primary crystallization is less than that of No. 0.5 turbidity liquid, and the clarity result is good.
By contrast, the inventors found that the final product has a clarity between 0.5 and 1 turbidity by repeating the recrystallization experiments of CN104031043, CN102731496 and CN 103172629.
Drawings
FIG. 1 is an HPLC chromatogram of moxifloxacin hydrochloride prepared by the method of the invention.
FIG. 2 is the NMR H spectrum of moxifloxacin hydrochloride prepared in example 1.
FIG. 3 is the NMR spectrum C of moxifloxacin hydrochloride prepared in example 1.
FIG. 4 is an IR detection spectrum of moxifloxacin hydrochloride prepared in example 1.
Detailed Description
(example 1)
The reaction route of the preparation method of moxifloxacin hydrochloride in the embodiment is as follows:
the preparation method of moxifloxacin hydrochloride of the embodiment comprises the following steps:
preparing 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate of the formula:
adding 320g of acetic anhydride and 40g of boric acid into a 2L reaction bottle, stirring to dissolve the materials, heating to 80 ℃ for reaction, and keeping the temperature at 80 ℃ and stirring for reaction for 1 h.
After the reaction of acetic anhydride and boric acid is finished, 200g of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester is added into a reaction bottle under stirring, the temperature is raised to 100 ℃, and the reaction is carried out for 2h at 100 ℃.
After the reaction is finished, quickly cooling the reaction solution to 10-20 ℃, precipitating crystals, and adding cold water at 10-20 ℃ for pulping for 1 hour;pulping, performing suction filtration, washing crystals with cold water at 10-20 ℃, and then performing vacuum drying for 4-6 h at 40-45 ℃ to obtain 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4256g of boron diacetate crystals (for later use), the molar yield of the crystals is 98 percent, and the purity of the crystals is 99.83 percent.
② 150g of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4-boron diacetate into a 2L reaction flask and 750mL acetonitrile to 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4After the boron diacetate had dissolved, 35.9g of triethylamine as an acid-binding agent and 44.7g of (S, S) -2, 8-diazabicyclo [4.3.0 ] were added to the reaction flask]Heating nonane to 40 ℃ for condensation reaction for 2 h.
The acid-binding agent can be triethylamine, N-methylimidazole, pyridine, sodium carbonate and N, N-diisopropylethylamine which are used as the acid-binding agent; therefore, the acid-binding agent is one or a composition of more than one of triethylamine, N-methylimidazole, pyridine, sodium carbonate and N, N-diisopropylethylamine.
And after the reaction is finished, concentrating the reacted materials under reduced pressure until no liquid drops are generated, and removing the solvent to obtain the borane condensation compound.
Adding 1L of water into a borane condensation product, stirring to completely dissolve the borane condensation product, dropwise adding 36-38% concentrated hydrochloric acid (30-35 mL in the embodiment) after dissolution, adjusting the pH of the borane condensation product solution to 2.0-3.0, and stirring to crystallize at 0-30 ℃ (8 ℃ in the embodiment) for 0.5-1.5 h h (1 h in the embodiment) for deprotection.
Then adding 5-10 mL of 36-38% concentrated hydrochloric acid to adjust the pH value to 1.0-2.0, and crystallizing at 0-30 ℃ (8 ℃ in the embodiment) for 0.5-1.5 h (1 h in the embodiment) for salt formation; after salification, suction filtration, washing and drying are carried out, and 129g of moxifloxacin hydrochloride crystals are obtained, the molar yield is 80%, and the purity is 99.97% through HPLC (high performance liquid chromatography) detection (figure 1).
The nuclear magnetic resonance H spectrogram and the nuclear magnetic resonance C spectrogram of the moxifloxacin hydrochloride prepared in the embodiment are shown in the figure 2 and the figure 3 respectively, and the IR detection spectrogram is shown in the figure 4 respectively, and the comparison with the standard spectrogram proves that the moxifloxacin hydrochloride prepared by the method provided by the invention.
(example 2)
The preparation method of moxifloxacin hydrochloride in the embodiment is the same as the embodiment 1 except that:
step I, preparing 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O 3，O4When the boric diacetate is boric ester diacetate, 558g of acetic anhydride and 70g of boric acid are added into a 3L reaction bottle, stirred and dissolved, heated to 90 ℃ for reaction, stirred at 90 ℃ and kept for reaction for 1 hour.
After the reaction of acetic anhydride and boric acid is finished, 300g of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester is added into a reaction bottle under stirring, and the mixture is heated to 110 ℃ for reaction for 2 h.
After the reaction is finished, quickly cooling the reaction solution to 10-20 ℃, precipitating crystals, and adding cold water at 10-20 ℃ for pulping for 1 hour; pulping, filtering, washing the crystal with cold water at 10-20 ℃, and vacuum drying to obtain 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4388g of boron diacetate crystals, 99 percent of molar yield and 99.79 percent of purity.
(example 3)
The preparation method of moxifloxacin hydrochloride in the embodiment is the same as the embodiment 1 except that:
in step (II), 200g of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate (N-O) -was charged into a 2L reaction flask, 1000mL of methylene chloride was added, and after it was dissolved, 52.6g of triethylamine and 65.6g of (S, S) -2, 8-diazabicyclo [4.3.0 ] were added ]Heating nonane to 38 ℃ for condensation reaction for 2 h.
After the reaction is finished, concentrating under reduced pressure until no liquid drops are generated, adding 1L of purified water into a borane condensation compound, stirring for dissolving, dropwise adding hydrochloric acid, adjusting the pH value to 2.0-3.0, stirring for crystallization at 10 ℃ for 1h for deprotection, adding hydrochloric acid for adjusting the pH value to 1.0-2.0, crystallizing at 10 ℃ for 1h to form salts, performing suction filtration, washing and drying to obtain 175g of moxifloxacin hydrochloride crystals, wherein the molar yield is 81%, and the purity is 99.95%.
(test examples, Crystal clarity comparison)
Comparative example: the 99.7% crude moxifloxacin hydrochloride is recrystallized in ethanol water solution and methanol water solution, and the clarity of the product is detected (the recrystallization method is carried out according to the method of CN 102731496 in example 11).
Test example: in the embodiment 1, 36 to 38 percent of concentrated hydrochloric acid and hydrochloric acid are added to adjust the pH value to 1.0 to 2.0, and the mixture is crystallized at the temperature of 8 ℃ to form the salt with clarity after 1 hour.
The test results are as follows:
| crystallization solvent | Clarity results |
| 75% ethanol aqueous solution | No. 0.5-No. 1 |
| 60% ethanol aqueous solution | No. 0.5-No. 1 turbidity liquid |
| 65% aqueous methanol solution | No. 0.5-No. 1 turbidity liquid |
| 75% aqueous methanol solution | No. 0.5-No. 1 turbidity liquid |
| Aqueous solution | Turbidity solution < 0.5% |
Compared with the preparation process adopting recrystallization in the prior art, the method does not need recrystallization, the clarity of the primary crystallization is less than 0.5 turbidity solution, and the clarity result is better.
Claims (10)
1. The preparation method of moxifloxacin hydrochloride is characterized by comprising the following steps:
preparation of 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4-boron diacetate;
② 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate ester with (S, S) -2, 8-diazabicyclo [4.3.0 ]]Condensing nonane in a solvent in the presence of an acid-binding agent to obtain a borane condensate, removing the solvent, dissolving the borane condensate in water, adding hydrochloric acid to form a salt, and crystallizing to obtain moxifloxacin hydrochloride.
2. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: step I, preparing 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4When boron diacetate is used, firstly, reacting acetic anhydride with boric acid at the temperature of 80-90 ℃ for 1-2 h in a heat preservation way, then adding 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester under stirring, and reacting for 1-2 h at the temperature of 100-110 ℃; cooling the reacted materials to 10-20 ℃, precipitating crystals, adding water with the temperature of 10-20 ℃ for pulping for 1h, then filtering, washing the crystals, and drying in vacuum to obtain 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O 3，O4-boron diacetate crystals.
3. The method for preparing moxifloxacin hydrochloride according to claim 2, characterized in that: boric acid, acetic anhydride and 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-quinolinecarboxylic acid ethyl ester, wherein the weight ratio of (0.2-0.25) to (1.5-2.0) is 1.
4. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: in the step (II), the solvent is acetonitrile or dichloromethane.
5. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: in the step (II), the acid-binding agent is one or a composition of more than one of triethylamine, N-methylimidazole, pyridine, sodium carbonate and N, N-diisopropylethylamine.
6. The method for preparing moxifloxacin hydrochloride according to claim 5, characterized in that: step (c), 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O3，O4Boron diacetate: (S, S) -2, 8-diazabicyclo [4.3.0]Nonane: the molar ratio of the acid-binding agent is 1 (1.0-1.3): (0.9-1.3).
7. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: in the second step, the condensation reaction temperature is 25-50 ℃.
8. The method for preparing moxifloxacin hydrochloride according to claim 7, characterized in that: in the second step, the condensation reaction temperature is 38-42 ℃.
9. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: dissolving a borane condensation compound in water, adding hydrochloric acid to form salt and crystallize, dissolving the borane condensation compound in water, adding hydrochloric acid to adjust the pH value to 2.0-3.0, stirring and crystallizing at 0-30 ℃ for 0.5-1.5 h, and deprotecting; then adding hydrochloric acid to adjust the pH value to 1.0-2.0, and crystallizing at 0-30 ℃ for 0.5-1.5 h to form salt.
10. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that: in the second step, when the borane condensation compound is dissolved in water, the mass ratio of the water to the borane condensation compound is (5-10): 1.
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Citations (4)
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|---|---|---|---|---|
| CN1059527A (en) * | 1990-07-06 | 1992-03-18 | 杏林制药株式会社 | (6,7-substituted-8-alkoxy base-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid-O 3,-O 4) two (boric acid ester of acyloxy-O) and salt thereof and their preparation methods |
| CN102617622A (en) * | 2011-01-31 | 2012-08-01 | 深圳信立泰药业股份有限公司 | Method for preparing moxifloxacin or its medicinal salt and its intermediate |
| CN102952131A (en) * | 2011-08-29 | 2013-03-06 | 成都国为医药科技有限公司 | Preparation method of moxifloxacin hydrochloride |
| CN108276402A (en) * | 2018-02-13 | 2018-07-13 | 北京博全健医药科技有限公司 | A kind of preparation method of moxifloxacin hydrochloride |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059527A (en) * | 1990-07-06 | 1992-03-18 | 杏林制药株式会社 | (6,7-substituted-8-alkoxy base-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid-O 3,-O 4) two (boric acid ester of acyloxy-O) and salt thereof and their preparation methods |
| CN102617622A (en) * | 2011-01-31 | 2012-08-01 | 深圳信立泰药业股份有限公司 | Method for preparing moxifloxacin or its medicinal salt and its intermediate |
| CN102952131A (en) * | 2011-08-29 | 2013-03-06 | 成都国为医药科技有限公司 | Preparation method of moxifloxacin hydrochloride |
| CN108276402A (en) * | 2018-02-13 | 2018-07-13 | 北京博全健医药科技有限公司 | A kind of preparation method of moxifloxacin hydrochloride |
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