CN114539244B - Preparation method of moxifloxacin hydrochloride - Google Patents
Preparation method of moxifloxacin hydrochloride Download PDFInfo
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- CN114539244B CN114539244B CN202011292878.9A CN202011292878A CN114539244B CN 114539244 B CN114539244 B CN 114539244B CN 202011292878 A CN202011292878 A CN 202011292878A CN 114539244 B CN114539244 B CN 114539244B
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a moxifloxacin hydrochlorideThe preparation method of (1). The preparation method comprises the following steps: 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid is used as a raw material, a tungsten reagent is used as a chelating agent, and a tungsten chelate is formed under heating, the chelate does not need to be separated, and a side chain S, S-2, 8-diazabicyclo [4,3,0] is directly added]Nonane and Et 3 And N, recrystallizing the aqueous solution of the alcohol, and salifying the hydrochloric acid to obtain the final product moxifloxacin hydrochloride. The method has the advantages of cheap and easily obtained raw materials and simple operation, and is more suitable for industrial production.
Description
The technical field is as follows:
the invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel preparation method of moxifloxacin hydrochloride.
Background art:
moxifloxacin hydrochloride (Moxifloxacin hydrochloride) is a novel 8-methoxy quinolone antibacterial drug with the chemical name of 1-cyclopropyl-7- { S, S-2, 8-diazabicyclo [4.3.0] nonane-8- } -6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinoline carboxylate and the structural formula as follows:
moxifloxacin hydrochloride is a quinolone drug developed by bayer company in Germany, is marketed in Germany in 9 months in 1999, is marketed in the United states in 12 months in the same year, is approved to be marketed in China in 2002, and has the trade name of bayfule. The traditional Chinese medicine composition is mainly used for Community Acquired Pneumonia (CAP), acute attack of chronic bronchitis, urogenital infection, acute sinusitis and the like in clinic. Moxifloxacin has the advantages of wide antibacterial spectrum, strong antibacterial activity, difficulty in generating drug resistance, excellent pharmacokinetic property and the like, and the clinical application of moxifloxacin is gradually increased.
Synthesizing moxifloxacin hydrochloride by firstly preparing mother nucleus C 7 Position and branching (S, S) -2, 8-diazabicyclo [4.3.0]]And (3) carrying out nucleophilic substitution reaction on nonane to generate moxifloxacin, and salifying to obtain the final product moxifloxacin hydrochloride. For side chain-linked reactions, C is present during the reaction 7 -F and C 6 Competitive substitution of-F, and parent nucleus C 8 The strong electron-pushing effect of the methoxy group reduces C 7 The leaving activity of the F is to generate a by-product of C-6 position isomer, the physical and chemical properties of the by-product are similar to those of moxifloxacin, the by-product is difficult to separate, and the yield is reduced.
Currently, the synthesis of moxifloxacin hydrochloride mainly comprises the following process routes:
the synthesis method of moxifloxacin hydrochloride disclosed in European patent EP550903 "Quinolone and naphthyridino carboxylic acid derivatives as antibacterial agents" is as follows:
under the condition that triethylamine is used as alkali, the mother nucleus and the side chain of moxifloxacin are directly condensed. The advantage of this route is that it is straightforward; disadvantages are that it is difficult to control competitive substitution of C6-F with C7-F, formation of C6 by-products, difficult separation, and reduced yield.
(II) patent EP0464823A1 (6,7-substitated-8-alkoxy-1-cyclopropy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids-O 3 ,O 4 ) The synthesis of moxifloxacin hydrochloride disclosed in bis (acyl-O) borate, and the salts therof, and methods for the same manufacture, and US20060264635 Process for preparation of moxifloxacin hydrochloride, is as follows:
boric acid and acetic anhydride first form B (OAc) 3 ，B(OAc) 3 Forming chelate with mother nucleus of moxifloxacin, and reacting chelate with (S, S) -2, 8-diazabicyclo [4,3,0]Nonane in triethylamineNucleophilic substitution in the presence, treating with sodium hydroxide and acetic acid to obtain moxifloxacin hydrochloride, and adding hydrochloric acid to obtain moxifloxacin hydrochloride. This route can avoid competitive substitution at the C-6 position, but is complicated to operate, requiring the use of a chelate, and then requiring de-chelation after attachment of the side chain. In WO2008059223, the exchange of acetic anhydride for propionic anhydride to form the corresponding chelating agent can also avoid the by-product of the C-6 positional isomer, but the formation and the chelation are still required. The operation is complicated.
(III) the synthesis Method of moxifloxacin hydrochloride disclosed in EP1832587 for promoting moxifloxacin and moxifloxacin hydrochloride is similar to the Method (II) described above, and the Method is as follows:
in the patent description, chelation is also formed first, then side chains are attached and then de-chelated, but boron trifluoride is used as a chelating agent. In the literature report, the moxifloxacin hydrochloride is prepared by a one-pot method, and the preparation of moxifloxacin is simplified by controlling the temperature and the feeding sequence. However, the quinolone carboxylic acid fluorine chelate complex is not easy to form, the reaction conditions are harsh, anhydrous and oxygen-free environments are required, the reaction time is long, and the quinolone carboxylic acid fluorine chelate complex is not suitable for industrial production.
In patent CN102351858, a method for synthesizing moxifloxacin with high selectivity discloses a method for synthesizing moxifloxacin hydrochloride, which comprises the following steps:
in the patent, trifluoroacetic anhydride boric acid ester formed by boric anhydride and trifluoroacetic anhydride is used as a chelating agent, and the chelating agent is chelated with a quinolone mother nucleus and then is connected with a side chain. The route has expensive raw materials and long reaction time (26 h), and the chelate needs to be separated and purified and then connected with a side chain, so the operation is complex and the large-scale production is not facilitated.
(V) patent CN103087063 "preparation method of moxifloxacin and salt thereof" discloses a preparation method of moxifloxacin hydrochloride, which comprises the following steps:
the method is similar to the previous routes, and a chelate is formed by using a chelating agent to avoid competitive substitution of the C6 position, and then nucleophilic substitution is carried out with a side chain. The chelating agent of the route adopts triphenyl tin chloride, and the route has the advantages of simple operation, no need of separating intermediate chelate and direct addition of side chain for nucleophilic substitution reaction. The disadvantages of this route are the relatively expensive raw materials and the long reaction times (about 16 h).
The synthetic routes of moxifloxacin have the advantages and the disadvantages, and triethylamine is directly used for connecting the parent nucleus and the side chain of the quinolone, so that a C6-site byproduct exists; the chelating agent can avoid the generation of C6-site by-products, but a chelate must be formed first and then chelated, the experiment operation is complex, and the yield is generally between 60 and 80 percent, even though the literature reports that moxifloxacin is synthesized by a one-pot method (CN 101941969), the chelate does not need to be separated, boric acid and acetic anhydride need to form boric acid ester, then the boric acid ester and a quinolone mother nucleus form the chelate, the reaction time is long (8 h), the acetic anhydride is wasted, the temperature needs to be repeatedly adjusted (80-110-80-rt-83 ℃), the operation is complex, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defect of complex operation in the existing moxifloxacin synthesis process, avoid separation of chelate and de-chelation, simplify experiment operation, and provide the moxifloxacin synthesis process which is simple, mild in reaction condition, simple in post-treatment, low in cost and suitable for industrial production and synthesis routes.
The preparation method of moxifloxacin provided by the invention comprises the following steps:
1) Preparing a chelate: 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid with a chelating agent in an organic solvent to form a chelate of tungsten;
2) Preparation of moxifloxacin hydrochloride: reacting the tungsten chelate obtained in the step 1) with a side chain S, S-2, 8-diazabicyclo [4,3,0] nonane under the action of organic alkali to obtain moxifloxacin, adding hydrochloric acid into the moxifloxacin to form salt, and recrystallizing to obtain the moxifloxacin hydrochloride.
Further, the preparation method of moxifloxacin is as follows:
1) Preparing a chelate: in an organic solvent, under the action of a catalyst of zinc chloride, 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid reacts with a chelating agent to generate a chelate of tungsten;
2) Preparation of moxifloxacin hydrochloride: reacting the tungsten chelate obtained in the step 1) with side chain S, S-2, 8-diazabicyclo [4,3,0] nonane under the action of organic alkali to obtain moxifloxacin, cooling the reaction solution to room temperature, completely evaporating the solvent to dryness, adding an alcohol organic solvent, filtering tungsten mud, adding hydrochloric acid to form salt, and recrystallizing to obtain moxifloxacin hydrochloride.
Wherein the content of the first and second substances,
in the step 1), the organic solvent is one or more of acetonitrile, methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran and N, N-dimethyl sulfoxide; acetonitrile is preferred.
In the step 1), the temperature is 50-120 ℃; more preferably 70-90 deg.c.
In step 1), the reaction time is 1 to 6 hours, more preferably 2 to 3 hours.
In step 1), the selected chelating agent is tungstic acid, tungsten dioxide, tungsten trioxide, sodium tungstate, potassium tungstate, calcium tungstate, cobalt tungstate, cadmium tungstate, ferrous tungstate, ammonium tungstate, zinc tungstate and tungsten carbide, and more preferably sodium tungstate dihydrate.
In step 1), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to chelating agent is 1.
In the step 2), the organic base is triethylamine, N-diisopropylethylamine, cyclohexylamine or diethylamine 、 Pyridine, 4-dimethylamino pyridine, morpholine and/or N-methyl morpholine, preferably triethylamine.
In the step 2), the temperature is 50-120 ℃; more preferably 70-90 deg.c.
In step 2), the reaction time is 0.5 to 6 hours, more preferably 0.5 to 1.5 hours.
In step 2), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to organic base is 1:0.5-1, more preferably 1:1.2; 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid with the side chain S, S-2, 8-diazabicyclo [4,3,0] nonane in a molar ratio of 1; more preferably 1;
in the step 2), the alcohol organic solvent is one or more of methanol, ethanol, propanol and isopropanol, and more preferably ethanol; the recrystallization temperature is 0 to 10 ℃ and preferably 0 ℃.
Taking sodium tungstate dihydrate as an example of the chelating agent, the reaction route of the method is as follows:
the innovation points of the invention are as follows:
1) Compared with the traditional boron chelate, the method takes the tungsten compound as the chelating agent for the first time, forms chelate without separation and purification, directly carries out nucleophilic substitution with a side chain to form moxifloxacin without de-chelating, removes tungsten mud by filtering after salifying with hydrochloric acid, and directly recrystallizes in an alcohol solvent to obtain the final product moxifloxacin hydrochloride, thereby greatly simplifying the operation steps, saving the reaction reagent, shortening the reaction time and saving the manpower.
2) The reaction is a one-pot method for directly synthesizing the moxifloxacin, the solvent and the temperature do not need to be changed, the reaction condition is mild, the operation is easy, the method is green and environment-friendly, the product purity is high, and the yield is high.
Detailed Description
The invention is further illustrated by the following examples:
example 1:
1) Preparing a chelate: to a 1000mL single-neck round-bottom flask was added 300mL of acetonitrile, and 30.0g (101.5 mmol) of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, 66.8g (202.5 mmol) of sodium tungstate dihydrate and 0.7g (5.05 mmol) of zinc chloride were added at room temperature, and the temperature was gradually raised to 83 ℃ and maintained under reflux for 2 hours to obtain a chelate compound.
2) Preparation of moxifloxacin hydrochloride: 19.2mL (152.2 mmol) of S, S-2, 8-diazabicyclo [4,3,0] nonane and 21.1mL (152.2 mmol) of triethylamine were added to the flask at 83 ℃ and the mixture was allowed to reflux for 2.5h. The reaction solution is cooled to room temperature, and the solvent is decompressed and rotary evaporated to obtain a yellow white solid. Ethanol 600ml and 1n HCl were added to adjust pH =1 to 2, and insoluble materials were removed by filtration. Cooling and crystallizing at 0 ℃. And (3) carrying out suction filtration to obtain a yellow solid, washing the filter cake for 2 times by using ethanol, and carrying out vacuum drying on the filter cake to obtain 26g of yellow solid, wherein the yield is 60.5 percent, and the purity is 99.91 percent.
MS(m/z):[M+H] + 402.2,[2M+H] + 803.4.
1 H-NMR(400MHz,DMSO-d 6 )δ:9.89(s,1H),8.77(s,1H),8.67(s,1H),7.70(d,1H,J＝14Hz),4.12-4.17(m,1H),4.05-4.10(m,1H),3.85-3.90(m,2H),3.73-3.78(m,1H),3.59(s,3H),3.58(s,1H),3.20(s,1H),2.90-2.97(m,1H),2.66(s,1H),1.17-1.83(m,4H),1.16-1.24(m,1H),1.08-1.15(m,1H),0.98-1.06(m,1H),0.83-0.90(m,1H).
13 C-NMR(100MHz,DMSO-d 6 )δ:175.95,165.84,153.68,151.20,150.29,140.33,136.72,134.50,117.25,106.37,61.88,54.42,54.02,52.00,41.41,40.63,34.11,20.53,17.53,9.85,8.38.
IR(KBr)/cm -1 :3528.0(ν O-H ),3469.3(ν N-H ),2927.7(ν -CH ),2796.9(ν -CH ),1709.5(ν C＝O ),1623.2(ν C＝C ),1515.7(ν C＝C ),1455.2(δ C-H ),1395.4(δ C-H ),1321.4(ν C-O ),803.4(δ Ar-H ).
Example 2:
1) Preparing a chelate: into a 1000mL single-neck round-bottom flask was added 300mL of acetonitrile, and 30.0g (101.5 mmol) of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, 50.2g (152.2 mmol) of sodium tungstate dihydrate and 0.7g (5.05 mmol) of zinc chloride were added at room temperature, and the mixture was gradually heated to 83 ℃ and kept under reflux for 2 hours to obtain a chelate.
2) Preparation of moxifloxacin hydrochloride: in the above reaction flask, 19.2mL (152.2 mmol) of S, S-2, 8-diazabicyclo [4,3,0] nonane and 21.1mL (152.2 mmol) of triethylamine were added while maintaining 83 ℃ and the reaction was maintained at reflux for 3.5h. The reaction solution is cooled to room temperature, and the solvent is decompressed and rotary evaporated to obtain a yellow white solid. Ethanol 600ml and 1n HCl were added to adjust pH =1 to 2, and insoluble materials were removed by filtration. Cooling and crystallizing at 0 ℃. And (3) carrying out suction filtration to obtain a yellow solid, washing the filter cake for 2 times by using ethanol, and carrying out vacuum drying on the filter cake to obtain 25g of the yellow solid, wherein the purity is 99.90 percent, and the yield is 58.2 percent.
Example 3:
1) Preparing a chelate: to a 1000mL single-neck round-bottom flask was added 300mL of acetonitrile, and 30.0g (101.5 mmol) of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, 66.0g (202.5 mmol) of potassium tungstate, and 0.7g (5.05 mmol) of zinc chloride were added at room temperature, and the mixture was gradually warmed to 83 ℃ and kept under reflux for 2 hours to obtain a chelate.
2) Preparation of moxifloxacin hydrochloride: in the above reaction flask, 19.2mL (152.2 mmol) of S, S-2, 8-diazabicyclo [4,3,0] nonane and 21.1mL (152.2 mmol) of triethylamine were added while maintaining 83 ℃ and the reaction was maintained at reflux for 2.5h. The reaction solution is cooled to room temperature, and the solvent is decompressed and rotary evaporated to obtain a yellow white solid. Ethanol 600ml and 1n HCl were added to adjust pH =1 to 2, and insoluble materials were removed by filtration. Cooling and crystallizing at 0 ℃. And (3) carrying out suction filtration to obtain a yellow solid, washing the filter cake for 2 times by using ethanol, and carrying out vacuum drying on the filter cake to obtain 25.2g of the yellow solid, wherein the purity is 99.91 percent, and the yield is 59.7 percent.
Claims (16)
1. The preparation method of moxifloxacin hydrochloride is characterized by comprising the following steps:
1) Preparing a chelate: 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid with a chelating agent in an organic solvent to form a chelate of tungsten;
2) Preparation of moxifloxacin hydrochloride: under the action of organic alkali, the chelate of tungsten obtained in the step 1) and a side chainS,S-2, 8-diazabicyclo [4,3,0]Nonane reacts to obtain moxifloxacin, hydrochloric acid is added into the moxifloxacin to form salt,recrystallizing to obtain moxifloxacin hydrochloride;
the chelating agent in the step 1) is tungstic acid, tungsten dioxide, tungsten trioxide, sodium tungstate, potassium tungstate, calcium tungstate, cobalt tungstate, cadmium tungstate, ferrous tungstate, ammonium tungstate, zinc tungstate and tungsten carbide;
in the step 1), the selected organic solvent is one or more of acetonitrile, methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran and N, N-dimethyl sulfoxide;
in the step 1), zinc chloride is used as a catalyst;
in the step 2), the organic base is one or more of triethylamine, N-diisopropylethylamine, cyclohexylamine, diethylamine, pyridine, 4-dimethylaminopyridine, morpholine and N-methylmorpholine.
2. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 1), the selected organic solvent is acetonitrile.
3. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that in step 1), the reaction temperature is 50-120 ℃, and the reaction time is 1-6h.
4. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in the step 1), the reaction temperature is 70-90 ℃, and the reaction time is 2-3h.
5. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein the chelating agent in step 1) is sodium tungstate dihydrate.
6. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein, in step 1), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to the chelating agent is 1.
7. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 1), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to chelating agent is 1.
8. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 2), the organic base is triethylamine.
9. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in the step 2), the reaction temperature is 50-120 ℃, and the reaction time is 0.5-6h.
10. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in the step 2), the reaction temperature is 70-90 ℃, and the reaction time is 0.5-1.5h.
11. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 2), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to organic base is 1: 0.5-1; 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acids with side chainsS,S-2, 8-diazabicyclo [4,3,0]The molar ratio of nonane is 1.
12. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 2), the molar ratio of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid to organic base is 1:1.2.
13. the method for preparing moxifloxacin hydrochloride according to claim 1, wherein in step 2), 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid is reacted with a side chainS,S-2, 8-diazabicyclo [4,3,0]The molar ratio of nonane is 1.5.
14. The preparation method of moxifloxacin hydrochloride according to claim 1, characterized in that the recrystallization method in step 2) is: cooling to room temperature, evaporating solvent, adding alcohol selected from one or more of methanol, ethanol, propanol and isopropanol, filtering to remove tungsten mud, adding hydrochloric acid to form salt, and standing at 0-10 deg.C for crystallization.
15. The method for preparing moxifloxacin hydrochloride according to claim 1, wherein the recrystallization reagent in step 2) is ethanol.
16. The method for preparing moxifloxacin hydrochloride according to claim 1, characterized in that in step 2), standing at 0 ℃ is performed for crystallization.
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