CN115403521A - Synthesis method of lomefloxacin hydrochloride intermediate - Google Patents
Synthesis method of lomefloxacin hydrochloride intermediate Download PDFInfo
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- CN115403521A CN115403521A CN202211211200.2A CN202211211200A CN115403521A CN 115403521 A CN115403521 A CN 115403521A CN 202211211200 A CN202211211200 A CN 202211211200A CN 115403521 A CN115403521 A CN 115403521A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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Abstract
The invention discloses a synthesis method of a lomefloxacin hydrochloride intermediate, which comprises the steps of carrying out coupling and cyclization reaction on 2,3, 4-trifluoroaniline and 2-chloromethylene diethyl malonate to obtain a lomefloxacin hydrochloride intermediate 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester; wherein the reaction temperature of the coupling reaction is 50-60 ℃, and the reaction temperature of the cyclization reaction is 85-95 ℃. The synthesis method of the invention adopts 2,3, 4-trifluoroaniline and 2-chloro-methylene diethyl malonate to carry out coupling reaction to prepare a coupling intermediate, the coupling reaction temperature is only 50-60 ℃, the reaction temperature is obviously lower than the reaction temperature of the prior art of more than 100 ℃, the energy consumption is obviously lower, and the method is more energy-saving and environment-friendly and is suitable for industrial mass production. The synthesis method disclosed by the invention adopts anhydrous phosphoric acid as a cyclization reagent, so that high-temperature cyclization can be avoided, the energy consumption is further reduced, the energy is saved, the environment is protected, and a product with higher quality can be obtained.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of lomefloxacin hydrochloride intermediate 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester.
Background
Lomefloxacin hydrochloride is the hydrochloride salt form of lomefloxacin, a bactericidal fluoroquinolone active against gram negative and gram positive bacteria, and it inhibits bacterial DNA gyrase (topoisomerase ii) and topoisomerase iv, which are essential for the transcription and replication of bacterial DNA, DNA gyrase being considered the primary quinolone target of gram negative bacteria, and topoisomerase iv being considered the primary target of gram positive bacteria. Inhibition of topoisomerase leads to strand breaks, supercoiling and resealing of bacterial chromosomes. Thus, DNA replication and transcription are inhibited. Lomefloxacin can be used for treating various infections such as respiratory tract infection, urinary tract infection, obstetric infection, gynecological infection, joint infection, skin infection, oral infection, ear infection, nose infection, throat infection and eye infection. Compared with other quinolone antibacterial drugs, lomefloxacin has the advantages of convenient administration, no need of adjustment of theophylline dosage and the like.
The 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is a key intermediate for synthesizing the lomefloxacin hydrochloride.
The synthesis methods of 6,7,8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester disclosed in the prior art are all obtained by two-step condensation and cyclization reaction of equimolar 2,3,4-trifluoroaniline and ethoxymethylene diethyl malonate (hereinafter referred to as EMME), for example, documents 1 to 5.
Document 1 discloses: the 2,3, 4-trifluoroaniline and EMME in the same mole are condensed at 130-140 deg.c and then cyclized in diphenyl ether solvent at 300-320 deg.c.
Document 2 discloses: the condensation reaction is carried out by using 2,3, 4-trifluoroaniline and EMME with equal mole at 140-150 deg. C, and then the cyclization reaction is carried out in diphenylethane solvent at 220-240 deg. C.
Document 3 discloses: the condensation reaction is carried out by using 2,3, 4-trifluoroaniline and EMME with equal mole at 140-150 deg. C, and then the cyclization reaction is carried out in petroleum wax solvent at 250-260 deg. C.
Document 4 discloses that: the 2,3, 4-trifluoroaniline and EMME in the same mole are condensed at 110-120 deg.c and then cyclized in diphenyl ether solvent at 250 deg.c.
Document 5 discloses that: the 2,3, 4-trifluoroaniline and EMME in the same mole are condensed at 110-120 deg.c and then cyclized in diphenyl ether solvent at 243 deg.c.
The problems existing in the prior art are as follows:
(1) The condensation reaction temperature is higher (more than 100 ℃), which causes higher energy consumption and is not in accordance with the development direction of energy conservation and environmental protection.
(2) The cyclization reaction is carried out in a high-boiling point solvent at high temperature, so that the energy consumption is high, the cyclization temperature is too high, black carbide impurities are easily generated, and the product quality is greatly influenced.
Document 1: japanese patent document JPS6165882A, published as 4.4.1986.
Document 2: "improvement of synthesis process of lomefloxacin hydrochloride", wang Er Hua et al, J.Med.Med.Industrials of China "1991, vol.22, no. 10, pp.437-439.
Document 3: "research on the synthesis process of lomefloxacin hydrochloride", yongcun et al, journal of Waxi pharmacy 1997, vol.12, 2 nd, pages 100-102.
Document 4: "Novel Glycoconjugate of 8-Fluoro Norfloxacin Derivatives as Gentamicin-resistant Staphylococcus aureus Inhibitors: synthesis and Molecular modeling ", chandra S.Azad et al, chemical Biology & Drug Design 2015 volume 86, 4, pages 440-446.
Document 5: chinese patent document CN114195760A, published 2022, 3 months and 18 days.
Disclosure of Invention
The invention aims to solve the problems and provides a synthesis method of a lomefloxacin hydrochloride intermediate, which has the advantages of low energy consumption, energy conservation, environmental protection and high product quality and is suitable for industrial mass production.
The technical scheme for realizing the purpose of the invention is as follows: a method for synthesizing a lomefloxacin hydrochloride intermediate adopts 2,3, 4-trifluoroaniline and 2-chloromethylene diethyl malonate to carry out coupling and cyclization reactions to obtain the lomefloxacin hydrochloride intermediate 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester.
The reaction formula is as follows:
the weight ratio of the diethyl 2-chloromethylene malonate to the 2,3, 4-trifluoroaniline is 1: 1.4-1: 2.1.
The coupling reaction is carried out in the presence of pyridine; the weight ratio of the diethyl 2-chloromethylene malonate to the pyridine is 1: 0.6-1: 0.8.
The reaction temperature of the coupling reaction is 50-60 ℃, and the reaction time is 8-10 h.
After the coupling reaction is finished, first post-treatment is also included; the first post-treatment is specifically as follows: diluting with methyl tert-butyl ether, washing with HCl aqueous solution, naOH aqueous solution and saturated saline solution in sequence, drying with anhydrous magnesium sulfate, and rotary steaming under reduced pressure to obtain the coupling product.
The mass concentration of the HCl aqueous solution is 5wt%, and the mass concentration of the NaOH aqueous solution is 10wt%.
The cyclization reaction is carried out in the presence of anhydrous phosphoric acid; the weight-to-volume ratio of the diethyl 2-chloromethylmalonate to the anhydrous phosphoric acid is 1: 5 to 1: 8 (g/mL).
Wherein, the anhydrous phosphoric acid is prepared by adding commercial 85wt% phosphoric acid into phosphorus pentoxide.
The reaction temperature of the cyclization reaction is 85-95 ℃, and the reaction time is 1.5-2.5 h.
The cyclization reaction also comprises a second post-treatment after combination; the second post-treatment is specifically as follows: cooling to 60 deg.C, adding saturated sodium bicarbonate ice water, stirring, extracting with dichloromethane, mixing organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, vacuum rotary evaporating to recover solvent to obtain crude product, and recrystallizing with ethyl acetate and petroleum ether to obtain pure product.
The invention has the following positive effects:
(1) The synthesis method of the invention adopts 2,3, 4-trifluoroaniline and 2-chloro-methylene diethyl malonate to carry out coupling reaction to prepare a coupling intermediate, the coupling reaction temperature is only 50-60 ℃, the reaction temperature is obviously lower than the reaction temperature of the prior art of more than 100 ℃, the energy consumption is obviously lower, and the method is more energy-saving and environment-friendly and is suitable for industrial mass production.
(2) The synthesis method disclosed by the invention adopts anhydrous phosphoric acid as a cyclization reagent, so that high-temperature cyclization can be avoided, the energy consumption is further reduced, the energy is saved, the environment is protected, and a product with higher quality can be obtained.
(3) The synthesis method adopts excessive 2,3, 4-trifluoroaniline and 2-chloro-methylene diethyl malonate to carry out coupling reaction, and the 2,3, 4-trifluoroaniline is used as a reaction raw material and a reaction solvent, so that the addition of pyridine can be greatly reduced, and the function of an acid-binding agent can be realized to neutralize HCl generated in the reaction process, thereby enabling the reaction to proceed in the forward direction, improving the conversion rate, ensuring the complete reaction of the 2-chloro-methylene diethyl malonate and further obtaining higher reaction yield.
Detailed Description
(example 1)
The synthesis method of the lomefloxacin hydrochloride intermediate of the embodiment specifically comprises the following steps:
(1) 2.0kg (9.68 mol) of diethyl 2-chloromethylene malonate and 4.2kg (28.55 mol) of 2,3, 4-trifluoroaniline are added into a reaction device, 1.6kg of pyridine is added in three batches, and the mixture is stirred and heated to 60 ℃ for reaction for 8 hours.
After the reaction, the reaction mixture was diluted with methyl tert-butyl ether, washed with a 5wt% aqueous HCl solution, a 10wt% aqueous NaOH solution, and a saturated brine in this order, dried over anhydrous magnesium sulfate, and finally evaporated under reduced pressure to obtain a coupling intermediate.
(2) And (2) adding 1.6L of anhydrous phosphoric acid into the coupling intermediate obtained in the step (1), and heating to 95 ℃ to react for 1.5h.
After the reaction is finished, cooling to 60 ℃, pouring into saturated sodium bicarbonate ice water, stirring, extracting with dichloromethane, combining organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, decompressing and rotary-distilling to recover the solvent to obtain a crude product of 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, and finally recrystallizing with ethyl acetate and petroleum ether to obtain 2.27kg of a pure product of 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, wherein the yield is 86.5%, and the HPLC purity is 98.3%.
Hydrogen spectrum 1 H NMR（300MHz,CDCl 3 ）δ：8.93(s,1H),8.01(t,J=8Hz,1H),4.37 (q,J=7 Hz,2H), 1.33(t,J=7Hz,3H)。
Carbon spectrum 13 C NMR（75 MHz,CDCl 3 ）δ：176.75，168.44，159.29，153.08，152.33，142.23，131.34，125.30，119.58，113.79，60.12，17.27。
Infrared spectrum IR (KBr method): 3012 2987, 3085, 1574, 1480, 1717, 1299, 1251, 1632cm −1 。
ESI-MS（m/z）：272.0593[M+H] + 。
(examples 2 to 3)
The synthesis methods of examples 2 to 3 are substantially the same as those of example 1 except for the differences shown in table 1.
(comparative example 1 to comparative example 2)
The synthesis methods of comparative examples 1 to 2 are substantially the same as those of example 1 except for the differences shown in table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | |
| 2,3, 4-Trifluoroaniline | 4.2kg | 2.8kg | 3.2kg | 1.42kg | 1.42kg |
| Pyridine compound | 1.6kg | 1.2kg | 1.4kg | 1.6kg | 3.2kg |
| Coupling reaction | 60℃、8h | 50℃、10h | 55℃、9h | 60℃、8h | 60℃、12h |
| Anhydrous phosphoric acid | 1.6L | 1.0L | 1.2L | 1.6L | 1.6L |
| Cyclization reaction | 95℃、1.5h | 85℃、2.5h | 90℃、2.0h | 95℃、1.5h | 95℃、3.0h |
| Weight of pure product | 2.27kg | 2.22kg | 2.25kg | 1.40kg | 1.62kg |
| Yield of the reaction | 86.5% | 84.6% | 85.7% | 53.3% | 61.7% |
| Purity of the product | 98.3% | 97.5% | 97.9% | 92.3% | 94.5% |
Claims (5)
1. A method for synthesizing a lomefloxacin hydrochloride intermediate is characterized by comprising the following steps: coupling and cyclizing 2,3, 4-trifluoroaniline and 2-chloromethylene diethyl malonate to obtain lomefloxacin hydrochloride intermediate 6,7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester; the reaction temperature of the coupling reaction is 50-60 ℃.
2. The method for synthesizing a lomefloxacin hydrochloride intermediate according to claim 1, wherein: the weight ratio of the diethyl 2-chloromethylene malonate to the 2,3, 4-trifluoroaniline is 1: 1.4-1: 2.1.
3. The method for synthesizing a lomefloxacin hydrochloride intermediate according to claim 1 or 2, wherein: the coupling reaction is carried out in the presence of pyridine; the weight ratio of the diethyl 2-chloromethylene malonate to the pyridine is 1: 0.6-1: 0.8.
4. The method for synthesizing a lomefloxacin hydrochloride intermediate according to claim 1 or 2, wherein: the cyclization reaction is carried out in the presence of anhydrous phosphoric acid; the reaction temperature of the cyclization reaction is 85-95 ℃.
5. The method for synthesizing a lomefloxacin hydrochloride intermediate according to claim 3, wherein: the cyclization reaction is carried out in the presence of anhydrous phosphoric acid; the reaction temperature of the cyclization reaction is 85-95 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115772176A (en) * | 2022-12-02 | 2023-03-10 | 常州兰陵制药有限公司 | Synthetic method of key drug intermediate of levofloxacin |
| CN115850297A (en) * | 2022-12-02 | 2023-03-28 | 常州兰陵制药有限公司 | Synthetic method of sarin antibiotic drug intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402917A (en) * | 2014-12-02 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method of novel ofloxacin intermediate |
| CN113929579A (en) * | 2021-11-22 | 2022-01-14 | 南京一苇医药科技有限公司 | Preparation method of clinafloxacin key intermediate |
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- 2022-09-30 CN CN202211211200.2A patent/CN115403521A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402917A (en) * | 2014-12-02 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method of novel ofloxacin intermediate |
| CN113929579A (en) * | 2021-11-22 | 2022-01-14 | 南京一苇医药科技有限公司 | Preparation method of clinafloxacin key intermediate |
Non-Patent Citations (1)
| Title |
|---|
| SOCORRO LEYVA ET AL.: "Thermochemical reaction of 7-azido-1-ethyl-6, 8-difluoroquinolone-3-carboxylate with heterocyclic amines. An expeditious synthesis of novel fluoroquinolone derivatives", TETRAHEDRON, vol. 63, pages 2093 - 2097, XP005858530, DOI: 10.1016/j.tet.2006.11.079 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115772176A (en) * | 2022-12-02 | 2023-03-10 | 常州兰陵制药有限公司 | Synthetic method of key drug intermediate of levofloxacin |
| CN115850297A (en) * | 2022-12-02 | 2023-03-28 | 常州兰陵制药有限公司 | Synthetic method of sarin antibiotic drug intermediate |
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