WO2013189117A1

WO2013189117A1 - One-step synthesizing method of levofloxacin and ofloxacin

Info

Publication number: WO2013189117A1
Application number: PCT/CN2012/079744
Authority: WO
Inventors: 吴政杰; 俞永平; 俞玩玩
Original assignee: 浙江大学
Priority date: 2012-06-18
Filing date: 2012-08-06
Publication date: 2013-12-27
Also published as: CN102850376B; CN102850376A

Abstract

The present invention provides a one-step synthesizing method of levofloxacin and ofloxacin. S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylic acid ester or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylic acid ester is adopted as a raw material to react with alkali in an organic solvent or water or a mixed solvent of an organic solvent and water, to obtain a corresponding carboxylic acid salt; the solvent is directly removed by evaporation after a hydrolysis process; the product is directly added into N-methylpiperazine in the form of a carboxylic acid salt; and a piperazine condensation reaction is carried out to obtain levofloxacin or ofloxacin. The method is easy to operate. A process of hydrolysis and acid adjustment is not necessary. The reaction cost is reduced, the production period is short, pollution is reduced, and the raw material utilization rate is high. The method is economical and simple, and the yield and purity of obtained levofloxacin and ofloxacin are high.

Description

One-step synthesis method of levofloxacin and ofloxacin

The invention belongs to the technical field of drug synthesis, and relates to a method for synthesizing a fluoroquinolone, in particular to a method for preparing levofloxacin and ofloxacin.

Background technique

Levofloxacin, chemical name (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-[4-methylpiperazinyl]-7 -oxo-7-hydropyrido[1,2,3- Δ]-[1,4]benzoxazine-6-carboxylic acid, a new generation of fluoroquinolones developed by Japan Daiichi Pharmaceutical Co., Ltd. Antibacterial drugs, the structural formula is as follows:

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Levofloxacin is a left-handed body of ofloxacin, a hemihydrate with a solubility in water ten times that of ofloxacin. Levofloxacin has excellent in vitro activity, is less toxic than infloxacin, has high safety and good pharmacokinetic properties, and is widely used in respiratory infections, gynecological infections, skin and soft tissue infections, surgical infections, biliary infections, sexual An oral or parenteral broad-spectrum fluoroquinolone antibacterial agent that spreads a variety of bacterial infections, such as diseases and otolaryngology infections. It has strong antibacterial activity against most Enterobacteriaceae bacteria such as Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella and Haemophilus influenzae, Legionella pneumophila, Neisseria gonorrhoeae Gram-negative bacteria such as bacteria have strong antibacterial activity. It also has antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Mycoplasma pneumoniae, and Chlamydia pneumoniae, but has a poor effect on anaerobic bacteria and Enterococcus.

Ofloxacin, chemical name 9-fluoro-2,3-dihydro-3-methyl-10-[4-methylpiperazinyl]-7-oxo-7-hydropyridine [1,2,3- Δ ]-[1,4]benzoxazine-6-carboxylic acid is a synthetic, broad-spectrum antibacterial fluoroquinolone. It was synthesized in 1982 and has advantages such as oral absorption, fast and complete, high blood concentration and long-lasting, and wide distribution of drugs in the body. Ofloxacin is a highly effective broad-spectrum antibacterial agent, which has a strong effect on gram-positive bacteria (including methicillin-resistant Staphylococcus aureus) and gram-negative bacteria (including Pseudomonas aeruginosa). Mycoplasma pneumoniae, Neisseria, anaerobic bacteria and Mycobacterium tuberculosis also have some activity. The structure is as follows:

The synthesis of levofloxacin and ofloxacin has been continuously improved over the past few decades. The last two steps in the synthesis of levofloxacin and ofloxacin, hydrolysis and the replacement of N-methylpiperazine, have varied in the past few decades. Methods. It mainly includes the following ideas and methods:

1. Acid hydrolysis: Hydrolysis of S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridine with an acid such as hydrochloric acid, glacial acetic acid or sulfuric acid [1,2, 3-A]-[l,4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridinium[ 1,2,3- Δ ]-[1,4]-benzoxazine-6-carboxylate is converted into a carboxylic acid, and the above carboxylic acid product is obtained by a substitution reaction with hydrazine-methylpiperazine to obtain a target molecule. This method is most common in the first hydrolysis reaction, such as the patents WO2006048889, US4777253, CN101519361 and the literature Chemical & Pharmaceutical Bulletin, 1984, 32(12), 4907-4913. and Chemical & Pharmaceutical Bulletin, 1987, 35(5), 1896 - 1902. The disadvantage is that a large amount of glacial acetic acid and sulfuric acid are required as solvents and reagents, which is costly and highly polluting.

2. Alkaline hydrolysis: Hydrolysis of S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridine with a base such as potassium hydroxide or sodium hydroxide [1,2 , 3- A ]-[l,4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridine [1,2,3- A ]-[1,4]-benzoxazine-6-carboxylate to a carboxylate, and then adjusted to pH with hydrochloric acid, sulfuric acid or glacial acetic acid to make it S-9 ,10-Difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]-benzoxazine-6-carboxylate Acid or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine- The 6-carboxylic acid is then charged to the second step of the piperazine reaction. This method is also used in the hydrolysis reaction, such as the patent CN10659669, the similar structure of WO2009035684 and the literature Journal of Medicinal Chemistr., 1987, 30(12), 2283-2286. and Tetrahedron, 2010, (66), 6565 - 6568. Etc. Their common feature is that after alkali hydrolysis, the pH is adjusted to acidity with an acid to convert the carboxylate to a carboxylic acid and then to a piperazine reaction. Although these methods can avoid the use of glacial acetic acid as a solvent, in the post-treatment, an acid is used to adjust the pH to acid to form a free carboxylic acid, followed by suction filtration to obtain a carboxylic acid.

3. Hydrolysis of complex enzymes: The hydrolysis of carboxylic acid esters is carried out by using a complex enzyme. As is true in the Chinese patent CN101974578, the conditions are mild, high temperature is not required for hydrolysis, and the discharge of the three wastes is reduced. However, there are problems of low yield and low efficiency.

4. N-methylpiperazine substitution reaction (referred to as piperidine reaction in the text): S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxygen is currently reported in the piperazine reaction. 7H-pyrido[1,2,3-A]-[1,4]-benzoxazine-6-carboxylic acid or 9,10-difluoro-2,3-dihydro-3-methyl-7 - Oxy-7H-pyrido[1,2,3- Δ]-[1,4]-benzoxazine-6-carboxylic acid as a raw material, reacting with an excess of hydrazine-methylpiperazine, the disadvantage of this reaction It is a salt formed by hydrofluoric acid and hydrazine-methylpiperazine formed during the substitution reaction, which reduces the recovery of hydrazine-methylpiperazine. It is also reported that the free carboxylic acid is used as a raw material to use a base or a catalyst such as a Chinese patent. CN101514208 and the like, but the above methods all carry out a further pipetting reaction using a raw material which is hydrolyzed to an acid. For the piperazine reaction, the main organic solvents used are: DMSO (e.g., Chemical & Pharmaceutical Bulletin, 1984, 32(12), 4907 - 4913., etc.), pyridine (e.g., patents WO2006048889, CN1357547, etc.), n-butanol ( For example, patent WO2006030452, etc., and water as solvent (eg, patents CN101880288 and CN10154208, etc.);

In addition, there are methods different from the conventional synthesis of levofloxacin and ofloxacin, such as Chemical & Pharmaceutical Bulletin, 1986, 34(10), 4098-4102. This literature reports that the idea of N-methylpiperazine substitution, re-cyclization, and final hydrolysis also provides different ideas for the synthesis of levofloxacin and ofloxacin.

Summary of the invention

The object of the present invention is to provide levofloxacin and oxygen for the defects of the prior art of the synthesis of levofloxacin and ofloxacin in the last two steps (hydrolysis, N-methylpiperazine substitution). A one-step synthesis method of flaroxacin, which is a simple, economical and efficient one-step synthesis method of levofloxacin and ofloxacin. It has high utilization rate of raw materials, high yield and purity, and simplifies the original The steps shorten the reaction cycle and facilitate industrial production.

In order to achieve the above requirements, the present invention employs S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-?]-[1 , 4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A ]-[1,4]-benzoxazine-6-carboxylate as a raw material, after hydrolysis by alkali 1, without adjusting the pH of the acid, directly concentrating a certain amount or all of the solvent, then adding N-methylpiperazine , organic solvent 2 or water or a mixed solvent thereof, complete the pipetting reaction, and finally post-treatment to obtain levofloxacin or ofloxacin finished product. Specifically achieved by the following technical solutions:

(1) using the starting material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]- Benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1 , 4]-benzoxazine-6-carboxylate, base 1, organic solvent 1 or water or a mixed solvent thereof, hydrolyzed at a temperature of 30 - 90 ° C for 2 - 8 hours, as far as possible during the hydrolysis The alcohol produced by the reaction is removed, and the hydrolysis is completed, and some or all of the solvent is distilled off under reduced pressure.

(2) The above prepared S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4 ]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]- [1,4]-benzoxazine-6-carboxylate, or a solution thereof, further adding an organic solvent 2 or water or a mixed solvent thereof, and adding N-methylpiperazine at a temperature of 80 to 140 ° C After 8-16 hours of piperazine reaction, the reaction is completed, the solvent and N-methylpiperazine are recovered under reduced pressure, and the concentrated levofloxacin crude or ofloxacin crude product is treated with organic solvent 3 and water. Dissolve, and then adjust the pH to 1.0 - 5.0 with acid 1, filter, extract, wash and other steps, then adjust the pH to 6.0 - 7.5 with alkali 2, then extract, wash, concentrate, etc., and finally concentrate the solid obtained. The organic solvent 4 is recrystallized, and the mother liquor is further concentrated, separated by column or recrystallized, and the solid is combined and dried to obtain levofloxacin (Reaction Formula 1) or ofloxacin (Reaction Formula 2).

shock

- 9,10-Difluoro- 2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3- Δ]-[1,4]-benzoxazine-6 3-Dihydro-3-methyl-7-oxo-7-pyrido[1,2,3-Δ]-[1,4]-benzoxime

Wherein R' is preferably a fluorenyl group or a cyclic fluorenyl group, further preferably -6

An anthracenyl group, a C ₃ - ₁₂ cyclic fluorenyl group, further preferably a methyl group or an ethyl group.

S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]-benzoxazine- 6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]-benzene And oxazin-6-carboxylate, preferably a sodium salt, a potassium salt, a calcium salt or a phosphonium salt.

S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1, as described in the step (1) 4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ] -[1,4]-benzoxazine-6-carboxylate and base 1 in a molar ratio of 1:1 - 2; S-9,10-difluoro-2,3-dihydro-3-methyl -7-oxo-7H-pyrido[1,2,3-A]-[l,4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro- Quality of 3-methyl-7-oxo-7H-pyrido[1,2,3- Δ]-[1,4]-benzoxazine-6-carboxylate and organic solvent 1 or water or mixed solvent The ratio is 1:1 - 6, further preferably 1:1

S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1, as described in the step (2) 4]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ] -[1,4]-benzoxazine-6-carboxylate and organic solvent 2 or water or mixed solvent mass ratio of 1:0-2, and N-methylpiperazine mass ratio of 1:1 - 6

The organic solvent 1 is tetrahydrofuran or acetonitrile; the organic solvent 2 is dimethyl sulfoxide or hydrazine, hydrazine-dimethylformamide or pyridine or n-butanol; and the organic solvent 3 is chloroform or ethyl acetate; The organic solvent 4 is methanol or ethanol or ethyl acetate or a mixed solvent thereof.

The base 1 described in the reaction is sodium hydroxide or potassium hydroxide or calcium hydroxide or barium hydroxide; the base 2 is sodium hydroxide or potassium hydroxide; and the acid 1 is hydrochloric acid or glacial acetic acid or sulfuric acid or hydrofluoric acid.

The present invention is S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]-[1,4]-benzo Oxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]-[1,4 ]-benzoxazine-6-carboxylate as raw material, The one-step method is subjected to hydrolysis and piperazine reaction to obtain a levofloxacin product. After the ester hydrolysis is completed, the step of adjusting the pH to the acid is not required, and the piperazine reaction is directly carried out without isolation and purification. During the hydrolysis reaction, the formed alcohol is removed as much as possible. After the hydrolysis is completed, all or part of the solvent is recovered, and N-methylpiperazine and the organic solvent 2 or water or a mixed solvent are directly added to carry out the piperazine reaction, and then the treatment is carried out to obtain the left-handed oxygen. Frofloxacin finished product.

The preparation method of levofloxacin and ofloxacin according to the present invention has the following advantages:

1. The invention can carry out alkaline hydrolysis by removing alcohol in the reaction process, avoiding the sulfuric acid currently used generally, and causing pollution by hydrolysis of acetic acid. After the hydrolysis is finished, the step of adjusting the pH to acid to obtain the free acid is not adopted. The form of the carboxylate is subjected to a piperazine reaction. Simplifying the reaction not only greatly shortens the reaction cycle, but also reduces reagent consumption while improving reaction yield and purity. Finally, it can be recrystallized from organic solvent 4 to obtain high purity (more than 99.5%), levofloxacin and ofloxacin final product with good properties.

2. The present invention employs S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4 ]-benzoxazine-6-carboxylate or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]- The form of [1,4]-benzoxazine-6-carboxylate is involved in the substitution reaction of N-methylpiperazine, which is not only a reactant but also an acid scavenger, so that the reaction does not require any base, and the carboxyl group The reaction in the form of an acid salt also reduces the amount of N-methylpiperazine and other solvents, which in turn reduces the cost of synthesis.

detailed description

The technical solutions of the present invention will be further specifically described below in conjunction with specific embodiments, but the present invention is not limited to the embodiments.

Example 1

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 30 g of tetrahydrofuran, 30 g of water and 4.3 g of sodium hydroxide, the reaction was kept at 60 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 5 hours. After the hydrolysis was completed, the remaining solvent was distilled off, and then 40 g of N-methylpiperazine, 70 g of DMSO was directly added to the three reaction flasks, and the mixture was heated at 90 ° C for about 10 hours. After N-methylpiperazine is completely replaced, N-methylpiperazine and DMSO are recovered under reduced pressure, and the crude levofloxacin is dissolved in chloroform and water, adjusted by acid and base pH, and extracted. , washing, concentration and other steps. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then recrystallized, and solids were combined and rinsed with cold methanol to obtain 33 g of levofloxacin, yield: 89.7%. The compound was confirmed by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and melting point, and the product quality was analyzed by high performance liquid chromatography and titration. Mp: 224 - 225 °C (literature: 224 - 226 °C); 1H NMR (500 MHz, CDC13): δ 15.09 (s, 1H), 8.65 (s, 1H), 7.67 (d, J = 12.2 Hz , 1H), 4.60 - 4.55 (m, 1H), 4.48 - 4.37 (m, 2H), 3.46 - 3.36 (m, 4H), 2.62 - 2.50 (m, 4H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H).; HRMS (ESI): m/z calcd for C ₁₈ H ₂₀ FN ₃ O ₄ (M) +: 361.1438. Found:

361.1439.

Example 2

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 60 g of acetonitrile and 6.5 g of potassium hydroxide, the reaction was incubated at 50 ° C, and the alcohol formed by the reaction was removed during the reaction. To be completely hydrolyzed, 50 g of N-methylpiperazine was directly added to the three reaction flasks, and the temperature was raised to reflux for about 16 hours. After N-methylpiperazine was completely replaced, N-methylpiperazine was recovered under reduced pressure. The crude levofloxacin remaining was dissolved in ethyl acetate and water and washed. After acid, alkali pH adjustment, through extraction, washing, concentration and other steps. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then recrystallized, and solids were combined and rinsed with cold methanol to obtain 32.9 g of the product of levofloxacin, yield: 89.8%. The compound was identified by melting point measurement, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy to confirm that the product was the same as that obtained in Example 1, and was a levofloxacin product. Example 3

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 40 g of acetonitrile, 20 g of water and 4.7 g of sodium hydroxide, the reaction was kept at 80 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 2 hours. To be completely hydrolyzed, 40 g of N-methylpiperazine was directly added to the three reaction flasks, and the temperature was raised to reflux for about 15 hours. After N-methylpiperazine was completely replaced, N-methylpiperazine was recovered under reduced pressure. The remaining levofloxacin is crude, and the remaining levofloxacin is dissolved in chloroform and water, adjusted by acid and alkali pH, and subjected to steps of extraction, washing and concentration. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then separated by column. The product was combined and rinsed with cold methanol to obtain 34.5 g of the product of levofloxacin, yield: 94.1%. The compound was identified by melting point measurement, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy to confirm that the product was the same as that obtained in Example 1, and was a levofloxacin product.

Example 4

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 30 g of water, 30 g of acetonitrile and 6.0 g of potassium hydroxide, the reaction is kept at 55 ° C, and the alcohol and acetonitrile formed by the reaction are removed during the reaction, and the reaction proceeds to about 6 hour. To be completely hydrolyzed, 50 g of DMSO and 30 g of N-methylpiperazine were directly added to the three-necked reaction flask, and the mixture was heated to reflux for about 12 hours. After N-methylpiperazine was completely replaced, N-methylpiperazine and DMSO were recovered under reduced pressure. The crude levofloxacin remaining is dissolved in chloroform and water, adjusted by acid and alkali pH, and subjected to steps of extraction, washing, concentration, and the like. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated, and then the column was separated, and solids were combined and rinsed with cold methanol to obtain 33.7 g of the product of levofloxacin, yield: 92%. Compounds are determined by melting point, high resolution mass spectrometry, and nuclear magnetic resonance spectroscopy to confirm product and The product obtained in Example 1 was the same and was the finished product of levofloxacin.

Example 5

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 150 g of water and 6 g of potassium hydroxide, the reaction was incubated at 70 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 4 hours. To be completely hydrolyzed, 40 g of N-methylpiperazine was added to the three-necked reaction flask, and the temperature was raised to reflux. After N-methylpiperazine is completely replaced, N-methylpiperazine is recovered under reduced pressure, and the crude levofloxacin remaining is dissolved in chloroform and water, adjusted by acid and alkali pH, and extracted and washed. , concentration and other steps. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then recrystallized, and solids were combined to obtain 33 g of levofloxacin, yield: 90%. The compound was identified by melting point measurement, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the product was the same as that obtained in Example 1, and was a levofloxacin product.

Example 6

Weigh 30 g of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - benzoxazine-6-carboxylate, 100 g of water, and 4.7 g of sodium hydroxide, the reaction was kept at 90 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 3 hours. To be completely hydrolyzed, 35 g of N-methylpiperazine was further added to the three-necked reaction flask, and the temperature was raised to reflux for about 16 hours. After N-methylpiperazine was completely replaced, N-methylpiperazine was recovered under reduced pressure. The crude levofloxacin remaining is dissolved in chloroform and water, adjusted by acid and alkali pH, and subjected to steps of extraction, washing, concentration, and the like. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated by column separation, and solids were combined to obtain 33.8 g of the product of levofloxacin, yield: 92.1%. The compound was identified by melting point measurement, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy to confirm that the product was the same as that obtained in Example 1, and was a levofloxacin product.

Example 7

Weigh 30 g of raw material 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4]-benzene And the oxazine-6-carboxylate, 30 g of acetonitrile, 30 g of water and 4.7 g of sodium hydroxide were incubated at 75 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 4 hours. To be completely hydrolyzed, the solvent was evaporated, and then 40 g of N-methylpiperazine and 40 g of DMSO were directly added to the three-necked reaction flask, and the mixture was heated to reflux for about 12 hours. After N-methylpiperazine was completely replaced, N-methylpiperazine and DMSO were recovered under reduced pressure. The crude levofloxacin remaining is dissolved in chloroform and water, adjusted by acid and alkali pH, and subjected to steps of extraction, washing, concentration, and the like. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then separated by column, and solids were combined to obtain 33.4 g of ofloxacin, yield: 91%. The compound was confirmed by high-resolution mass spectrometry, melting point measurement, and nuclear magnetic resonance spectroscopy, and the product quality was analyzed by high performance liquid chromatography and titration. Purity: 99.5%, mp: 254 - 256 °C (literature value: 250 - 257 °C); 1H NMR (500 MHz, CDC13): δ 15.03 (brs, 1H), 8.64 (s, 1H), 7.69 ( d, J = 12.5 Hz, 1H), 4.57 - 4.55 (m, 1H) 4.48 - 4.46 (m, 1H), 4.39 - 4.37 (m, 1H), 3.45 - 3.43 (m, 2H), 3.39 - 3.37 (m, 2H), 2.56 (s, 4H), 2.37 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H).; HRMS (ESI): m/z calcd for C ₁₈ H ₂₀ FN ₃ O ₄ (M) +: 361.1438. Found: 361.1441.

Example 8

Weigh 30 g of raw material 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4]-benzene The oxazine-6-carboxylate, 30 g of tetrahydrofuran, 30 g of water and 6.0 g of potassium hydroxide were incubated at 60 ° C, and the alcohol and tetrahydrofuran formed by the reaction were removed during the reaction, and the reaction was carried out for about 5 hours. After the hydrolysis was completed, the remaining solvent was distilled off, and then 40 g of N-methylpiperazine, 40 g of DMSO was directly added to the three reaction flasks, and the mixture was heated to reflux for about 12 hours. After the N-methylpiperazine was completely substituted, N-methylpiperazine and a solvent were recovered under reduced pressure. The crude ofloxacin is dissolved in chloroform and water, adjusted by acid and alkali pH, and subjected to steps of extraction, washing, concentration, and the like. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated and then recrystallized, and solids were combined to obtain 30.4 g of ofloxacin, yield: 83%. The compound was determined by measuring the melting point, molecular weight by high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the product was the same as that of the product obtained in Example 10, and was the finished ofloxacin.

Example 9

Weigh 30 g of raw material 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4]-benzene The oxazine-6-carboxylate, 150 g of water and 6.0 g of potassium hydroxide were incubated at 70 ° C, and the alcohol formed by the reaction was removed during the reaction, and the reaction was carried out for about 4 hours. To be completely hydrolyzed, 40 g of N-methylpiperazine was directly added to the three reaction flasks, and the temperature was raised to reflux until the starting materials disappeared. After N-methylpiperazine was completely replaced, N-methylpiperazine was recovered under reduced pressure. After acid and alkali pH adjustment, through extraction, washing, concentration and other steps. Finally, the solid obtained by concentration was recrystallized from methanol, suction filtered, and the mother liquid was concentrated, and then separated by a column, and solids were combined to obtain 32.4 g of ofloxacin, yield: 88.3%. The compound was determined by measuring the melting point, molecular weight by high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the product was the same as that of the product obtained in Example 10, and was the finished ofloxacin.

Example 10

Weigh 30g of raw material 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]-benzo Oxazine-6-carboxylate, 100g of glacial acetic acid, 10g of concentrated sulfuric acid, put into a three-necked flask, reflux and stir at 110 °C, keep warm for 6 hours, stir to cool to room temperature, stir and freeze to below 0 °C, let stand 5 After more than one hour, it was filtered, rinsed with a large amount of water to obtain a white solid, and dried to give a sulfuric acid (26.2 g). 26.2 g of carboxylic acid, 100 g of DMSO, 50 g of N-methylpiperazine to a three-necked flask, stirred at 90 ° C for 6 hours, reduced to dryness under reduced pressure, 150 g of water, 5 g of base, stirred and dissolved until clear, filtered, mother liquor Adjust the pH to 7, a large amount of solids are precipitated, filtered, and the crude ofloxacin is obtained. The crude product was put into a three-necked flask, and then 150 g of water and 8 g of glacial acetic acid were added, stirred and dissolved, filtered, and the pH of the mother liquid was adjusted to 7, a large amount of solid was precipitated, and filtered to obtain oxygen fluoride. The crude product was put into a three-necked flask, and then 100 g of medicinal alcohol was added thereto, and the mixture was refluxed for 2 hours, cooled, filtered to obtain a solid, and dried to obtain 27 g of ofloxacin, a yield of 80%. The total yield in two steps was 77%.

Example 11

Weigh 30 g of the starting material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-A]-[1,4]- Benzoxazine-6-carboxylate, 100g of glacial acetic acid, 10g of concentrated sulfuric acid, put into a three-bottle flask, reflux and stir at 110 °C, keep warm for 6 hours, stir to cool to room temperature, stir and freeze to below 0 °C, let stand After 5 hours or more, it was filtered, washed with a large amount of water to obtain a white solid, which was dried to give a solvent (26.2 g). 26.2 g of carboxylic acid, 100 g of water, 50 g of N-methylpiperazine and 4.5 g of sodium hydroxide were placed in a three-necked flask. At 90 ° C, the reaction is completed, the pressure is reduced to dryness, 100 g of water is added, stirred at room temperature, filtered, and the pH of the mother liquid is adjusted to 7, a large amount of chloroform is extracted, and chloroform is recovered to dryness to obtain crude levofloxacin, 100 g 95 The medicinal alcohol was recrystallized, filtered, and the mother liquor was concentrated and recrystallized to obtain 29.6 g of levofloxacin. The total yield of the two steps was 80.5%.

The specific embodiments described in the present invention are merely illustrative of the spirit of the invention. The present invention and its embodiments are subject to various additions or modifications, or in a similar manner, after the above-described teachings of the present invention, which are equivalent to the claims of the present application. The scope defined by the book. In addition, all of the patents and documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the

Claims

Claim

A one-step synthesis method of levofloxacin using 8-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-711-pyridine and [1,2,3 -Δ]-[1,4]-benzoxazine-6-carboxylate as a raw material, which is characterized by:

(1) Preparation of 8-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-711-pyrido[1,2,3]-[1,4]-benzo Oxazine-6-carboxylate: Starting from the starting material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]- [1,4]-benzoxazine-6-carboxylate, base 1, organic solvent 1 or water or a mixed solvent thereof, hydrolyzed to obtain a carboxylate; the 8-9,10-difluoro-2 , 3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylate and base 1 mole The ratio is 1:1 -2, S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]-[1, 4]- benzoxazine-6-carboxylate and organic solvent 1 or water or mixed solvent mass ratio of 1:1 -6; hydrolysis at a temperature of 30 - 90 V for 2-8 hours;

(2) Preparation of levofloxacin: using the above prepared S-9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyridine

[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylate or a solution thereof, and further adding an organic solvent 2 or water or a mixed solvent of water and organic solvent 2, and adding hydrazine - Methylpiperazine is reacted at a reaction temperature of 80 - 140 V, and the reaction time is 8 - 16 hours. After the reaction is completed, the solvent and hydrazine-methyl piperazine are recovered under reduced pressure, and the concentrated levofloxacin is concentrated. The organic solvent 3 and water are dissolved, and then adjusted to pH 5.0 to 5.0 with acid 1, filtered, extracted, washed, and then adjusted to pH 6.0 to 7.5 with alkali 2, extracted, washed, concentrated, and finally concentrated. The solid is recrystallized from the organic solvent 4, and the mother liquor is further concentrated, separated by column or recrystallized, and the solid is combined and dried to obtain levofloxacin; the mass ratio of the carboxylate to the organic solvent 2 or water or the mixed solvent is 1:0-2, the mass ratio of the carboxylate to the Ν-methylpiperazine is 1:1 -6;

Reaction formula:

Wherein R' is selected from the group consisting of d fluorenyl, (: ₃ - ₁₂ ring fluorenyl.

The method for synthesizing levofloxacin according to claim 1, wherein: (1) the alcohol produced by the reaction is removed as much as possible during the hydrolysis, and the hydrolysis is completed, and some or all of the solvent is distilled off under reduced pressure.

The method for synthesizing levofloxacin according to claim 1, wherein: the S-9, 10-difluoro-2,3-dihydro-3-methyl group in the step (1) The mass ratio of -7-oxo-7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylate to organic solvent 1 or water or mixed solvent is 1: 1.

The method for synthesizing levofloxacin according to claim 1, wherein: (2) removing the generated alcohol as much as possible during the hydrolysis reaction, and after the hydrolysis is completed, all or part of the solvent is recovered, and then directly added to N. -methylpiperazine and an organic solvent 2 or water or a mixed solvent, subjected to a piperazine reaction, and then worked up to obtain a levofloxacin product.

The method for synthesizing levofloxacin according to any one of claims 1 to 4, wherein the organic solvent 1 is tetrahydrofuran or acetonitrile during the reaction; the organic solvent 2 is dimethyl sulfoxide or N,N-dimethylformamide or pyridine or n-butanol; organic solvent 3 is chloroform or ethyl acetate; organic solvent 4 is methanol or ethanol or ethyl acetate or a mixed solvent thereof.

The method for synthesizing levofloxacin according to any one of claims 1 to 4, wherein the base 1 is sodium hydroxide or potassium hydroxide or calcium hydroxide or barium hydroxide during the reaction. The base 2 is sodium hydroxide or potassium hydroxide; the acid 1 is hydrochloric acid or glacial acetic acid or sulfuric acid or hydrofluoric acid.

7. A one-step synthesis of ofloxacin using 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ] -[1,4]_benzoxazine-6-carboxylate as a raw material, which is characterized by:

(1) Preparation of 9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-711-pyrido[1,2,3-octa]-[1,4]-benzo Oxazine-6-carboxylate: The starting material 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-711-pyrido[1,2,3-oc]-[1 , 4]-benzoxazine-6-carboxylate, base 1, organic solvent 1 or water or a mixed solvent thereof, hydrolyzed to obtain a carboxylate; the 9, 10-difluoro-2, 3- The molar ratio of dihydro-3-methyl-7-oxo-7-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylate to base 1 is 1 :1 -2; 9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-7Η-pyrido[1,2,3-Δ]-[1,4]_benzo The mass ratio of the oxazine-6-carboxylate to the organic solvent 1 or water or the mixed solvent is 1:1 -6; the hydrolysis reaction temperature is 30 - 90 。. C, reaction time 2-8 hours;

(2) Preparation of ofloxacin: Using 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1, 2, 3-Δ] prepared above -[1,4]-benzoxazine-6-carboxylate or a solution thereof, and further adding an organic solvent 2 or water or a mixed solvent of water and organic solvent 2, and adding hydrazine-methylpiperazine for reaction, reaction temperature 80-140 ° C, 8 - 16 hours, until the end of the reaction, recover the solvent and N-methyl piperazine under reduced pressure, and concentrate the concentrated ofloxacin, dissolve it with organic solvent 3 and water, and then pass Adjust the pH to 1.0-5.0 with acid 1, filter, extract, wash, then adjust the pH to 6.0-7.5 with alkali 2, extract, wash and concentrate. Finally, the concentrated solid is recrystallized from organic solvent 4, and the mother liquor is further concentrated. After separation by column or recrystallization, after drying, the obtained ofloxacin product is obtained; the mass ratio of the carboxylate to the organic solvent 2 or water or the mixed solvent is 1:0-2, carboxylate and N-A The mass ratio of the piperazine is 1:1 -6;

Reaction formula: OH

The method for synthesizing ofloxacin according to claim 7, wherein: (1) the alcohol produced by the reaction is removed as much as possible during the hydrolysis, and the hydrolysis is completed, and some or all of the solvent is distilled off under reduced pressure.

The method for synthesizing ofloxacin according to claim 7, wherein: 9,10-difluoro-2,3-dihydro-3-methyl-7- described in the step (1) The mass ratio of the oxygen-7H-pyrido[1,2,3_?]-[1,4]-benzoxazine-6-carboxylate to the organic solvent 1 or water or the mixed solvent is 1:1.

The method for synthesizing ofloxacin according to claim 7, wherein: (2) removing the generated alcohol as much as possible during the hydrolysis reaction, and after the hydrolysis is completed, all or part of the solvent is recovered, and then the hydrazine is directly added. Methylpiperazine and an organic solvent 2 or water or a mixed solvent are subjected to a piperazine reaction, followed by treatment to obtain anloxacin finished product.

The method for synthesizing ofloxacin according to any one of claims 7 to 10, wherein the organic solvent 1 is tetrahydrofuran or acetonitrile during the reaction; and the organic solvent 2 is dimethyl sulfoxide or hydrazine. , hydrazine-dimethylformamide or pyridine or n-butanol; organic solvent 3 is chloroform or ethyl acetate; organic solvent 4 is methanol or ethanol or ethyl acetate or a mixed solvent thereof.

The method for synthesizing ofloxacin according to any one of claims 7 to 10, wherein: the alkali 1 in the reaction is sodium hydroxide or potassium hydroxide or calcium hydroxide or barium hydroxide; The base 2 is sodium hydroxide or potassium hydroxide; the acid 1 is hydrochloric acid or glacial acetic acid or sulfuric acid or hydrofluoric acid.