Synthesis method of norfloxacin

Abstract

The invention discloses a synthesis method of norfloxacin, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: mixing 7-chloro-1-ethyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester, propionic anhydride and a boron compound, and carrying out a boronation reaction, so as to obtain a boron chelate; the preparation method comprises the following steps: carrying out condensation reaction on a boron chelate and piperazine in a solvent medium, sequentially adding an alkali solution and an adsorption material to carry out hydrolysis and adsorption impurity removal, filtering and separating the adsorption material, adding an acid solution to neutralize, settle and filter to obtain norfloxacin, the method has the advantages of simple steps, mild reaction conditions and high target product yield, and is favorable for reducing the drug cost.

Description

Technical Field

[0001] The invention relates to a synthesis method of norfloxacin, in particular to a synthesis method for improving the yield of norfloxacin, belonging to the technical field of drug synthesis. Background Art

[0002] Norfloxacin is a third-generation quinolone antibacterial drug that inhibits the action of DNA gyrase of pathogenic bacteria in the digestive tract, hinders bacterial DNA replication, and has an inhibitory effect on bacteria. It is a commonly used drug for the treatment of enteritis and dysentery. The current synthesis method of norfloxacin is costly, cumbersome, and has a high reaction temperature.

[0003] Norfloxacin is a norfloxacin antibacterial drug with strong antibacterial activity, broad antibacterial spectrum, high bioavailability, good tissue permeability, no cross-resistance with other antibiotics, and few side effects. According to the different starting materials, the synthesis methods of norfloxacin can be summarized into the following 6 types.

[0004] The document (J. Med. Chem., 1980, 23, 1358) discloses that 3-chloro-4-fluoroaniline is used as a starting material, reacted with ethoxymethyl methyl ester (EMME), and then reacted with pyrazine after cyclization, N-ethylation, hydrolysis, and then reaction. This route has simple raw materials, but the reaction of 3-chloro-4-fluoroaniline with ethoxymethyl methyl ester (EMME) is prone to form isomer impurities. At the same time, the reaction temperature is too high, and the feasibility in on-site production is poor.

[0005] The literature (J. Med. Chem., 1985, 28, 1558) discloses that 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropionic acid ethyl ester is used as a raw material, reacted with triethyl orthoformate, then N-ethylated with ethylamine, cyclized, hydrolyzed, and then reacted with pyrazine. This route has a low conversion rate and lengthy steps, which is not conducive to large-scale production.

[0006] The Chinese patent (CN116462631A) uses 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester as the raw material, which is chelated with borate, and then reacted with pyrazine and hydrolyzed to obtain norfloxacin. However, the acetic anhydride used in the reaction process of this route is a precursor reagent, and the borate generated during the hydrolysis process has a poor separation effect, which leads to a decrease in yield and excessive salt in the product. Summary of the invention

[0007] In view of the shortcomings of the prior art, the present invention aims to provide a method for synthesizing norfloxacin, which is simple, has mild reaction conditions, high product yield and is conducive to large-scale production.

[0008] In order to achieve the above technical purpose, the present invention provides a method for synthesizing norfloxacin, which comprises the following steps:

[0009] S1: Compound 1, propionic anhydride and a boron compound are mixed to perform a boronization reaction to obtain compound 2;

[0010] S2: Compound 2 and piperazine undergo condensation reaction in a solvent medium to obtain a reaction solution containing compound 3;

[0011] S3: adding an alkaline solution and an adsorbent material to the reaction solution containing compound 3 to perform a hydrolysis reaction and adsorption and impurity removal. After the reaction is completed, cooling is performed, filtering is performed to remove the adsorbent material, and an acid solution is added to the filtrate to adjust the pH to neutral for precipitation, and filtering is performed to obtain norfloxacin;

[0012] The compound 1 has the following structure:

[0013]

[0014] The compound 2 has the following structure:

[0015]

[0016] The compound 3 has the following structure:

[0017]

[0018] The key to the synthesis method of norfloxacin of the present invention is that: on the one hand, propionic anhydride is used to synthesize the boric acid chelate, and compound 1 (7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester), propionic anhydride and boron compound can be directly and efficiently converted into boric acid chelate through a one-step reaction, and its conversion rate is significantly higher than that of homologues such as acetic anhydride and butyric anhydride, which is mainly based on the special steric hindrance effect and electronic effect of the ethyl group in propionic anhydride, resulting in the borylation reaction being easier to proceed smoothly, and the borylation efficiency is very high. On the other hand, the intermediate of compound 3 does not need to be separated, but an alkali solution and activated carbon are directly added to the reaction solution for hydrolysis reaction and adsorption and impurity removal, which can greatly improve the yield of norfloxacin.

[0019] As a preferred embodiment, the molar ratio of the compound 1, propionic anhydride and boron compound is 1 to 2: 8 to 10: 1 to 5. The molar ratio of the compound 1, propionic anhydride and boron compound is more preferably 1: 8: 1.5.

[0020] As a preferred embodiment, the boron compound includes at least one of boric acid, hydrated sodium tetraborate, sodium tetraborate, potassium borate, calcium borate, zinc perborate and ulexite.

[0021] As a preferred solution, the boronization reaction conditions are: temperature of 90-100°C, time of 1-5h. As a more preferred solution, the reaction is first carried out at 90-100°C for 1-5h, then cooled to 20-30°C, water is added and stirred to precipitate compound 2.

[0022] As a preferred solution, the solvent medium includes at least one of N-methylpyrrolidone, propylene carbonate, dimethyl sulfoxide, 1,2-dichloroethane, toluene, xylene, chloroform, tetrahydrofuran, and dimethyltetrahydrofuran.

[0023] As a preferred embodiment, the molar ratio of the compound 2 to piperazine is 1:1 to 1.5.

[0024] As a preferred solution, the conditions of the condensation reaction are: temperature of 90-100° C. and time of 1-5 h.

[0025] As a preferred solution, the alkaline solution includes at least one of a sodium hydroxide solution, a sodium bicarbonate solution, and a potassium hydroxide solution.

[0026] As a preferred solution, the acid solution includes at least one of acetic acid, boric acid, hydrochloric acid, sulfuric acid, tartaric acid, phosphoric acid, and citric acid.

[0027] As a preferred solution, the adsorption material includes activated carbon and / or graphite. Activated carbon or graphite is mainly used as an adsorption material to remove impurities and colorants in the reaction solution.

[0028] The chemical structural formula of norfloxacin synthesized by the present invention is:

[0029] Compared with the prior art, the beneficial technical effects of the technical solution of the present invention are as follows:

[0030] The synthesis method of norfloxacin provided by the invention is simple, has mild reaction conditions, high product yield and is conducive to large-scale production. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0032] Example 1

[0033]

[0034] 1. Add compound 1 (50.00 g, 1 eq), propionic anhydride (8 eq) and boric acid (15.58 g, 1.5 eq) into a three-necked flask, heat to 95°C, and stir for 2 h.

[0035] 2. The reaction system was cooled to 25°C, water (100 ml) was added, and the temperature was further cooled to 5°C. The mixture was stirred for 1 h, filtered, and the filter cake was dried to obtain 71.30 g of compound 2 with a yield of 99.63%.

[0036] 1H NMR (400MHz, DMSO-d6) δ9.62(s,1H),8.82(d,J=6.0Hz,1H),8.36(d,J=8.6Hz,1H),4.91(t ,J=7.2Hz,2H),2.24(qd,J=7.5,1.0Hz,4H),1.52(t,J=7.1Hz,3H),0.90(t,J=7.5Hz,6H).

[0037] Ms m / z=426.1[M+1]+.

[0038] 3. Add compound 2 (60.00 g, 1 eq), piperazine (18.20 g, 1.4 eq) and dimethyl sulfoxide (120 ml) into a three-necked flask, heat to 95°C, and stir for 2 h to obtain a reaction solution containing compound 3;

[0039] 4. The reaction solution containing compound 3 was cooled to 45°C, 10% aqueous sodium hydroxide solution (4 eq) and activated carbon (3 g, 5%) were added, the mixture was stirred for 1 h, filtered, and the pH of the filtrate was adjusted to neutral with acetic acid. 52.63 g of norfloxacin was obtained by filtration, with a yield of 98.33%.

[0040] 1 H NMR(500MHz,Deuterium Oxide)δ8.33(s,1H),7.68(d,J=13.5Hz,1H),6.77(d,J=7.0Hz,1H),4.15(q,J=7.2Hz,2H),3.02(dt,J=53.1,4.5Hz,8H),1.35(t,J=7.2Hz,3H).

[0041] Ms m / z=320.1[M+1] + .

[0042] Example 2

[0043] 1. Add compound 1 (50.00 g, 1 eq), acid anhydride (acetic anhydride, propionic anhydride or butyric anhydride) (8 eq), and boric acid (15.58 g, 1.5 eq) into a three-necked flask, raise the temperature to 95°C, and stir for 2 h.

[0044] 2. The reaction system was cooled to 25°C, water (100 ml) was added, and the temperature was further cooled to 5°C. The mixture was stirred for 1 h, filtered, and the filter cake was dried to obtain a boric acid chelate.

[0045]

[0046] Table 1

[0047]

[0048] From Table 1 above, it can be seen that the efficiency of synthesizing boric acid chelates using propionic anhydride is higher than that of acetic anhydride and butyric anhydride. The difference between them may be due to the electronic effect and steric effect of the groups carried by the anhydride.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing norfloxacin, characterized in that: The following steps are involved: S1: Compound 1, propionic anhydride and a boron compound are mixed to perform a boronization reaction to obtain compound 2; S2: Compound 2 and piperazine undergo condensation reaction in a solvent medium to obtain a reaction solution containing compound 3; S3: adding an alkaline solution and an adsorbent material to the reaction solution containing compound 3 to perform a hydrolysis reaction and adsorption and impurity removal. After the reaction is completed, cooling is performed, filtering is performed to remove the adsorbent material, and an acid solution is added to the filtrate to adjust the pH to neutral for precipitation, and filtering is performed to obtain norfloxacin; The compound 1 has the following structure: The compound 2 has the following structure: The compound 3 has the following structure:

2. A method for synthesizing norfloxacin according to claim 1, characterized in that: The molar ratio of the compound 1, propionic anhydride and boron compound is 1-2:8-10:1-5.

3. A method for synthesizing norfloxacin according to claim 1 or 2, characterized in that: The boron compound includes at least one of boric acid, hydrated sodium tetraborate, sodium tetraborate, potassium borate, calcium borate, zinc perborate and ulexite.

4. A method for synthesizing norfloxacin according to claim 1, characterized in that: The conditions of the boronization reaction are: temperature of 90-100° C. and time of 1-5 hours.

5. A method for synthesizing norfloxacin according to claim 1, characterized in that: The solvent medium includes at least one of N-methylpyrrolidone, propylene carbonate, dimethyl sulfoxide, 1,2-dichloroethane, toluene, xylene, chloroform, tetrahydrofuran, and dimethyltetrahydrofuran.

6. A method for synthesizing norfloxacin according to claim 1, characterized in that: The molar ratio of the compound 2 to piperazine is 1:1 to 1.

5.

7. A method for synthesizing norfloxacin according to claim 1, characterized in that: The conditions of the condensation reaction are: temperature of 90-100° C. and time of 1-5 h.

8. A method for synthesizing norfloxacin according to claim 1, characterized in that: The alkaline solution includes at least one of a sodium hydroxide solution, a sodium bicarbonate solution, and a potassium hydroxide solution; The acid solution includes at least one of acetic acid, boric acid, hydrochloric acid, sulfuric acid, tartaric acid, phosphoric acid, and citric acid; and the adsorption material includes activated carbon and / or graphite.

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