CN102070650B - Preparation method for levofloxacin-N-oxide - Google Patents

Abstract

The invention provides a preparation method for levofloxacin-N-oxide and relates to the field of a levofloxacin medicament. The preparation method comprises the following steps of: mixing the levofloxacin and 0.1mol/L hydrochloric acid solution according to a proportion of 0.03mol: 500ml, and dissolving the mixture at the temperature of between 80 and 100 DEG C; adding 100ml of hydrogen peroxide solution having the mass concentration of 30 percent by three times at the temperature of between 60 and 80 DEG C; reacting for 3 to 5 hours each time to obtain reaction solution; drying the reaction solution through distillation; and recrystallizing the residual water. The selection of the raw materials is convenient for the subsequential separating operation; by adding the hydrogen peroxide solution in steps, the progress of the reaction is controlled, the generation of byproducts is reduced, the conversion rate of the levofloxacin-N-oxide is improved and the generation of impurities is reduced; and by the method, the condition is easy to control, the route is simple, the solvent is obtained easily, the yield is 88.7 percent, the cost of the levofloxacin-N-oxide serving as a contrast is reduced greatly, and the product purity is high and over 99.5 percent, so the levofloxacin-N-oxide can be used as a working contrast.

Description

The preparation method of levofloxacin-N-oxide compound

Technical field

The present invention relates to medicine levofloxacin field, the preparation method of particularly a kind of levofloxacin-N-oxide compound.

Background technology

Levofloxacin (Levofloxacin) is the levo form of Ofloxacine USP 23, has has a broad antifungal spectrum, characteristics that anti-microbial effect is strong.Japan Daiichi Pharmaceutical Co., Ltd. in 1993 at Japanese list marketing levofloxacin raw material and tablet, and at present in multinational listings such as Britain, the U.S..The Levaquin of present domestic listing mainly contains tablet, little pin, glucose injection and eye drops etc.At present domestic and international more bibliographical information the known impurities of Ofloxacine USP 23; And it is less about the research report of levofloxacin known impurities; But known impurities and synthetic route through Ofloxacine USP 23 can be inferred; Levofloxacin contains with the identical and three-dimensional configuration different processes of Ofloxacine USP 23 structural formula impurity probably, and its steric configuration all should be levo form, and this impurity research to levofloxacin has higher reference value.

The quality standard of levofloxacin is recorded in national standard and import standard at present; All known impurities is not controlled, according to bibliographical information, [Lalitha Devi M such as M. Lalitha Devi; Chandrasekhar K B. A validated stability-indicating RP-HPLC method for levofloxacin in the presence of degradation products; Its process related impurities and identification of oxidative degradant [J]. J Pharm Biomed Anal, 2009,50 (5): 710-707] the employing reversed-phased high performace liquid chromatographic; Levofloxacin acid, alkali, oxidation, illumination, high temperature are destroyed sample and detects; The result finds that levofloxacin is more stable under conditions such as alkali (0.5N NaOH), high temperature, illumination, does not detect the generation degraded product basically, and in acid (0.5N HCL); Place after 7 days, micro-degraded product occurred for 70 ℃; H 0.01% ₂O ₂The middle placement after 12 hours produces tangible degraded product.Wherein at H ₂O ₂The middle placement in the degraded product that produces contained levofloxacin-N-oxide compound, CAS 178964-53-9, and molecular formula is C ₁₈H ₂₀FN ₃O ₅, molecular weight is 377, chemical name: 4-[(S) 6-carboxyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H-pyrido [1,2,3- De]-1,4-benzoxazine-10-yl]-1-N-METHYL PIPERAZINE-1-oxide compound, English name be 4-[( S)-6-carboxy-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H-pyrido [1,2,3- De]-1,4-benzoxazine-10-yl]-1-methylpiperazine 1-oxide, though the existing abroad bibliographical information of the structural research of this impurity, its preparation method does not still have public reported both at home and abroad.

Summary of the invention

In order to overcome the above problems, the invention provides the method that levofloxacin prepares levofloxacin-N-oxide compound of passing through that a kind of technology is simple, product purity is high.

The present invention realizes through following measure:

The preparation method of a kind of levofloxacin-N-oxide compound may further comprise the steps:

(1) hydrochloric acid soln of levofloxacin and 0.1mol/L is pressed 0.03mol: the mixed of 500ml is stirred to dissolving under 80～100 ℃ of conditions of temperature;

Add mass concentration under (2) 60～80 ℃ of conditions and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml, reaction 3～5h adds hydrogen peroxide solution 100ml, reaction 3～5h, reaction soln;

(3), and remove residual H with the reaction soln water bath method ₂O ₂, get residue, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.

Recrystallization may further comprise the steps:

(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter; Filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 1;

(2) recrystallization: get levofloxacin-N-oxide compound bullion 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound bullion 1 dissolving, filter; Filtrating is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 2;

(3) repeating step (2) is 1-2 time, and the gained crystal is levofloxacin-N-oxide compound.

The hydrochloric acid soln of levofloxacin and 0.1mol/L mixes in the reaction flask of prolong is housed.

Reaction formula is as shown in the formula 1:

Method of the present invention is raw material with the levofloxacin, adopts HCL and H ₂O ₂As oxygenant, accurately control levofloxacin and HCL, levofloxacin and H ₂O ₂Ratio, and H ₂O ₂Dividing three times adds; Can make oxidizing reaction more abundant; Reduce other the oxidized probability of N; Control the transformation efficiency of levofloxacin-N-oxide compound, reduce the generation of side reactions such as decarboxylation, demethyl (seeing reaction formula 2 and reaction formula 3), as far as possible to improve the purity of gained levofloxacin-N-oxide compound as far as possible; Adopt repeatedly water recrystallization, control strength of solution and Tc, the impurity that will contain is as wide as possible removed, and has also improved the purity of levofloxacin-N-oxide compound.

Reaction formula 2:

Reaction formula 3:

Beneficial effect of the present invention:

1, with the levofloxacin be raw material, employing HCL is a reaction medium, H ₂O ₂As oxygenant, HCL and H ₂O ₂Can pass through heated volatile, not introduce new impurity, be convenient to follow-up mask work, through the substep adding of hydrogen peroxide solution, the progress of control reaction reduces the generation of by product, improves the transformation efficiency of levofloxacin-N-oxide compound, the generation of minimizing impurity;

2, condition of the present invention is prone to control, and route is simple, and solvent is easy to get, and productive rate is 88.7%, can reduce the cost of levofloxacin-N-oxide compound as reference substance greatly;

3, the levofloxacin-N-oxide compound of the present invention's preparation is through the water recrystallization, and products obtained therefrom purity is high, can reach more than 99.5%, can be used as the work reference substance and uses;

4, synthetic levofloxacin-N-oxide compound impurity of not being merely levofloxacin is identified and impurity detects reference substance is provided; For the raising of the quality standard of levofloxacin and preparation thereof and the quality control of product provide useful reference, also reference is provided for similar compound synthetic.

Description of drawings

The HPLC spectrogram of the levofloxacin that accompanying drawing 1 obtains for the inventive method-N-oxide compound.

Embodiment

Below in conjunction with embodiment method of the present invention is further specified.

(1) get levofloxacin raw material 0.03mol, quality is 10.83g, puts into the reaction flask that prolong is housed, and adds the hydrochloric acid soln 500ml of 0.1mol/L, under 80～100 ℃ of conditions of temperature, is stirred to the levofloxacin dissolving;

Add mass concentration in (2) 80～100 ℃ of condition downhill reaction bottles and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml again, reaction 3～5h adds hydrogen peroxide solution 100ml again, reaction 3～5h, reaction soln;

(3), and remove residual HCL and H with the water bath method of reaction soln with 100 ℃ ₂O ₂, get residue 11.2g, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.

The step of recrystallization is following:

(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter; Filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 1;

(2) recrystallization: get levofloxacin-N-oxide compound bullion 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound bullion 1 dissolving, filter; Filtrating is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 2;

(3) repeating step (2) is 1-2 time, and gained crystal 10g is levofloxacin-N-oxide compound, and ultimate yield is greater than 88%.

Adopt the HPLC method to the detecting of levofloxacin-N-oxide compound of obtaining through the inventive method, collection of illustrative plates is seen Fig. 1.The purity that draws levofloxacin-N-oxide compound that the inventive method obtains with the peak area normalization method reaches more than 99.5%, satisfies the request for utilization as the work reference substance fully.

Claims (3)

1. the preparation method of levofloxacin-N-oxide compound is characterized in that may further comprise the steps:

(1) hydrochloric acid soln of levofloxacin and 0.1mol/L is pressed 0.03mol: the mixed of 500ml is stirred to dissolving under 80～100 ℃ of conditions of temperature;

Add mass concentration under (2) 60～80 ℃ of conditions and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml again, reaction 3～5h adds hydrogen peroxide solution 100ml again, reaction 3～5h, reaction soln;

(3), and remove residual H with the reaction soln water bath method ₂O ₂, get residue, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.

2. method according to claim 1 is characterized in that recrystallization may further comprise the steps:

(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter; Filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 1;

(2) recrystallization: get levofloxacin-N-oxide compound bullion 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound bullion 1 dissolving, filter; Filtrating is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separates out crystal, filters; Crystal is used the water washing several times, and merging filtrate and washing lotion are concentrated into 200ml, puts 4 ℃ of refrigerators and places 2 hours; Separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound bullion 2;

(3) repeating step (2) is 1-2 time, and the gained crystal is levofloxacin-N-oxide compound.

3. method according to claim 1 and 2 is characterized in that the hydrochloric acid soln of levofloxacin and 0.1mol/L mixes in the reaction flask of prolong is housed.

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