Preparation and purification process of levofloxacin lactate

Abstract

The invention discloses a preparation and purification process of lactic acid levofloxacin, and relates to the technical field of medical chemistry. The preparation and purification process comprises the following steps: by taking a compound a as an initial raw material, racemizing under the action of a catalyst to obtain a compound b, reacting the compound b with lactic anhydride to obtain a compound d, namely a levofloxacin lactate crude product, and purifying to obtain the levofloxacin lactate. And crystallizing the compound d levofloxacin lactate crude product through a mixed solvent of an acetate solvent and water to obtain a compound d levofloxacin lactate finished product. The catalyst is a chiral ionic catalyst, has the advantages of good activity, high efficiency and the like, can effectively promote the reaction, and can improve the yield and purity of the product through crystallization of a mixed solvent of an acetic ester solvent and water.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation and purification process of levofloxacin lactate. Background Art

[0002] Levofloxacin is a broad-spectrum antibacterial agent, and its lactate form has better water solubility and bioavailability.

[0003] The existing synthesis of levofloxacin mainly includes chiral resolution and direct synthesis using chiral source as raw materials. Traditional chiral resolution is to react ofloxacin with a racemic resolving agent (such as chiral acid or chiral base) to form diastereoisomers. The traditional racemization reaction has a long reaction time and low conversion rate. However, the cost of direct synthesis using chiral source as raw material is relatively high.

[0004] Aiming at the problem of low racemization conversion rate of existing ofloxacin, the present invention provides a new preparation and purification process of levofloxacin lactate, which has the advantages of high racemization conversion rate, high product purity, etc. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation and purification process of levofloxacin lactate to solve the problems of long reaction time and low conversion rate in traditional racemization reaction.

[0006] The technical solution of the present invention is as follows:

[0007] A synthesis and purification process of levofloxacin lactate includes the following synthesis and purification steps:

[0008] (1) Using compound a as the starting material, compound a undergoes racemization under the action of compound b to obtain compound c;

[0009] (2) Compound c reacts with lactic anhydride under the action of a catalyst to obtain crude product of compound d levofloxacin lactate;

[0010] (3) The crude product of compound d levofloxacin lactate is crystallized by a mixed solvent of acetate solvent and water to obtain levofloxacin lactate;

[0011] The specific reaction is as follows:

[0012]

[0013] Further, in step (1), the reaction conditions for racemization are as follows: the amount of the reaction solvent triethylene glycol is 4.5 times the weight of compound a, the molar ratio of the chiral ionic catalyst compound b to compound a added is 1:1.5 - 1:1.8, the reaction temperature is 40 - 45 °C, and the reaction time is 5 - 7 hours under argon protection. Adjust the pH of the system to 5.8 - 6.2, maintain the temperature at 5 - 15 °C for crystallization and separation to obtain the crude product of compound c. The crude product of compound c is heated to 55 - 65 °C and dissolved in 2 - 3 times the weight of isopropanol, and while maintaining the temperature, slowly add 3 times the weight of water of isopropanol, and cool down to 5 - 15 °C for crystallization and filtration to obtain compound c.

[0014] The reaction in step (1) can be judged whether it is complete according to the conventional methods in the art, such as HPLC technology.

[0015] Further, the preparation method of the chiral ionic catalyst compound b is as follows: under argon protection, dissolve compound e in 4 - 5 times the weight of tert-butyl methyl ether and stir to dissolve. Heat up to 55 - 65 °C, and slowly add ferric chloride with a molar ratio of 1:1.02 - 1:1.09 to compound e. After adding, keep the temperature for reaction for 3 - 4 hours, then distill off the solvent under reduced pressure, obtain a solid, slurry it with absolute ethanol at 30 - 35 °C, and filter to obtain compound b;

[0016]

[0017] Further, the reaction conditions in step (2) are as follows: the amount of the reaction solvent acetone is 3 times the weight of compound c, the molar ratio of lactic anhydride to compound c is 1.75:1 - 2.10:1, the molar ratio of the added catalyst 4-dimethylaminopyridine to compound c is 0.21:1 - 0.28:1, the reaction temperature is 60 - 70 °C, and the reaction time is 4 - 5 hours.

[0018] After the reaction of the present invention, the reaction product can be treated by the common treatment methods in the art, such as concentration, organic solvent extraction; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product.

[0019] Further, the crystallization conditions in step (3) are as follows: the amount of the crystallization solvent propylene glycol monomethyl ether acetate is 1 - 1.5 times the weight of compound d levofloxacin lactate, the amount of water is 5 - 6 times the weight of compound d levofloxacin lactate, the dissolution temperature is 55 - 60 °C, the crystallization temperature is 0 - 5 °C, and the drying is vacuum drying, and the drying temperature is 45 ± 5 °C.

[0020] Beneficial effects:

[0021] 1. In the present invention, levofloxacin is obtained by racemization reaction of ofloxacin and a chiral ionic catalyst at 40-45 °C, and then by adjusting the pH for crystallization and separation. The racemization reaction conditions of the present invention are simple, the reaction materials are easy to obtain, the cost is low, and the racemization conversion rate is high compared with the traditional racemization process.

[0022] 2. The levofloxacin lactate of the present invention is obtained by crystallization and purification with a mixed solvent of propylene glycol methyl ether acetate and water. Compared with the traditional purification process, the purified levofloxacin lactate of the present invention has high purity, uniform particle size distribution, simple purification operation, and is suitable for commercial production. Description of the Drawings

[0023] Figure 1 It is the chemical structure diagram of levofloxacin lactate.

[0024] Figure 2 It is the nuclear magnetic resonance diagram of levofloxacin lactate of the present invention.

[0025] Figure 3 It is the HPLC diagram of levofloxacin lactate of the present invention.

[0026] Figure 4 It is the particle size distribution diagram of levofloxacin lactate of the present invention. Detailed Embodiments

[0027] The present invention will be described in detail below in conjunction with embodiments. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other.

[0028] Example 1 (1)

[0030]

[0031] Under argon protection, 50 g of compound e was dissolved in 210 g of tert-butyl methyl ether and stirred to dissolve. The temperature was raised to 60 °C, and 76.40 g of ferric chloride was slowly added. After completion of the addition, the reaction was carried out under insulation for 3 hours, then tert-butyl methyl ether was removed by distillation under reduced pressure until no liquid was collected. Anhydrous ethanol was added to the residue for pulping at 30 °C for 2 h, filtered, and dried in vacuo to obtain 118.0 g of compound b in a yield of 96.1%. (2)

[0033]

[0034] Under argon protection, 100.0 g of compound a and 450 g of triethylene glycol were added into the reaction flask, and 51.0 g of chiral ionic catalyst compound b was added. The reaction temperature was 40 °C, and the reaction time was 7 hours under argon protection. The reaction process was monitored by HPLC; the pH of the system was adjusted to 6.0, and the temperature was maintained at 10 °C for crystallization separation to obtain 80 g of crude compound c; 200 g of isopropanol was added to the crude compound c, heated to 65 °C to dissolve and clarify, and 600 g of water was slowly added while maintaining the temperature, and then cooled to 8 °C for crystallization and filtration to obtain 72.6 g of compound c, with a yield of 72.6%. (3)

[0036]

[0037] 70.0 g of compound c was added into the reaction flask, 210 g of acetone and 24.5 g of lactic anhydride were added, and 6 g of catalyst 4-dimethylaminopyridine was added. The reaction temperature was 65 °C, and the reaction was carried out for 5 hours. Then the reaction solution was cooled to 15 °C, and 200 g of water was slowly added, and crystallization was stirred for 4 hours. Filtration was carried out, and the filter cake was washed with a small amount of acetone-water mixed solvent, drained, and dried at 50 °C under vacuum to obtain 79.9 g of crude levofloxacin lactate (compound d), with a yield of 91.2%.

[0038] (4) 75 g of the crude levofloxacin lactate (compound d) obtained from the previous step was added into the reaction flask, and then 110 g of propylene glycol methyl ether acetate was added, heated to 60 °C, and stirred to dissolve and clarify; then 375 g of water was slowly added, and stirred for 1 hour; cooled to 2 °C, and crystallization was stirred for 3 hours. Filtration was carried out, and the filter cake was washed with a small amount of propylene glycol methyl ether acetate-water mixed solvent, drained, and dried at 45 °C under vacuum to obtain 70.3 g of levofloxacin lactate (compound d), with a yield of 93.7%. The molecular formula of the product is C 21 H 26 FN 3 O 7 , and the molecular weight is 451.45. Analysis results: HPLC purity analysis > 99.9%, elemental analysis: C 55.82%, H 5.76%, F 4.21%, N 9.30%, O 24.81%. The nuclear magnetic resonance, purity analysis, and particle size distribution of levofloxacin lactate are as shown in Figure 2 、 Figure 3 、 Figure 4 shown.

[0039] Example 2 (1)

[0041]

[0042] Under argon protection, 50 g of compound e was dissolved in 210 g of tert-butyl methyl ether and stirred until dissolved. The temperature was raised to 55 °C, and 79.30 g of iron(III) chloride was slowly added. After completion of the addition, the mixture was kept at the same temperature for reaction for 4 hours. Then, tert-butyl methyl ether was removed by distillation under reduced pressure until no liquid was distilled out. Anhydrous ethanol was added to the residue, and the mixture was slurried at 35 °C for 2 h, filtered, and dried in vacuo to obtain 117.1 g of compound b with a yield of 95.4%. (2)

[0044]

[0045] Under argon protection, 100 g of compound a and 450 g of triethylene glycol were added to the reaction flask, and 42.4 g of chiral ionic catalyst compound b was added. The reaction temperature was 45 °C, and the reaction was carried out for 5 hours under argon protection. The reaction process was monitored by HPLC; the pH of the system was adjusted to 6.2, and the temperature was maintained at 15 °C for crystallization separation to obtain 83 g of crude compound c; 249 g of isopropanol was added to the crude compound c, and the mixture was heated to 60 °C until dissolved and clarified. While maintaining the temperature, 747 g of water was slowly added, and then the temperature was lowered to 15 °C for crystallization. After filtration, 70.8 g of compound c was obtained with a yield of 70.8%. (3)

[0047]

[0048] 70 g of compound c was added to the reaction flask, 210 g of acetone and 29.3 g of lactic anhydride were added, and 6.6 g of catalyst 4-dimethylaminopyridine was added. The reaction temperature was 70 °C, and the reaction was carried out for 4 hours. Then the reaction solution was cooled to 15 °C, and 200 g of water was slowly added, and the mixture was stirred for crystallization for 4 hours. After filtration, the filter cake was washed with a small amount of acetone-water mixed solvent, drained, and dried in vacuo at 50 °C to obtain 80.8 g of crude levofloxacin lactate (compound d). The yield was 92.3%.

[0049] (5) 75 g of the crude levofloxacin lactate (compound d) obtained from the previous step was added to the reaction flask, and 75 g of propylene glycol methyl ether acetate was added. The mixture was heated to 60 °C and stirred until dissolved and clarified; then 450 g of water was slowly added, and the mixture was stirred for 1 hour; the temperature was lowered to 5 °C, and the mixture was stirred for crystallization for 3 hours. After filtration, the filter cake was washed with a small amount of propylene glycol methyl ether acetate-water mixed solvent, drained, and dried in vacuo at 50 °C to obtain 71.1 g of levofloxacin lactate (compound d) with a yield of 94.8%. Molecular formula of the product: C 21 H 26 FN 3 O 7 , molecular weight: 451.45. Analysis results: HPLC purity analysis > 99.9%, elemental analysis: C 55.82%, H 5.76%, F 4.21%, N 9.30%, O 24.81%.

[0050] Example 3 (1)

[0052]

[0053] Under argon protection, 50 g of compound e was dissolved in 210 g of tert-butyl methyl ether and stirred until dissolved. The temperature was raised to 65 °C, and 74.30 g of ferric chloride was slowly added. After completion of the addition, the mixture was kept at the temperature for reaction for 3.5 hours, then tert-butyl methyl ether was removed by distillation under reduced pressure until no liquid was distilled out. Anhydrous ethanol was added to the residue, and the mixture was slurried at 33 °C for 2 h, filtered, and dried in vacuo to obtain 116.4 g of compound b with a yield of 94.8%. (2)

[0055]

[0056] Under argon protection, 100 g of compound a and 450 g of triethylene glycol were added into the reaction flask, and 47.3 g of chiral ionic catalyst compound b was added. The reaction temperature was 43 °C, and the reaction was carried out for 6 hours under argon protection. The reaction process was monitored by HPLC; the pH of the system was adjusted to 5.8, and the temperature was maintained at 5 °C for crystallization separation to obtain 84.6 g of crude compound c; 170 g of isopropanol was added to the crude compound c, and the mixture was heated to 55 °C until dissolved and clarified. While maintaining the temperature, 510 g of water was slowly added, and then the temperature was lowered to 5 °C for crystallization. After filtration, 72.1 g of compound c was obtained with a yield of 72.1%. (3)

[0058]

[0059] 70 g of compound c was added into the reaction flask, 210 g of acetone and 26.6 g of lactic anhydride were added, and 5 g of catalyst 4-dimethylaminopyridine was added. The reaction temperature was 65 °C, and the reaction was carried out for 4 hours. Then the reaction solution was cooled to 20 °C, and 200 g of water was slowly added, followed by stirring for crystallization for 4 hours. The mixture was filtered, and the filter cake was washed with a small amount of acetone-water mixed solvent, drained, and dried in vacuo at 45 °C to obtain 80.9 g of crude levofloxacin lactate (compound d). The yield was 92.4%.

[0060] (4) 75 g of the crude levofloxacin lactate (compound d) obtained from the previous step was added into the reaction flask, and then 97.5 g of propylene glycol methyl ether acetate was added. The mixture was heated to 58 °C and stirred until dissolved and clarified; then 450 g of water was slowly added, followed by stirring for 1 hour; the temperature was lowered to 0 °C, and stirring for crystallization was carried out for 3 hours. The mixture was filtered, and the filter cake was washed with a small amount of propylene glycol methyl ether acetate-water mixed solvent, drained, and dried in vacuo at 40 °C to obtain 70.8 g of levofloxacin lactate (compound d). The yield was 94.4%. Molecular formula of the product: C 21 H 26 FN 3 O 7, Molecular weight: 451.45. Analysis results: HPLC purity analysis > 99.9%, elemental analysis: C 55.82%, H 5.76%, F 4.21%, N 9.30%, O 24.81%.

[0061] The above-described embodiments merely represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A synthesis and purification process of levofloxacin lactate, characterized in that: The process includes the following synthesis and purification steps: S1, using compound a as a starting material, and subjecting it to racemization under the action of compound b to obtain compound c; S2, compound c reacts with lactic anhydride under the action of a catalyst to obtain compound d, a crude product of levofloxacin lactate; S3. The crude product of compound d levofloxacin lactate is then crystallized through a mixed solvent of an acetate solvent and water to obtain levofloxacin lactate; the specific reaction is as follows:

2. The synthesis and purification process of levofloxacin lactate according to claim 1, characterized in that: The compound c reacts with lactic anhydride under the action of a catalyst. Specifically, the compound c is dissolved in acetone, lactic anhydride and a catalyst 4-dimethylaminopyridine are added, and the reaction obtains the compound d levofloxacin lactate.

3. The synthesis and purification process of levofloxacin lactate according to claim 1, characterized in that: The acetate solvent is propylene glycol methyl ether acetate.

4. The synthesis and purification process of levofloxacin lactate according to claim 1, characterized in that: The reaction conditions for racemization are as follows: the amount of the reaction solvent triethylene glycol is 4.5 times the weight of compound a, the molar ratio of the added chiral ion catalyst compound b to compound a is 1:1.5-1:1.8, the reaction temperature is 40-45°C, and the reaction time is 5-7 hours under argon protection; l adjust the system pH to 5.8-6.2, maintain the temperature at 5-15°C, separate and crystallize to obtain a crude compound c; the crude compound c is heated to 55-65°C and dissolved in 2-3 times the weight of isopropanol, maintain the temperature and slowly add water 3 times the weight of isopropanol, cool to 5-15°C, crystallize and filter to obtain compound c.

5. The synthesis and purification process of levofloxacin lactate according to claim 4, characterized in that: The preparation method of the chiral ion catalyst compound b is as follows: under argon protection, compound e is dissolved in 4 to 5 times the weight of tert-butyl methyl ether, and stirred to dissolve; the temperature is raised to 55 to 65° C., and ferric chloride is slowly added in a molar ratio of 1:1.02 to 1:1.09 to compound e; after the addition is completed, the reaction is kept warm for 3 to 4 hours, and the solvent is evaporated under reduced pressure to obtain a solid, and anhydrous ethanol is added at 30 to 35° C. for pulping, and the compound b is filtered; 6. The synthesis and purification process of levofloxacin lactate according to claim 2, characterized in that: The reaction conditions for the reaction of compound C with lactic anhydride under the action of a catalyst are as follows: the amount of the reaction solvent acetone is 3 times the weight of the compound C, the molar ratio of lactic anhydride to compound C is 1:0.7-1:0.9, the molar ratio of the added catalyst 4-dimethylaminopyridine to compound C is 0.21:1-0.28:1, the reaction temperature is 60-70°C, and the reaction time is 4-5 hours.

7. The synthesis and purification process of levofloxacin lactate according to claim 1, characterized in that: The crystallization conditions of this process are as follows: the amount of the crystallization solvent propylene glycol methyl ether acetate is 1 to 1.5 times the weight of compound d levofloxacin lactate, the amount of water is 5 to 6 times the weight of compound d levofloxacin lactate, the dissolution temperature is 55 to 60°C, the crystallization temperature is 0-5°C, the drying is vacuum drying, and the drying temperature is 45±5°C.

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