JP2006273718A - Method for producing levofloxacin-1/2 hydrate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for converting a crude levofloxacin raw material to levofloxacin-1/2 hydrate in a high yield. <P>SOLUTION: This method for producing the levofloxacin 1/2 hydrate is characterized by recrystallizing the levofloxacin from a water-containing lower alcohol or water-containing lower ketone having ≥0.14 and <4 vol% water content, or an aqueous ammonia-containing lower alcohol or aqueous ammonia-containing lower ketone containing ≥1 and ≤5 vol% conc. aqueous ammonia. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing levofloxacin 1/2 hydrate, an antibacterial compound, and more specifically, levofloxacin 1/2 which obtains the 1/2 hydrate in high yield by recrystallizing levofloxacin. It relates to a method for producing hydrates.

  Levofloxacin ((S) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1 , 4] benzoxazine-6-carboxylic acid) is a compound having high antibacterial activity and high safety (see Patent Document 1), and its 1/2 hydrate is known as an excellent synthetic antibacterial agent. Yes.

  In this levofloxacin, in addition to the above-mentioned 1/2 hydrate, there are known monohydrates having different numbers of water of crystallization, and the presence of anhydrous crystals produced by dehydration from hydrates. In order to use as an antibacterial agent, it is necessary to make these into 1/2 hydrate.

  Conventionally, levofloxacin hemihydrate is obtained by mixing a crystal of levofloxacin monohydrate or anhydride (hereinafter referred to as “levofloxacin crude material”) with a mixed solvent of ethanol and diethyl ether or concentrated aqueous ammonia and ethanol (patented) It was obtained by recrystallization from 4-11% hydrous ethanol or hydrous acetone and crystallization.

  However, in the former method using the mixed solvent, levofloxacin crude raw material monohydrate (hereinafter simply referred to as “monohydrate”) is precipitated in addition to levofloxacin, which is a half hydrate, at the time of crystallization. However, this may be mixed. In the latter case, monohydrate may be precipitated and mixed, which is insufficient as a method for obtaining high-purity levofloxacin.

Japanese Patent Publication No. 3-27534

  Accordingly, there is a demand for the development of a method capable of changing the raw levofloxacin raw material to levofloxacin 1/2 hydrate with a high yield, and it is an object of the present invention to provide such a method.

  In order to solve the above problems, the present inventor has intensively studied a recrystallization method for obtaining levofloxacin 1/2 hydrate, and recrystallizes levofloxacin in a solvent having a very low water content. Thus, it was found that levofloxacin hemihydrate can be obtained stably and in high yield, and the present invention was completed.

  That is, the present invention provides levofloxacin 1/2 hydrate characterized by recrystallizing levofloxacin from water-containing lower alcohols or water-containing lower ketones having a water content of 0.14% by volume or more and less than 4% by volume. It is a manufacturing method.

  The present invention also provides levofloxacin / 1/2 water characterized by recrystallizing levofloxacin from ammonia water-containing lower alcohols or ammonia water-containing lower ketones containing 1 to 5% by volume of concentrated aqueous ammonia. It is a manufacturing method of Japanese products.

  According to the present invention, it is possible to convert a levofloxacin crude raw material to levofloxacin 1/2 hydrate in a high yield. Therefore, it can be used as a method for producing levofloxacin 1/2 hydrate from levofloxacin crude raw materials produced by various methods.

  In one embodiment of the present invention, levofloxacin 1/2 hydrate is obtained by recrystallizing a crude levofloxacin raw material from water-containing lower alcohols or water-containing lower ketones having a water content of 0.14% by volume or more and less than 4% by volume. It is a manufacturing method.

  The levofloxacin raw material to be used includes levofloxacin monohydrate and anhydride, but is not limited to this, and ½ hydrate containing impurities or mixed with the monohydrate or anhydride. Goods may be used as crude raw materials.

  The solvent that can be used for recrystallization (hereinafter referred to as “recrystallization solvent”) is not particularly limited as long as it is a solvent that is miscible with a small amount of water and can dissolve the levofloxacin raw material. For example, anhydrous methanol, anhydrous ethanol Examples thereof include lower alcohols such as isopropanol and butanol, and lower ketones such as acetone and methyl ethyl ketone.

  The recrystallization solvent needs to have a water content of 0.14% by volume or more and less than 4% by volume, and particularly preferably has a water content of 0.5% by volume or more and 2% by volume or less.

  When lower alcohols are used as the recrystallization solvent, the amount may be in the range of 4 to 8 times by weight with respect to the levofloxacin raw material, and usually 6 to 7 times by weight is desirable. When a lower ketone is used as the recrystallization solvent, it may be in the range of 10-50 times by weight of the raw levofloxacin raw material, and usually 20-30 times by weight is desirable. Furthermore, it is not necessary to use the above-mentioned amount from the beginning of the treatment, and the amount used for the recrystallization solvent may be adjusted to the above amount by dissolving in a larger amount of the recrystallization solvent in advance.

  The heating temperature for dissolving the levofloxacin crude raw material in this recrystallization solvent is in the range of 50 ° C to 80 ° C, and when the recrystallization solvent is a lower alcohol, a temperature of about 75 to 80 ° C is usually preferable. When the recrystallization solvent is a lower ketone, it is usually preferably 50 ° C to 60 ° C. Moreover, the cooling temperature after melt | dissolution is the range of 25 degreeC to -5 degreeC, and about 5 degreeC is preferable normally. The cooling time may range from 2 hours to 2 days and nights, preferably day and night.

  The recrystallization of levofloxacin 1/2 hydrate is preferably performed after the levofloxacin crude raw material is dissolved in a recrystallization solvent by heating, and then immediately cooled and allowed to stand for crystallization.

  On the other hand, in another embodiment of the present invention, concentrated levofloxacin raw material is concentrated 1% to 5% by volume, preferably 1.5% to 2.5% by volume of concentrated aqueous ammonia (27% aqueous ammonia). This is a process for producing levofloxacin 1/2 hydrate, which is recrystallized from ammonia water-containing lower alcohols or ammonia water-containing lower ketones.

  The invention according to this aspect can be carried out in the same manner as the invention according to the first aspect, except that the above ammonia water-containing lower alcohols or ammonia water-containing lower ketones are used as the recrystallization solvent. That is, the amount of solvent used, the heating temperature, and the cooling temperature may be substantially the same as described above.

  The water content of the ammonia water-containing lower alcohols or ammonia water-containing lower ketones (hereinafter referred to as “ammonia-containing recrystallization solvent”) containing concentrated ammonia water as described above is the same as the amount of concentrated ammonia water. In addition, the conditions of the invention of the first aspect can be generally satisfied.

  The method for producing levofloxacin 1/2 hydrate according to the present invention described above can include a purification step prior to the recrystallization and crystallization. For example, after the levofloxacin crude raw material is dissolved, a purification process such as decolorization can be added using activated carbon or the like.

  Further, levofloxacin hemihydrate obtained by the method of the present invention is dried to obtain a final product. It is preferable to perform the drying of the crystals under conditions that can remove only the solvent from the target product. For example, the drying temperature is about 20-45 ° C., preferably about 35-40 ° C., and the degree of vacuum is about 5-100 mmHg. Preferably it is about 5-10 mmHg. The drying time is preferably about 8 hours, and various drying methods such as an inverted conical screw agitation vacuum dryer, a vertical vibration vacuum dryer, or a box-type box vacuum dryer can be used as the drying method. Mention may be made of a drying method using a machine.

  The thus obtained levofloxacin 1/2 hydrate can be made into various forms of antibacterial agents by combining it with a known pharmaceutical carrier.

  EXAMPLES Next, although an Example is given and this invention is demonstrated still in detail, this invention is not restrict | limited at all by this.

Example 1
In a 100 mL eggplant-shaped flask, 10 g of levofloxacin crude raw material (anhydrous; water content: 0.994%) was weighed, and 2 v / v% water was added to absolute ethanol (water content: 0.14 v / v%). The solution made up to 65 mL was added and heated in a water bath. The crude levofloxacin raw material was dissolved at 77.3 ° C. and then allowed to cool. The mixture was allowed to cool at room temperature for one day and night, then filtered under reduced pressure and air-dried. 9.51 g of levofloxacin 1/2 hydrate was obtained.

Moisture value (Karl Fisher method Hiranuma Sangyo Co., Ltd. AQ-55C):
2.56% (theoretical value 2.43%)
Infrared absorption spectrum (IR-5000 manufactured by JASCO Corporation):
1724, 1005 Kaiser
Powder X-ray crystal diffraction (2θ):
6.5 °, 9.5 °, 12.9 °, 13.5 °, 19.2 °

Example 2
To a 100 mL eggplant-shaped flask, weighed 10.00 g of crude levofloxacin raw material (1/2 hydrate; moisture content 2.462%), added 70 mL of absolute ethanol (water content 0.14 v / v%), Heated in a water bath. Levofloxacin was dissolved at 79 ° C. and then allowed to cool. The mixture was allowed to cool at room temperature for 1 day and then filtered under reduced pressure and air-dried. 9.41 g of levofloxacin 1/2 hydrate was obtained.

Moisture value (Karl Fisher method Hiranuma Sangyo Co., Ltd. AQ-55C):
2.69% (theoretical value 2.43%)
Infrared absorption spectrum (IR-5000 manufactured by JASCO Corporation):
1724, 1006 Kaiser X-ray powder diffraction (2θ):
6.5 °, 9.5 °, 12.9 °, 13.5 °, 19.2 °

Example 3
In a 100 mL eggplant-shaped flask, weighed 10.00 g of levofloxacin crude raw material (anhydrous; water content 0.9994%), and added 2v / v% concentrated ammonia to absolute ethanol (water content 0.14 v / v%). A solution was made up to 60 mL by adding water and heated in a water bath. Since the crude levofloxacin was dissolved at 77.5 ° C., it was then allowed to cool. The mixture was allowed to cool at room temperature for 1 day and then filtered under reduced pressure and air-dried. 9.24 g of levofloxacin 1/2 hydrate was obtained.

Moisture value (Karl Fisher method Hiranuma Sangyo Co., Ltd. AQ-55C):
2.36% (theoretical value 2.43%)
Infrared absorption spectrum (IR-5000 manufactured by JASCO Corporation):
1724, 1006 Kaiser X-ray powder diffraction (2θ):
6.5 °, 9.5 °, 12.9 °, 13.5 °, 19.2 °

Example 4
A levofloxacin crude raw material (anhydrous; water content of 0.9994%) (1.000 g) was weighed into a 500 mL eggplant-shaped flask, and 260 mL of a solvent containing acetone (water content 0.07%) and water 2% was added thereto. In addition, it was heated in a water bath. Since the crude levofloxacin was dissolved at 51.6 ° C., it was then allowed to cool. The mixture was allowed to cool at room temperature for 1 day and then filtered under reduced pressure and air-dried. 6.80 g of levofloxacin 1/2 hydrate was obtained.

Moisture value (Karl Fisher method Hiranuma Sangyo Co., Ltd. AQ-55C):
2.688% (theoretical value 2.43%)
Infrared absorption spectrum (IR-5000 manufactured by JASCO Corporation):
1724, 1006 Kaiser X-ray powder diffraction (2θ):
6.5 °, 9.5 °, 12.8 °, 13.5 °, 19.1 °

According to the method of the present invention, levofloxacin / 1/2 hydrate can be efficiently obtained from a raw levofloxacin raw material, which is advantageous as a method for economically producing an antibacterial agent containing levofloxacin / 1/2 hydrate as an active ingredient. It can be used for.

more than

Claims (12)

  A process for producing levofloxacin 1/2 hydrate, characterized by recrystallizing levofloxacin from water-containing lower alcohols or water-containing lower ketones having a water content of 0.14% by volume or more and less than 4% by volume.   The method for producing levofloxacin 1/2 hydrate according to claim 1, wherein the water content of the water-containing lower alcohol or water-containing lower ketone is 0.5 vol% or more and 2 vol% or less.   The method for producing levofloxacin 1/2 hydrate according to claim 1 or 2, wherein 4 to 8 times by weight of water-containing lower alcohol is used relative to levofloxacin.   The method for producing levofloxacin ½ hydrate according to claim 1 or 2, wherein 10 to 50 times by weight of water-containing lower ketone is used relative to levofloxacin.   The method for producing levofloxacin 1/2 hydrate according to any one of claims 1 to 4, wherein the levofloxacin is an anhydride or monohydrate of levofloxacin.   A process for producing levofloxacin 1/2 hydrate, characterized by recrystallizing levofloxacin from ammonia water-containing lower alcohols or ammonia water-containing lower ketones containing 1 to 5% by volume of concentrated aqueous ammonia.   The levofloxacin / 1/2 water according to claim 6, wherein the ammonia water-containing lower alcohol or the ammonia water-containing lower ketone contains 1.5% by volume to 2.5% by volume of concentrated ammonia water. Japanese recipes.   The method for producing levofloxacin 1/2 hydrate according to claim 6 or 7, wherein the lower alcohols containing ammonia water 4 to 8 times by weight thereof are used relative to levofloxacin.   The method for producing levofloxacin 1/2 hydrate according to claim 6 or 7, wherein 10 to 50 times by weight of an aqueous ammonia-containing lower ketone is used relative to levofloxacin.   The method for producing levofloxacin 1/2 hydrate according to any one of claims 6 to 9, wherein levofloxacin is an anhydride or monohydrate of levofloxacin.   Levofloxacin is dissolved at a temperature of 75-80 ° C. in water-containing ethanol having a water content of 6-7 times its weight and a water content of 0.5% by volume to 2% by volume. A process for producing the characteristic levofloxacin 1/2 hydrate. Levofloxacin was dissolved at a temperature of 75 to 80 ° C. in ethanol containing ammonia water containing 6 to 7 times its weight and concentrated ammonia water at 1.5 to 2.5% by volume. A process for producing levofloxacin 1/2 hydrate, characterized by cooling to room temperature.