JPH069523A - Purification of 4-dedimethylaminotetracycline - Google Patents

Abstract

PURPOSE:To obtain a high-purity 4-dedimethylaminotetracycline only by single recrystallization without using a large quantity of a solvent for recrystallization. CONSTITUTION:The purification of 4-dedimethylaminotetracycline is characteristically carried out by dissolving a mixture containing 4- dedimethylaminotetracycline in 1,4-dioxane, concentrating the resultant solution, dissolving the concentrated solution in methylene chloride and then precipitating 4-dedimethylaminotetracycline from the resultant solution.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for purifying 4-dedimethylaminotetracycline. The 4-dedimethylaminotetracycline purified according to the present invention has anti-collagen-destroying enzyme activity or anti-collagenase activity and does not have antibacterial activity. It is useful for treating diseases characterized by destruction (see JP-A-61-243023).

[0002]

2. Description of the Related Art 4-Dedimethylaminotetracycline can be synthesized by converting tetracycline into a quaternary ammonium salt using methyl iodide and then reducing the quaternary ammonium salt with zinc in an aqueous acetic acid solution. Reported [JRD McCormick et al., Journal
Of American Chemical Society (J. Amer.
Chem. Soc.), 79, 2849 (1957).
Year), and JH Boothe et al., Journal of American Chemical Society (J. Amer. Chem.So.
c.), Vol. 80, p. 1654 (1958)].
Further, the above literature describes a method for purifying 4-dedimethylaminotetracycline. JRD McCorm
ick et al. reported a method for recrystallizing crude 4-dedimethylaminotetracycline from methanol, and
JH Boothe et al. Have used crude 4-dedimethylaminotetracycline in boiling ethyl acetate and petroleum ether (boiling point 9
A method of recrystallizing from a 1: 1 mixed solvent (0 to 100 ° C.) is reported.

[0003]

When 4-dedimethylaminotetracycline is used as an active ingredient of a medicine, it is necessary to effectively remove impurities produced during the synthesis and highly purify it. According to the method described in the above document, high purity 4-dedimethylaminotetracycline cannot be obtained. That is, JRD
An attempt was made to dissolve crude 4-dedimethylaminotetracycline in methanol to crystallize it according to the method of McCormick et al. However, 4-dedimethylaminotetracycline could not be obtained as crystals. Also, J.
An attempt was made to recrystallize crude 4-dedimethylaminotetracycline from a mixed solvent of hexane and ethyl acetate (composition 1.25: 1) according to the method of H. Boothe et al., And the recrystallization operation was performed twice or more. Purity 9 only after repeated
8% or more of 4-dedimethylaminotetracycline was obtained. However, this purification method was carried out in the recrystallization operation by using 1 g of crude 4-dedimethylaminotetracycline.
A large amount of solvent, about 180 ml, is required. When industrially obtaining 4-dedimethylaminotetracycline, a purification method that is simple in operation and economically feasible is required. Therefore, an object of the present invention is to provide a purification method that industrially advantageously provides highly pure 4-dedimethylaminotetracycline.

[0004]

According to the present invention, the above object is achieved by dissolving a mixture containing 4-dedimethylaminotetracycline in 1,4-dioxane, concentrating the obtained solution, and concentrating the solution. This is accomplished by providing a process for purifying 4-dedimethylaminotetracycline, which comprises dissolving the liquid in methylene chloride and then precipitating 4-dedimethylaminotetracycline from the resulting solution.

A mixture containing 4-dedimethylaminotetracycline (hereinafter, abbreviated as crude 4-dedimethylaminotetracycline) is prepared by converting tetracycline into a quaternary ammonium salt using methyl iodide according to the method described in the literature. Afterwards, the quaternary ammonium salt is reduced with zinc in aqueous acetic acid and the reaction mixture obtained is filtered,
The filtrate is poured into water to precipitate as crystals.

The step of dissolving crude 4-dedimethylaminotetracycline in 1,4-dioxane can be carried out at room temperature or under heating, but it is convenient to carry out at room temperature. 1,4-dioxane is preferably used in an amount in the range of 1 to 10 ml per 1 g of crude 4-dedimethylaminotetracycline. In the crystallization process, in order to easily crystallize 4-dedimethylaminotetracycline and obtain it with high purity, it is preferable to reduce the proportion of coexisting impurities in advance. From this viewpoint, for example, crude 4-dedimethylaminotetracycline 1,
It is preferable to treat the 4-dioxane solution with activated carbon, and since the crude 4-dedimethylaminotetracycline contains some water, the 1,4-dioxane solution of the crude 4-dedimethylaminotetracycline is treated with anhydrous sulfuric acid. It is preferable to dry using a desiccant such as magnesium. Specifically, activated carbon is added to a solution of crude 4-dedimethylaminotetracycline in 1,4-dioxane, the mixture is stirred, and the resulting mixture is filtered through a layer of a drying agent such as anhydrous magnesium sulfate.

Concentration of a crude 1,4-dioxane solution of crude 4-dedimethylaminotetracycline can be carried out by a method usually adopted for concentrating a solution of an organic compound, but it is convenient to carry out the concentration under reduced pressure. Is. The concentration is usually performed until the concentrated liquid becomes a viscous liquid, but it is preferable that the remaining 1,4-dioxane is 1 ml or less per 1 g of crude 4-dedimethylaminotetracycline.

After the concentrated liquid obtained by the above-mentioned concentration step is dissolved in methylene chloride, 4-dedimethylaminotetracycline is precipitated from the obtained methylene chloride solution. Methylene chloride is preferably used in an amount in the range of 1 to 40 ml, and more preferably in the amount of 5 to 15 ml, per 1 g of crude 4-dedimethylaminotetracycline. The operation of depositing 4-dedimethylaminotetracycline is preferably performed at a temperature in the range of -10 ° C to room temperature.

The precipitated 4-dedimethylaminotetracycline can be separated from the solvent by a conventional operation such as filtration. High-purity 4-dedimethylaminotetracycline can be obtained by removing the solvent from the obtained crystals of 4-dedimethylaminotetracycline.

[0010]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these examples. In the examples, the purity of 4-dedimethylaminotetracycline was measured by high performance liquid chromatography [column: Supersphere RP-18 (e) 12.5.
cm, grain system 4 μm (Merck), eluent: 0.1
M phosphate buffer (pH 2.2) / acetonitrile = 6
/ 4 (volume ratio)].

Reference Example 300 g of tetracycline in 6 l of tetrahydrofuran
And 705 ml of methyl iodide were added, and the resulting reaction mixture was stirred at room temperature for 6 days and then left at 0 ° C. for 2 days. The reaction mixture was filtered, and the solvent was removed from the obtained solid under reduced pressure to obtain 402.6 g of a quaternary ammonium salt of tetracycline. 402.6 g of quaternary ammonium salt of tetracycline was added to 50% acetic acid aqueous solution 11.
195 g of zinc was added to the resulting solution while stirring vigorously, and the mixture was further stirred for 15 minutes. Zinc was removed from the obtained reaction mixture by filtration, and the filtrate was poured into 39 l of an aqueous solution containing 10% concentrated hydrochloric acid and ice-cooled for 2 hours. The deposited precipitate was filtered, washed with water, and dried to give 4-dedimethylaminotetracycline in an amount of 1
86.9 g was obtained (yield 69%, purity 87%).

Example 1 62.3 g of 4-dedimethylaminotetracycline obtained in the reference example was dissolved in 300 ml of 1,4-dioxane, 6 g of activated carbon was added to the resulting solution and the mixture was stirred, and the mixed solution was mixed with anhydrous sulfuric acid. Filter through a magnesium layer. The filtrate is concentrated under reduced pressure until it becomes a viscous liquid, and the concentrated solution is concentrated to 100
g was obtained. 500 g of methylene chloride was added to 100 g of the obtained concentrated liquid.
After adding ml to make a uniform solution, the solution was allowed to stand overnight in a refrigerator to precipitate crystals of 4-dedimethylaminotetracycline. The precipitated crystals are collected by filtration,
After washing with methylene chloride, the solvent was removed under reduced pressure to obtain 58.7 g of 4-dedimethylaminotetracycline (purity 98.8%).

Comparative Example 4-dedimethylaminotetracycline was added to 100 g of 4-dedimethylaminotetracycline obtained in Reference Example and 6 g of activated carbon, and heated to dissolve 4-dedimethylaminotetracycline. Activated carbon was removed from the resulting mixed solution by filtration, and 10 l of hexane was added to the filtrate. By leaving the obtained homogeneous solution at room temperature overnight, 4-
Crystals of dedimethylaminotetracycline were deposited. The precipitated crystals were collected by filtration and washed with hexane,
By removing the solvent under reduced pressure, 77.6 g of 4-dedimethylaminotetracycline was obtained (purity 95.1).
%). Then, 50 g of the obtained 4-dedimethylaminotetracycline having a purity of 95.1% was recrystallized by the same operation as above using 4 l of ethyl acetate and 5 l of hexane,
39.7 g of 4-dedimethylaminotetracycline was obtained (purity 98.2%).

[0014]

According to the present invention, highly pure 4-dedimethylaminotetracycline can be obtained by using a small amount of recrystallization solvent and performing a single recrystallization operation.

Claims (1)

[Claims] 1. A mixture containing 4-dedimethylaminotetracycline is dissolved in 1,4-dioxane, the resulting solution is concentrated, the concentrated solution is dissolved in methylene chloride, and then 4 -A method for purifying 4-dedimethylaminotetracycline, which comprises depositing dedimethylaminotetracycline.