JPH0737434B2 - Method for collecting 7-dimethylamino-6-demethyl-6-deoxytetracycline - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for collecting pharmaceuticals. More specifically, 7-dimethylamino-6- which is a tetracycline antibiotic
The present invention relates to a method for collecting demethyl-6-deoxytetracycline (hereinafter referred to as minocycline).

Prior Art Minocycline is an antibiotic useful as a medicine.
A typical synthetic method for minocycline is reductive dimethylamination with 7-nitro-6-demethyl-6-deoxytetracycline and formalin. USP3,226,436, J.Med.Chem., 10 , 44 (1967), Shokoku Sho
42-8380 Reductive dimethylamination with 7- [1,2-bis (carbobenzyloxy) hydrazino] -6-demethyl-6-deoxytetracycline and formalin. USP3,4
03,179, Japanese Patent Publication No. 50-37666 7- (4-Sulfophenylazo) -6-demethyl-
Reductive dimethylamination with 6-deoxytetracycline and formalin. Fr.Add.92,088 etc. are known. Minocycline obtained by those methods, by any method, the reaction solution after reductive dimethylation is placed in a large amount of minocycline-insoluble solvent such as ether or acetone to precipitate crystals (dilution method) Or obtained by extracting the reaction solution in a neutral state without salt formation with a water-insoluble organic solvent such as chloroform or ethyl acetate (extraction method).

Problems to be Solved by the Invention In the method of collecting minocycline by the above-mentioned known method, a large amount of industrially troublesome ether or acetone is used in the dilution method, or extraction is performed in the extraction method using an organic solvent. Both methods are economically disadvantageous due to the drawback of low efficiency.

Means for Solving the Problems The present inventors have accomplished the present invention as a result of intensive studies to solve the above problems. That is, the present invention is characterized in that an aqueous solution containing 7-dimethylamino-6-demethyl-6-deoxytetracycline (minocycline) is subjected to adsorption treatment with a nonpolar high-porous polymer and then eluted with an eluent to collect minocycline. Provide the law.

The method of the present invention will be described in detail.

In the collecting method of the present invention, a high-porous polymer obtained from a copolymer of styrene and divinylbenzene is preferably used as the adsorbent. Among such high-porous polymers, the specific surface area is 500-730 m ² / g, pore volume
It is more preferably 0.69 to 1.08 ml / g. Specific examples of such adsorbents include Diaion HP-10, -20, -2
1, -30, -40, -50 (trade name, manufactured by Mitsubishi Kasei), Amberlite XAD-1, XAD-2, XAD-4, XAD-5 (trade name, manufactured by Rohm & Hass) To be

The amount of adsorbent used is 10 to 100 times the amount of minocycline in the minocycline-containing aqueous solution to be treated (cc / g).
The amount is more preferably 20 to 50 times (cc / g).

A polar organic solvent miscible with water is used as an eluent for eluting the minocycline adsorbed on the adsorbent described above, and particularly preferred is an organic solvent containing minocycle and an acid equivalent to or more than the equivalent amount.

As the polar organic solvent, alkanols such as methanol, ethanol and isopropyl alcohol, alkoxyalkanols such as 2-methoxyethanol, 2-ethoxyethanol and 1-ethoxypropanol, glycols such as ethylene glycol and propylene glycol, dimethylformamide and dimethyl. Examples thereof include aprotic polar solvents such as acetamide, dimethylimidazolidinone and dimethyl sulfoxide, and lower alkanols are particularly preferable. As the acid, a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as chou acid is used, and hydrochloric acid or sulfuric acid is preferable.

The polar organic solvent may contain water.

In the method of the present invention, for example, water is first added to a reaction solution containing minocycline to form an aqueous solution thereof, and the pH thereof is 3-9.
More preferably, it is adjusted to 5 to 8 and then adsorbed on the adsorbent. If the pH of the solution is 3 or less, the adsorption to the adsorbent becomes poor, and if the pH is 9 or more, the minocycline becomes unstable, which is not preferable. At pH 5 to 8, 98% or more of minocycline is adsorbed on the adsorbent.
The minocycline-containing aqueous solution to be adsorbed may contain a water-soluble organic solvent (for example, methanol, ethanol, methyl cellosolve, DMF, etc.), but the water content is 1/3 or more of the total, and more preferably 1 / It is better to adjust it to be 2 or more. When the composition of the organic solvent increases, the adsorption rate of minocycline on the adsorbent tends to decrease. The adsorption method on the adsorbent may be either a column method or a batch method, but the column method is preferred. The adsorption temperature may be in a normal room (about 10 to 50 ° C). After adsorbing minocycline on the adsorbent, the adsorbent is first developed with a large amount of water to elute impurities other than the tetracycline type (at this time, the leakage of minocycline is usually less than 1%). Elute the minocycline.
The eluted minocycline is usually 95% or more of the amount present in the aqueous solution before adsorption.

In the case of minocycline produced by the above-mentioned production method and formalin is present in the reaction solution, treatment with an amine such as hydroxylamine before the adsorption treatment will increase the purity of minocycline. It is effective. Further, the composition of the eluate obtained by the elution treatment is, for example, “organic polar solvent + water” → “organic polar solvent only” →
Elution in the order of "organic polar solvent to which acid is added" makes it possible to obtain higher purity minocycline.

The eluate containing minocycline thus obtained is concentrated and the pH is adjusted to 4 to 8 to obtain minocycline crystals (hydrate). The minocycline (hydrate) thus obtained had sufficient purity to be used as a medicine. If necessary, the adsorption treatment may be performed again according to the method of the present invention to obtain minocycline with higher purity.

After elution of minocycline, the adsorbent can be regenerated by washing with a large amount of neutral water. High porous
Despite being a polymer adsorbent, it remained effective even after 50 durability tests.

EXAMPLES Next, the present invention will be described more specifically by way of examples.

Example 1. 11a-Chloro-6-demethyl-6 according to Fr. Add.92,088
30 g of -deoxy-7- (4-sulfophenylazo) -tetracycline and 30.8% of 37% formalin were subjected to hydrogen reduction and reductive methylation in 600 ml of methyl cellosolve in the presence of a palladium carbon catalyst. After removing the catalyst, 640 g of a yellow-orange solution containing 16.3 g of 7-dimethylamino-6-demethyl-6-demethyl-6-deoxytetracycline (free form) were obtained. Among these are 7-dimethylamino-6-
It also contains demethyl-6-deoxytetracycline and an equimolar amount of 4-dimethylaminobenzenesulfonic acid.

This solution is then dissolved in 2000 ml of water containing 15.7 g of hydroxylamine sulfate to remove excess formalin,
After stirring at room temperature for about 20 minutes, the pH was adjusted to 7.4 with 20% caustic soda. This is the Diaion HP-20 resin (specific surface area 72
Minocycline was adsorbed (room temperature) through a 400 ml column (0 m ² / g, pore volume 1.08 ml / g). Then deionized water 10
Compounds other than tetracycline were eluted and removed by developing and eluting. Almost no distillation of minocycline was observed in this operation.

Next, the minocycline adsorbed on the adsorbent was developed and eluted with 1500 ml of a methanol solution containing 7.5 g of concentrated hydrochloric acid to obtain 1300 ml of an eluate containing 16.0 g (recovery rate 98%) of minocycline. The purity was analyzed by liquid chromatography and found to be 95% or more (area percentage). When this eluate was concentrated and the pH was adjusted to 4.0 with 10% caustic soda, a pale yellow precipitate was deposited, which was separated and vacuum dried at room temperature to yield a pale yellow powder, minocycline monohydrochloride dihydrate. 15.3
g was obtained. When this product was analyzed by liquid chromatography, the purity was 99.2% (titer: 910 μg / mg anhydrous, titer was determined by USP). The recovery rate after reductive dimethylation was 80.9%.

In the mother liquor in which the eluate separated in the above column was concentrated and the pH was adjusted to remove the precipitated precipitate, minocycline was considerably dissolved. This mother liquor (containing 2.79 g of minocycline) was adjusted to pH 7.4 with 20% caustic soda, adsorbed again on DIAION HP-21, and eluted with methanol-hydrochloric acid to obtain minocycline with a recovery rate of 90%. It was

Example 2. Adsorbent used in Example 1, Diaion HP-20
Was carried out in the same manner as in Example 1 except that DIAION SP-900 was used.
15.5 g was obtained. When this product was analyzed by liquid chromatography, the purity was 95.1% (titer: 876 μg / mg anhydrous product).

Example 3 According to JP-B-42-8380, 7-nitro-6-demethyl-
10 g of 6-deoxytetracycline sulfate was subjected to hydrogen reduction and reductive methylation by adding 37% formalin in the presence of a palladium carbon catalyst in 200 ml of methyl cellosolve. After the reaction was completed, the catalyst was separated to obtain 280 g of a yellow crude solution containing 7.0 g of minocycline (as a free form).

Next, this solution was dissolved in 2000 ml of water containing 11.9 g of hydroxylamine sulfate, and the pH was adjusted with 20% aqueous sodium hydroxide solution.
After adjusting to 6.8, Diaion HP-2 was used as in Example 1.
Adsorption treatment was performed at 0, and then elution treatment was performed. The resulting eluate was concentrated and the pH of the concentrate was adjusted to 4.0 to obtain 5.3 g of minocycline hydrochloride dihydrate.

When this product is analyzed by liquid chromatography, the purity is
It was 99.1% (titer 909 μg / mg anhydrous equivalent).

Example 4. 25 ml (1 ml of mother liquor obtained from recrystallization of minocycline hydrochloride
(Containing 8.4 g of epimer and 23.8 mg of minocycline) was diluted with water to 100 ml, and the pH was adjusted to 7.0 with 20% caustic soda. This was passed through a column of 20 ml of Diaion HP-40 resin to adsorb minocycline. Then deionized water 10
After elution treatment with 0 ml, methanol-water (1: 1) 50 ml, and then elution treatment with 100 ml of a methanol solution containing 0.4 g of concentrated hydrochloric acid gave an eluate containing 0.788 g of minocycline (20% of which is an epimer). Obtained. Concentrate the eluate and adjust the pH to 4.0 with hydrochloric acid or 10% caustic soda to precipitate a yellow precipitate. Separately, vacuum-dry it at room temperature to obtain pale yellow powder minocycline hydrochloride dihydrate 0.32 g (Of which 3%
Is an epimer).

EFFECTS OF THE INVENTION By a single adsorption-elution operation with a non-polar high-porous polymer (adsorbent), it becomes possible to obtain highly efficient minocycline with high purity without using special reagents or organic solvents. It was

Claims (1)

[Claims] 1. 1-Dimethylamino-6-demethyl-6-
7-Dimethylamino-6, characterized in that an aqueous solution containing deoxytetracycline is subjected to adsorption treatment with a nonpolar high-porous polymer and then eluted with an eluent.
-Demethyl-6-deoxytetracycline collection method