HK1083488B - Process for purifying diacerein - Google Patents

Description

Process for purifying diacerein

Technical Field

The present invention relates to a process for the purification of diacerein which makes it possible and easy to obtain diacerein with a low content of aloe-emodine (less than 100ppm, or, if desired, 0 to 5 ppm).

Background

Diacerein (1, 8-diacetoxy-3-carboxy-anthraquinone) is a known compound with anti-arthritic activity and can be obtained by various methods (see "merck index", XIII, 2979; EP 0243698; EP 0520414; EP 636602; PCT EP00/03691, PCT EP 01/06019), generally by acetylation of aloin (10-glucopyranosyl-1, 8-dihydroxy-3-hydroxymethyl-9 (10H) -anthrone; "merck index", XIII, 304) followed by chromium oxidation of the acetylated derivative. The method was disclosed about one hundred years ago by R.Robinson and J.L.Simonsen (Journal of the Chemical Society, Transactions, 1909, 1085-. Aloin is referred to in the above-mentioned papers by its synonym aloin (see "merck index", XIII, 304); a substantially similar process is also disclosed in the aforementioned EP0636602, which also discloses a process for purifying the crude diacerein obtained to a level of aloe-emodin (1, 8-dihydroxy-3-hydroxymethyl-anthraquinone) below 70-20 ppm. Indeed, although aloe-emodin is defined as a cathartic compound ("merck index", XIII edition, 303), it also has mutagenic properties, although no convincing evidence has been given in this regard. According to current Good Manufacturing Practice (GMP), marketed drugs must contain the lowest possible amount of impurities (this is based on the assumption that substances which do not have a therapeutic effect are harmful merely because of the fact that they are chemicals); in the case of diacerein, numerous attempts have been made to minimize the content of aloin-emodin which is said to have mutagenic action, for example by crystallization of the crude diacerein in various solvents. For example, the aloe-emodin content can be reduced to 50-100ppm by crystallization from acetic anhydride mixed with acetic acid, as disclosed in PCT/EP00/03691, whereas according to EP0636602 (page 4, lines 25-28), crystallization of crude diacerein from 2-methoxyethanol or dimethylacetamide can result in aloe-emodin contents of less than 70 ppm. The patent also reports an aloe-emodin content (page 5, lines 7-9) of less than 20ppm, which can be obtained by the methods described on page 4, page 5 (lines 1-6) and in the examples, as outlined below.

Operation of example 1 in EP 0636602:

a) drying the diacerein crude product obtained in the oxidation step until the water content is lower than 1%;

b) salifying with triethylamine in dichloromethane and filtering the solution;

c) the filtrate was acidified with aqueous acetic acid and further acidified with 32% hydrochloric acid;

d) centrifuging and drying at 70-80 deg.C until the loss on drying is less than 0.5%;

e) crystallizing from 2-methoxy ethanol by heating under reflux for 3 hours, cooling to +5 ℃, centrifuging the precipitate, and drying until the loss on drying is less than 0.5%;

f) crystallization from anhydrous dimethylacetamide by heating at 110 ℃ for 30 minutes, cooling to 0 ℃, centrifugation, resuspension of the solid in deionized water, re-centrifugation, washing 6 times with water and finally drying.

The overall yield of steps b) to f) was 74%.

Operation of example 2 in EP 0636602:

a) see example 1 above;

b) crystallizing from dimethylacetamide and acetic anhydride by heating at 100 ℃ for 15 minutes, filtering while hot, cooling to 0-2 ℃, centrifuging and drying;

c) a second crystallization from dimethylacetamide as described under b);

d) a third crystallization from dimethylacetamide as described under b);

e) final purification was performed by: heated in refluxing ethanol for 1 hour, cooled to 0-2 ℃, centrifuged, washed with deionized water to remove most of the alcohol and finally dried.

The overall yield of steps b) to e) was 65%.

It is not clear whether emodin levels below 70ppm (page 4, line 28) or 20ppm (page 5, line 9) can be achieved according to example 1 or 2, respectively, or vice versa according to example 2 or 1.

However, it is clear that both of these processes are cumbersome to operate and result in a significant reduction in the yield of pure diacerein relative to crude diacerein. Moreover, both processes are very expensive in terms of solvents, equipment and time, not only in terms of obtaining pure diacerein, but also in terms of recovering diacerein lost in the various steps and in large quantities of methoxyethanol and dimethylacetamide.

EP 520414 and EP 554880 teach obtaining diacerein with a very low content of aloe-emodin by liquid-liquid separation. The process is carried out with diacerein and rein-9-antron-8-glycoside, respectively, wherein the rein-9-antron-8-glycoside is obtained from senna leaves and subsequently converted to diacerein. In both cases the yield was high, but the liquid-liquid separation procedure required the use of a specific instrument ("Mixer-Settler-Apparatus" with 60 mixing-separation units) and 30 volumes of organic phase per volume of mixture from which the aloe-emodin would be extracted. Furthermore, the whole process (from the starting material to pure diacerein) comprises at least six steps.

Disclosure of Invention

It has now been found that diacerein with a very low aloe-emodin content can be obtained by: the crude diacerein (obtained from aloin according to the method described by Robinson e Simonsen) is salified with a weak base, the organic-aqueous solution of said salt is extracted discontinuously or continuously in a water-immiscible or slightly miscible solvent, and the pure diacerein is precipitated by acidification.

In the present application, the term "aloe-emodin" refers to "aloe-emodin" as such, or to mixtures of aloe-emodin with corresponding mono-, di-and/or tri-acetylated derivatives, which may also be present in the crude diacerein.

The weak base is preferably a weak organic base, more preferably selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, pyrrolidine and mixtures thereof. The molar ratio of diacerein to organic base is 1: 1 to 1: 1.15; preferably the ratio of diacerein and organic base is substantially stoichiometric.

The water-organic solvent is a mixture of water and a solvent selected from the group consisting of: acetone, methyl ethyl ketone, ethanol, propanol, isopropanol, other water-soluble solvents, and mixtures thereof. The volume ratio of water to solvent (or solvent mixture) is from 20: 80 to 80: 20, preferably from 60: 40 to 40: 60, depending on the organic solvent.

Suitable water-immiscible or slightly miscible solvents are lower alcohols such as C₂-C₄Acetates or propionates or butyrates of alcohols, aromatic hydrocarbons, aliphatic or aromatic halohydrocarbons and mixtures thereof. Especially preferred are lower alcohols such as C₂-C₄Acetates of alcohols, especially ethyl or butyl acetate, toluene, xylene or dichloromethane. The number of extraction steps depends on the solvent and on the volume ratio of solvent/diacerein salt solution, and can be easily determined by the skilled person in the art by preliminary tests, depending on the content of aloe-emodin in the final product. The same applies to the extraction carried out in a continuous extractor.

The aloe-emodin content was determined by HPLC using an external standard method. The reference solution was prepared as follows: accurately weighing 40mg of diacerein, 10mg of aloe-emodin and 20mg of rein, and dissolving in 50ml of dimethylacetamide; 1ml of this solution was diluted to 100ml with mobile phase (see below). The chromatographic conditions were as follows:

^＊ instrument for measuring the position of a moving object: perkin Elmer chromatograph series, 200 pumps, equipped with diode arrays or similar devices;

^＊ column: lichrosphere 100RP-18(5(m), 250mm × 4mm I.D.) or an equivalent thereof;

^＊ mobile phase: acetic acid (pH 2.7)/acetonitrile (53/47) solution;

^＊ flow rate of flow: 0.8 ml/min;

^＊ detection wavelength：254nm；

^＊ Injection volume：20μl；

^＊ Analysis time: 35 minutes;

^＊ integral parameter: clustering factor 3, threshold area 50, noise 100 (these values are only hints and should be adjusted to optimize the integral for the specific situation);

the following retention times were obtained under the above conditions:

^＊ diacerein：7.2；

^＊ Aloe-emodin：11.5；

^＊ Rein：12.2。

The reference solution (20. mu.l) was injected and eluted. If the peak resolution between aloe-emodin and rein in the chromatogram is below 1.4, the column is washed with water (15 min; flow rate 1 ml/min), 50/50 water/acetonitrile mixture (15 min; flow rate 1 ml/min), acetonitrile (15 min; flow rate 1 ml/min) and the test repeated.

Recovering pure diacerein from the salt solution by acidification, for example with hydrochloric acid or phosphoric acid; after centrifugation, diacerein is crystallized from acetic acid/acetic anhydride, washed with water and dried, as disclosed in PCT/EP00/03691 and PCT/EP 01/06019.

The following examples illustrate the invention in more detail.

Example 1

15.6kg of a suspension of diacerein crude containing about 500ppm of aloe-emodin in a mixture of 80 l of acetone and 80 l of water was added, together with 4.27kg of triethylamine. The resulting solution was extracted with 4 aliquots of butyl acetate (100 liters each); the organic phases are combined and the butyl acetate is recovered and recycled to the process. Acidifying diacerein salt solution with dilute HCl; the precipitated diacerein was centrifuged, washed thoroughly with water and dried to obtain 14.8kg of diacerein having an aloe-emodin content not higher than 2 ppm. Followed by crystallization from acetic anhydride/acetic acid as reported above.

Example 2

The procedure was carried out in the same manner as in example 1, with the extraction being limited to three times (final aloe-emodin content-45 ppm) or two times (final aloe-emodin content 85 ppm).

Example 3

The procedure was carried out in the same manner as in example 1, using toluene as the extraction solvent. After five successive extractions, diacerein contained no more than 3ppm of aloe-emodin (about 33ppm after four extractions).

Example 4

The procedure was carried out in the same manner as in example 1, using methylene chloride as the extraction solvent. After four extractions diacerein with an aloe-emodin content of about 3ppm was obtained.

Example 5

The procedure was carried out in the same manner as in the previous example, using tributylamine as the base and butyl acetate as the extraction solvent. The aloe-emodin content is less than 2 ppm.

Example 6

A solution of 100 g of crude diacerein (aloe-emodin content about 500ppm) in 500ml of methyl ethyl ketone, 500ml of water, 27.5 g of triethylamine and 50ml of dichloromethane was charged into a Soxhlet extractor suitable for liquid-liquid extraction. A round bottom flask was charged with 1 liter of dichloromethane as the extraction solvent and heated to reflux temperature. The extraction was continued for about 1 hour (the extraction solvent having a higher density than the aqueous ketone phase passed up through the aqueous ketone phase and overflowed from the main part of the Soxhlet extractor, siphoned into a flask containing dichloromethane to remove the extracted aloe-emodin), after which the extraction solvent was replaced with 500ml of fresh dichloromethane and the extraction was continued for another 1 hour. The aqueous-keto solution of diacerein salt is left to stand, then separated from the dichloromethane phase (containing traces of emodin) and acidified to pH 1 with dilute hydrochloric acid to precipitate diacerein. After filtration and vacuum drying at 60 ℃, diacerein (94 g) contained less than 4ppm of aloe-emodin. When the aloe-emodin content is low enough for the intended application, the extraction can also be stopped and no fresh dichloromethane is added.

Diacerein can be obtained in high purity by crystallization from acetic acid/acetic anhydride (70/9 v/v).

Claims (8)

1. A process for obtaining diacerein with an aloe-emodin and mono-, di-and tri-acetylated derivatives thereof content lower than 100ppm, characterized in that an aqueous-organic solution of a salt of diacerein with a weak base is extracted with a water-immiscible or slightly miscible solvent, wherein the weak base is trimethylamine, triethylamine, tripropylamine or tributylamine or a mixture thereof, the organic solvent in the aqueous-organic solution is acetone, methyl ethyl ketone or a mixture thereof, and the extraction solvent is C₂-C₄Acetate or propionate or butyrate esters of alcohols, toluene, xylene orDichloromethane or mixtures thereof.

2. The method of claim 1, wherein the aloe-emodin and mono-, di-and tri-acetylated derivatives thereof are present in an amount of 0-5 ppm.

3. The process according to claim 1, characterized in that the volume ratio of water and organic solvent in the aqueous-organic solution is between 80: 20 and 20: 80.

4. The process according to claim 3, characterized in that the volume ratio is 60: 40 to 40: 60.

5. The process according to claim 1, characterized in that the extraction solvent is selected from the group consisting of ethyl acetate, butyl acetate, toluene, xylene, dichloromethane or mixtures thereof.

6. The process according to claim 1, characterized in that the extraction is carried out in a discontinuous manner.

7. The process according to claim 1, characterized in that the extraction is carried out in a continuous manner.

8. The process of claim 1 further comprising precipitating pure diacerein by acidification after the extraction step.