DD220961A1 - PROCESS FOR PREPARING 6- (1-METHYL-4-NITRO-5-IMIDAZOLYL) MERCAPTOPURINE - Google Patents

Abstract

6- (1-Methyl-4-nitro-5-imidazolyl) -mercaptopurine can be prepared industrially in high yield and purity by reacting 6-mercaptopurine with 5-chloro-1-methyl-4-nitro-imidazole in ethanol Reacts the presence of aqueous ammonia.

Description

Field of application of the invention

The invention relates to a process for the preparation of 6- (1-methyl-4-nitro-5-imidazolyl) -mercaptopurine (I) which is used as an immunosuppressant.

Characteristic of the known technical solutions

For the production of I, various processes or process variations are known. Thus, I can be prepared according to DD-PS 24169 from anhydrous 6-mercaptopurine and 5-chloro-1-methyl-4-nitro-imidazole in Di met hy Isu If oxide in the presence of anhydrous, sodium acetate.

According to SU-PS 172814, 6-mercaptopurine monohydrate is reacted with 5-chloro-1-methyl-4-nitro-imidazole in an aqueous-alcoholic medium in the presence of a strong base, such as NaOH, to I. In PL-PS 75532, the preparation of I from 6-mercaptopurine monohydrate and 5-chloro-1-methyl-4-nitro-imidazole in a solvent mixture of dimethylformamide or dimethyl sulfoxide and tetrahydrofuran or from dimethylacetamide and tetrahydrofuran or only tetrahydrofuran alone described, wherein as the acid-binding agent aqueous ammonia or an amine dissolved in water is added. · Ι

These known methods adhere to various disadvantages which are unfavorable or uneconomical for the industrial production of I. _;

Thus, the use of anhydrous 6-mercaptopurine requires additional drying of the monohydrate present

Substance that is laborious and leads to losses. '

yFurthermore, the use of dimethylsulphoxide leads to the risk of oxidative side reactions leading to losses in yield! and lead to contamination of I. These side reactions are favored by the long reaction time of 7 hours.

Likewise, the use of caustic soda as HCl acceptor leads to the hydrolysis of both the I already formed and the j

hydrolytic cleavage of the purine ring in 6-mercaptopurine and hydrolysis of the S-chloro-i-methyl-nitro-imidazole, see above;

that it comes to yield losses and contamination of I.

Also, the solvent combination described in the PL-PS 75532 is technically complicated, since a recovery of the same is difficult, or it also contains dimethyl sulfoxide with its oxidative properties. The I produced by this method is therefore also not clean and must be redirected.

Object of the invention

By means of the invention it is possible to eliminate the disadvantages of the known preparation processes and to produce them technically simply in high yield and purity.

The inventive method is particularly simple and economical, since only a very simple solvent is used, only short reaction times are required and a virtually quantitative conversion to I is achieved.

(Another advantage of the invention is that a costly recrystallization or reprecipitation as well as a drying of the 6-mercaptopurine monohydrate is eliminated.

It is also surprising and unexpected that the reaction according to the invention proceeds without the addition of dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide as rapidly and almost quantitatively and results in a thin-layer-purified end product which requires no further complicated purification.

The following table shows the considerable advantage of the method according to the invention;

manufactured solvent reaction time yield Thin Film according to hours % chromatqgramm PL-PS 75 632 DMSO / THF, NH ₄ OH 2 74.5 2 secondary fractions 0.4% PL-PS 75 532 DMF / THF, NH ₄ OH 3 77.0 3 secondary fractions 0.3% PL-PS 75 532 THF, NH ₄ OH 3 62.0 2 secondary fractions 0.4% SU-PS172814 Ethanol, NaOH 3 82.0 3 secondary fractions 0.5% This invention : Ethanol, NH ₄ OH 1 96.0 no secondary groups

The thin-layer chromatograms were carried out on Merck precast sheets. Mobile phase: n-butanol / NH ₄ OH saturated.

Abbreviations:

DMSO dimethyl sulfoxide

DMF dimethylformamide

THF tetrahydrofuran,

parsing the essence of the invention

The invention has for its object to find a technically simple process for the preparation of pure 6- (1-methyl-4-nitro-5-imidazolyO-mercaptopurine, which corresponds to the high requirements of a specific drug for pharmaceutical purposes.

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-2-254576

In this case, the ammonia can be supplied to the reaction mixture both as aqueous or alcoholic solution or by units of ammonia gas.

The temperature can vary within wide limits. Suitably, the reaction of the invention is carried out at temperatures of 50 ° C to the boiling temperature of the reaction mixture, wherein a preferred embodiment of the invention is that the reaction is carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the temperature used. The progress of the reaction is externally evident from the appearance of a thick yellow precipitate, it being useful to include a certain post-reaction time to complete the reaction.

For example, when the reaction is carried out under reflux conditions, a thick yellow precipitate already precipitates after 20-30 minutes, and the reaction can be stopped after about 1 hour of heating to reflux. After the reaction has ended, the reaction mixture, if appropriate after cooling to room temperature, can be adjusted to a pH of 5-6 with acetic acid and the precipitated I separated off.

Appropriately, one proceeds in the process according to the invention so that first the 6-mercaptopurine . dissolves monohydrate in ethanol by the addition of aqueous ammonia, 5-chloro-1-methyl-5-nitro-imidazole added and the solution heated to reflux. After the reaction has ended, which in this case lasts about 1 hour, the reaction mixture is allowed to cool, the pH of the reaction mixture is adjusted to 5-6 with acetic acid, the pure I is separated off, washed with ethanol and dried.

Embodiment.

20.4 g of 6-mercaptopurine monohydrate are heated in 200 ml of ethanol to 40-45 ⁰ C and 80 ml of concentrated ammonia added, the 6-mercaptopurine goes into solution. Thereafter, 19.4 g of 5-chloro-1-methyl-4-nitro-imidgzol are added. The result is a yellow solution which is heated under reflux for 1 hour, after 20-30 minutes, a thick yellow precipitate precipitates. After cooling to room temperature, the pH is adjusted to 5-6 with 5 ml of acetic acid, stirred for 1 hour and filtered with suction. The precipitate is washed with 60 ml of ethanol and dried at 100 ⁰ C. Exploiter: 32.0 g & 96% of theory on I -

Mp: 245-247 ° C (Mettler curve) · ".,

DC: no secondary spots

Claims (5)

-1- 254576 4 Invention claims: 1. A process for the preparation of pure 6- (1-methyl-4-nitro-5Mmidazolyl) -mercaptopurine by reacting 6-mercaptopurine monohydrate with 5-chloro-1-methyl-4-nitro-imidazole in an aqueous-alcoholic solvent in '. Presence of an acid acceptor, characterized in that the reaction is carried out in ethanol in the presence of ammonia as an acid acceptor. 2. The method according to item 1, characterized in that one carries out the reaction at temperatures of 50 ° C to the boiling temperature of the reaction mixture. 3. The method according to the items 1 and 2, characterized in that one carries out the reaction under reflux. 4. The method according to items 1 to 3, characterized in that the ammonia is added as an aqueous or alcoholic solution to the reaction mixture. 5. The method according to items 1 to 3, characterized in that the ammonia by introducing ammonia gas the; Reaction mixture is supplied.