DD151629B1 - TECHNICAL, WHERE APPROPRIATE, CONTINUOUS PROCESS FOR PREPARING HIGH-PURITY DIPYRIDAMOL - Google Patents

Description

Title of the invention

Technical, optionally continuously feasible process for the preparation of high purity dipyridamole

Field of application of the invention

The invention relates to a technical, optionally continuously feasible process for the preparation of high purity dipyridamole, which in the thin-layer chromatogram except the Dipy'ridamolf leak (R · TM 45) no further spots' has.

Characteristic of the known technical. solutions

The dipyridamole obtainable in a known manner by reacting 2,6-dichloro-4,8-dipiperidino-pyrimido-5,4-d-7-pyrimidine with diethanolamine contains a number of by-products, the compulsory formation of which has already been described in DD-PS 117 456 and 117 966 was pointed out. From both patents and DE-OS 19 62 261, 23 04 982 and DD-PS 109 971 it can be seen that the purification of the crude dipyridamole by the customary in organic chemistry crystallization processes from organic solvents leads to no satisfactory result.

-AW-0202686

In addition to the described in DE-OS 19 62 261, suitable only for laboratory approaches column chromatographic purification of Rohdipyridamols were significant cleaning effects by the formation of sparingly soluble salts of dipyridamole, namely the monohydrochloride according to DD-PS 117 966 bzw.des p-Toluolsulfonates according to · DE Achieved -OS 23 04 982. By this technically feasible, but because of the necessary crystallization time and the separation of the crystalline salts of the mother liquor only discontinuously running process, it is possible, especially the quantitatively relatively strong represented compound 2,4,6-tris- (diethanolamine ^ -8-piperidino-pyrimido_ / 5, 4-d_7pyrimidine (III), which forms a slightly soluble hydrochloride or p-toluenesulfonate, to separate so far from the dipyridamole that the subsequent crystallization process dipyridamole with very low levels of (III) and 2-diethanolamino-4, 6,8-tripiperidino-pyrimido, / ~ 5, 4-d_7pyrimidine (IV), in the best case without (III) and with low proportions (IV).

It has also been proposed, from the reaction mixture obtained in the preparation of the dipyridamole, depending on the reaction in an amount of 5 to 20 % contained 2-diethanol-amino-6-chloro-4,8-dipiperidinopyrimido_ / 5,4-d_7pyrimidin ( II), which can be used as the only of the resulting byproducts for the direct dipyridamole preparation, thereby recovering that the reaction mixture with dilute aqueous solutions of ammonium or alkali metal hydrogen sulfate be: temperatures between 10 and 80 ⁰ C stirred, the undissolved remaining (II) and the dipyridamole precipitates from the aqueous-acidic solution by alkalization (DD-PS 143 522).

According to DD-PS 117 456, the content of the resulting by-products can already be greatly reduced by the course of the reaction under vacuum. However, the resulting from the sparingly soluble monohydrochloride and subsequent crystallization from butyl acetate Reindipyridamol is not completely free of the by-products (III) and (IV).

The complete removal of all byproducts from the dipyridamole requires additional crystallization effort and is no longer economically useful as a result of the ratio of by-product proportions of 0.05 to 0.1 % to the main product, since the total product must be dissolved, heated, cooled again and crystallized. For this reason, the commercially available dipyridamole of high overall purity for all manufacturers in the thin layer chromatogram shows in addition to the dipyridamole stain (R "45) several secondary compounds, but in each case the compound (IV) (Rp 55) in amounts up to 0.5 % and bears the trade name "monospot". A higher chromatographic purity of dipyridamole is currently unknown.

Object of the invention

The invention enables a technical, optionally continuously feasible production of high purity dipyridamole without isolation of sparingly soluble salts of dipyridamole, the quantitatively most significant side compounds (III) and (IV) before the necessary for the crystal form final crystallization from organic solvents in the thin-layer chromatogram no longer detectable are.

As the end product of the process according to the invention dipyridamole is obtained, which in Dünnschichtchromatogramm.unter under the specified determination methods of

χ) AB 2 next to the main spot (Rp 45) indicates no further spots.

The process according to the invention avoids the separation operations and solid product movements associated with the isolation of the sparingly soluble salts of dipyridamole. The process according to the invention makes it possible to carry out the purification operations in continuous form, since only solutions are used and no solids are separated, with the exception of the end product.

The purification effect of the process according to the invention was generally not to be expected to this extent in the known difficulties of dipyridamole purification under technical conditions without formation of sparingly soluble and readily crystallizing salts and in particular in its selective and quasi-quantitative manner in the structural similarity between dipyridamole and can not foresee the by-products from the hitherto known and described in the literature difficulties.

Explanation of the essence of the invention

The present invention is based on the object, from the process-related component mixture of the reaction of 2, 6-dichloro-4, 8-dipiper idino-pyrimido- / ~ 5,4-d_7pyrimidin with diethanolamine to dipyridamole, optionally after separation of the also resulting from the process incurred 2-Diethanolamino-6-chloro-4,8-dipiperidinopyrimido / ~ 5,4-d_7pyrimidine (II) according to DD-PS 143 522, a high purity dipyridamole, especially high thin layer χ) of the GDR

chromatographic purity, the thinschi chtehromatogramm only the dipyridamole patch (R ₁ , 45) shows.

According to the invention, this is achieved by removing crude pyridamol, from which, if appropriate, DD-PS 143 522, the 2-diethanolamino-6-chloro-4, 8-dipiperidino-pyrimido- / ~ 5,4-d_7pyrimidin (II) was removed in CHCl- dissolves, the solution at temperatures between 5 and 40 ⁰ C, preferably between 15 and 25 ⁰ C with 2- 10% acetic acid, the aqueous phase containing the by-products with an Rp value ^ 45, but especially By-product (III), separated, the CHCl ^ layer then with a 5-10% aqueous oxalic acid solution at temperatures between 5 and 40 - ⁰ C, preferably between 15 and 25 ⁰ C, intensively mixed, the CHCl ^ layer , those who . By-products with an R _p value ^ 45, but especially the by-product (IV) contains, separated and either

a) from the oxalic acid aqueous phase, the dipyridamole with alkalis, e.g. with dilute sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution or ammonia water, precipitates and, if desired, recrystallized from organic solvents or

b) the oxalic acid aqueous phase with acetic acid esters, e.g. Ethyl acetate or butyl acetate, mixed, by addition of alkali, for. Example, dilute sodium hydroxide, potassium hydroxide, sodium carbonate or ammonia water, the dipyridamole sets free and crystallized after separation of the organic phase from this dipyridamole.

In both cases, the final product obtained is dipyridamole in high purity, which shows no further secondary spots in the thin-field chromatogram in addition to the main spot (Rp 45).

A particular embodiment of the invention consists in that this purification is carried out continuously in corresponding extraction apparatuses, e.g. by countercurrently with 2 successive turntable extractors, e.g. with three theoretical plates, first acetic and then oxalic.

A further embodiment of the invention comprises, from the crude dipyridamole, the 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimidoe / 5, 4-d_7- contained therein. / pyrimidine (II) for reuse in the Dipyridamolsynthese previously separated according to the method according to DD-PS 143 before it is purified according to the present invention.

For this purpose, the Rohdipyridamol is stirred with aqueous solutions of ammonium or alkali hydrogen sulfate at temperatures. Between 10 and 80 ⁰ C, the undissolved remaining II separated, taken from the Piltrat Rohdipyridamol by alkalization and extraction in CHCl- and then separated according to the present invention.

A prior separation of (II) is not mandatory, since this compound is otherwise separated in the inventive process in both extraction stages.

It is surprising that <materially solve 45 ~ 'better in the dilute acetic acid as the dipyridamole and the by-products with a Rj ₁ value> In this procedure, first, the by-products with a Rp value 45, this creates in the CHCl ^ - On the other hand, the dipyridamole forms a readily soluble in water oxalate and the remaining by-products remain with a Rt ₁ value ^ 45 in the organic phase.

It is also surprising that these two separations proceed continuously very easily and completely even with a single extraction or in extraction columns, i. until the absence of visual proof in the thin-layer chromatogram.

embodiments

example 1

500 kg of moist Rohpyridamol (= about 350 kg dry weight) are dissolved in a 3200 1 stirred tank with stirring in 750 1 of a 10% aqueous sodium hydrogen sulfate and the undissolved 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimido_ / ~ 5, 4-d_7pyrimidine separated. The dissolved dipyridamole is precipitated from the filtrate by neutralization with sodium hydroxide solution and isolated Yield: 420 kg of water-moist crude dipyridamole (= 300 kg dry matter)

The water-moist Rohdipyridamol obtained is dissolved in a 3200 1 stirred tank in 1200 1 CHCl ₃ , the resulting solution with 500 1 of 10% acetic acid stirred vigorously for 15 minutes and the aqueous phase separated. The extraction is repeated 2 times with 500 1 of a 2% acetic acid.

Subsequently, the CHCl.sub.1 solution is mixed with 1200 l of a 7% strength aqueous oxalic acid solution, intimately mixed for 10 minutes, and then the chloroform phase is separated off. The aqueous solution is neutralized by adding dilute potassium hydroxide, whereby the dipyridamole is precipitated.

After centrifuging the dipyridamole from the mother liquor, the purified product is introduced into 1200 l of methanol. The hot methanolic solution is filtered to obtain

Concentrated and cooled to a high crystallizate amount up to 2/3 of its initial volume. The crystallized dipyridamole is spun off and washed with a little methanol.

The yield after drying the separated Reindipyridamols 250 kg with a Pp 166 - 167 ⁰ C, which indicates no further spots in the thin layer chromatogram according to the methods of the Pharmacopoeia der'DDR, 2nd Edition.

Example 2

A solution of Rohdipyridamoi analogous to Example 1 is extracted in countercurrent in a rotary disk extractor with three theoretical plates with 800 1 10% acetic acid, The emerging at the bottom CHCl.-.- layer is in a second offset turntable extractor with three theoretical Soils extracted with 1200 1 of a 7% solution of oxalic acid and pumped running at the top of the column aqueous oxalic acid solution in submitted dilute sodium hydroxide solution. With good stirring, the dipyridamole is precipitated, separated at pH 6.5-7.0 from the aqueous mother liquor, - added in butyl acetate, the adhering water is removed azeotropically and receive reindipyridamole on cooling. After separation of the Reindipyridamols from the mother liquor and drying 235 kg of reindipyridamole with Pp 166 - 167 ⁰ C and absolute DC purity, ie with only one spot at R ^ value 45 obtained (DC method of the Pharmacopoeia of the GDR, 2 . Output).

Example 3

250 kg of a water-moist technical crude product of the dipyridamole synthesis, whose content of 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimido _: / ~ 5, 4-d_7pyrimidine is 8.5% by densitometric measurements, are suspended in 1500 l of water , After adjusting the suspension to

a pH 6.5 - 7.0 by adding 10% sulfuric acid are added at temperatures of 40 - 50 ⁰ G 50 kg of sodium bisulfate. The undissolved 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimidino / ^ 5,4-d_7-pyrimidine is separated off.

The aqueous-acidic solution, which contains the dipyridamole in addition to the thermally induced conversion products is treated with 1000 1 CHClOo and with stirring with 50 1 ammonia water f22%). The chloroform layer, which contains the dipyridamole with its by-products, is separated from the aqueous Na-NH 2 -SiFlat layer.

The chloroform layer is thoroughly mixed with 500 l of a 5% strength aqueous acetic acid and after phase separation is stirred twice more with 500 l of a 2% strength acetic acid. Subsequently, to the chloroform layer 1200 1 4% aqueous oxalic acid. Added and the mixture stirred thoroughly for 10 minutes.

The oxalic acid layer containing the dipyridamole in pure form as dipyridamole oxalate is washed with 500 l of butyl acetate to remove chloroform traces. Subsequently, the dipyridamole oxalate is slowly neutralized by the addition of 10% sodium hydroxide solution, the precipitated reindipyridamole separated and washed with 3 times 300 1 of water and recrystallized from ethyl acetate to obtain a corresponding crystal structure.

Of 250 kg of the technically water-moist crude dipyridamole with a dry content of 70% v / ground 140-145 kg Reindipyridamol mp 165 -167 ⁰ C and absolute DC-purity, ie with only one spot at the Rn value 45 obtained (DC Method of the Pharmacopoeia of the GDR, 2nd edition).

Claims (2)

claims 1. Technical process for the preparation of high purity dipyridamole, which in the thin layer chromatogram according to the methods of the Pharmacopoeia of the GDR, 2nd edition, next to the main spot R 45 indicates no further spots, characterized in that one dissolves Rohdipyridamol in CHCl ^, the solution at temperatures between 5 and 40 ⁰ C, preferably between 15 and 25 ⁰ C, thoroughly mixed with 2-10% acetic acid, the aqueous phase separated, the CHClo layer then with a 5-10% aqueous oxalic acid solution at temperatures between 5 and 40 ⁰ C, preferably between 15 and 25 ⁰ C, intensively mixed, the CHClo layer · separated and either a) from the oxalic acid aqueous phase · the dipyridamole precipitates with alkalis and recrystallized from organic solvents or b) the oxalic acid aqueous phase is treated with acetic acid esters, the dipyridamole is released by the addition of alkali and, after separation of the organic phase, the high-purity dipyridamole is crystallized therefrom. 2. The method according to item 1, characterized in that one uses a Rohdipyridamol, from which the 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimido_ / 5, 4-d_7pyrimidin (II) by stirring with dilute aqueous solutions of Ammonium or alkali hydrogen sulfate at temperatures between 10 and 80 ⁰ C and separating according to DD-PS 143 522 was removed. A method according to item 2, characterized in that after the separation of the 2-diethanolamino-6-chloro-4,8-dipiperidino-pyrimido_ / 5,4-d_7pyrimidin (II), the remaining reaction mixture of Rohdipyridamol from the resulting hydrosulfate acidic aqueous filtrate by alkalization and extraction in CHCl-, and then further separated according to the present invention.