DD290878A5 - TECHNICAL PROCESS FOR THE PREPARATION OF PURE NIFEDIPINE FROM THE RAW PRODUCT INVOLVED IN SYNTHESIS - Google Patents

Abstract

Pure nifedipine can be readily prepared from a large scale by recrystallizing the crude nifedipine obtained in the synthesis with solutions of organic, solid at room temperature acids in an inert organic solvent in which these organic solid acids are soluble at room temperature.

Description

Field of application of the invention

The invention relates to a technical ancestor for the preparation of pure nifedipine (I) from the crude product (II) obtained in the synthesis. Nifedipine is used in medicine as a coronary and antihypertensive.

Characteristic of the known state of the art The preparation of nefedipine [= 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester] Reaction of o-nitrobenzaldehyde, methyl acetoacetate and ammonia is both in DE-OS 1670827 and in the DD-PS 120019 has been described. In both cases, reference is made to the emergence of synthetic new products as well as decomposition products found in the

crude nifedipine (II) are inevitably included. In addition to a number of chromatographically detectable, not chemically.

defined substances are the compounds 2,6-dimethyl-4- (2'-nitrosophenyl) -pyridine-3,5-dicarboxylic acid dimethyl ester and 2,4-bis (2'-nitrophenyl) -5-carbomcthoxy-6-methyl-1, 2,3,4-Totrahydropyrimidin obtained as isolable by-products.

From DD-PS 120019 is also known that the separation of said by-products by recrystallization of II

in the. common organic solvents such as methanol, ethanol, isopropanol, ethyl acetate, acetone, benzene or toluene is not possible (see DD-PS 120019 page 2 last section).

In DD-PS 120019 has been described that these by-products by recrystallization of Il at room temperature

liquid acids such as formic acid, acetic acid or propionic acid can be removed.

On an industrial scale, the amount of byproducts formed during nifedipine synthesis can indeed be reduced in this way

be lowered because these by-products preferably remain dissolved in the resulting mother liquor, a complete

However, removal of them is not possible. This way of working ^bes' zt However, on an industrial scale further disadvantages. Thus, for large-scale approaches to nefedipine residence times in the respective acids, which are considerably higher than those in

DD-PS 120 019 cited laboratory approaches are.

Even with high-throughput dissolving and filtration units, nifedipine is in large-scale technical approaches

several hours in the temperature range around or over 10J ⁰ C. This range must not be fallen below, because otherwise the low solubility of the Nifedipins in these acids on the one hand as well as unwanted crystallization phenomena in the

On the other hand, the piping system makes the technical process ineffective. However, under the abovementioned temporal and temporal conditions, new forms are formed in the thin-chain chromatogram

detectable by-products, which increase in the destiüativer: processing of the mother liquors in addition.

This procedure also has the disadvantage that the large-scale handling of the listed in DD-PS 120019

liquid acids, including the preferred acetic acid, extensive protection of the damaged against the irritant

and caustic effect of aerosols and vapors of these acids in the handling of the solvent-moist nifedipine and other accumulating Grundopf.rationen requires.

Additional problems also arise from Qcr view of the corrosion protection for the equipment used. Another disadvantage of the method. DD-PS 120019 is that to avoid unwanted Methyl ester formations of the acids used it is additionally necessary that the resulting in the synthesis

methanol wet raw nifedipine is dried before the recrystallization process.

Object of the invention The invention enables the industrial production of pure nifedipine from the crude product obtained in the synthesis

^r Ve under avoidance of the use of formic acid, acetic acid or propionic acid and the resulting impediments to the technical implementation of the method.

The invention makes it possible to obtain pure nifedipine from the crude product in one, the modern pharmacopoeia, for example USP XXI, BP80,2.AB of the GDR, to obtain appropriate quality. A particular advantage arises from the fact that the mother liquor obtained after separation of the pure nifedipine

can be used several times without intermediate purification as a solvent.

The thermal load of nifedipine is reduced and thereby the formation of new by-products during the Recrystallization excluded. Another advantage is that the required working temperatures are significantly lower than those in DD-PS120019

mentioned lie.

The inventive method leads to the selective enrichment of the by-products in the mother liquor

decreasing solubility of this mother liquor for nifedipine in repeated use thereof as a solvent.

Explanation of the essence of the invention The present invention has for its object to provide a simple, industrially feasible method for Production of pure nifedipine to develop from the obtained by known method crude product. In accordance with the present invention, this is accomplished by reacting the crude nifedipine incident on the synthesis base

with solutions of organic, solid at room temperature acids in an inert organic solvent in which these organic solid acids are soluble at room temperature, recrystallized.

The crude nifedipine to be purified can be both dry and solvent-moist, as in its preparation

obtained, for example, methanol damp or water-methanol damp.

The order of addition of the individual partners is arbitrary according to the present invention. So you can to For example, first dissolve the organic solid acid in the solvent and then add the crude nifedipine or first the

Suspend crude nifedipine in the solvent and then add the organic solid acid. But you can also add the inert organic solvent last.

As organic, solid at room temperature acids are, for example, halogenated aliphatic monocarboxylic acids

such as mono-, di- or trichloroacetic, aliphatic di- or tricarboxylic acids which may be substituted by hydroxyl groups, such as oxalic acid, tartaric acid or citric acid, or aromatic carboxylic or sulfonic acids such as

Benzoic acid or toluenesulfonic acid, wherein the di- and tricarboxylic acids optionally in the form of their acidic salts Alkalis can be used. As inert organic solvents in which the solid at room temperature acids at room temperature sufficient

Soluble are, for example, lower aliphatic alcohols such as methanol or ethanol or optionally substituted aromatic hydrocarbons such as toluene or chlorobenzene.

A particular embodiment of the invention comprises reacting the crude nifedipine and the acid in a molar ratio

from 1: 0.1 to 1:10, although below and above molar ratios are possible.

Another embodiment of the invention is that the recrystallization at temperatures between 50 and

9O ⁰ C, but preferably between 60 and 75 ⁰ C, performs.

Another embodiment of the invention consists in that the mother liquor obtained in the recrystallization

used several times.

The results of the process according to the invention are surprising and could not be foreseen, since the data in the DD-PS 120019 the use of conventional organic solvents, including those used in the invention Solvents, exclude for purification of nifedipine. It was also not to be expected that the solutions used according to the invention of organic, solid at room temperature Acids in an inert organic solvent in which these organic solid acids are soluble at room temperature,

cause a marked increase in nifedipine solubility on warming.

In this case, the formation of salts of nifedipine can be excluded because regardless of the acid used and the

used solvent is always pure nifedipine obtained and the molecular structure does not expect salt formation.

It is also surprising that these acid / solvent mixtures used according to the invention have a selective action Cause separation effect between K'ifedipln and its by-products, wherein the resulting mother liquor after

Repeated use as a solvent for raw nifedipine increasingly depleted of nifedipine and enriched with the by-products. Nor was it to be expected that pure nifedipine would precipitate in the crystallization process without trapped or entrained acid particles.

Particularly valuable for the technical reaction 'is the thermal stability of the dissolved nifedipine in the View acid / solvent mixtures, with longer residence times to no additional Zersdtzungsprodukten

of Nifedipin leader ..

The nifedipine is obtained in high purity and meets the quality requirements of 2.AB DDR and the USP XXI. Ausführungsbeisplelo example 1

In a solution of 18kg oxalic acid (0.2kmol) in 1600I methanol, 200kg of water-methanol wet nifedipine (160kg dry weight = 0.46 kmol) are added. Dio suspension is heated to 60 ⁰ C, whereby the nifedipine dissolves. To remove mechanical impurities is filtered and cooled the clear solution. The crystallized nifedipine is separated from the mother liquor, washed with methanol and provides after Trocknon a product of mp. 172.5-173.5 ° C, which corresponds in all conditions to the requirements of 2. AB DDR and the USP XXI.

Yield: 135kg = 84% of theory based on the crude product used. Example 2 In a solution of 158kg monochloroacetic acid (1.67 kmol) in 2OOOI toluene are added 208kg dry nifedipine (0.6kmol)

entered. At a temperature of 85 ⁰ C, the resulting solution is treated as in Example 1.

Yield: 181 kg = 87% of theory based on the crude product used. The quality corresponds to that of Example 1.

Example 3

In 2000 l of ethanol, 16 kg (0.1 kmol) of trichloroacetic acid and 208 kg of dry crude nifedipine (0.6 kmol) are introduced. The suspension is at 75 ⁰ C in a solution. After filtration of the solution, the same is cooled, the precipitated nifedipine separated from the mother liquor, washed with ethanol and distilled water and dried.

Yield: 174 kg nifodipine = 84% of theory based on the crude product. Mp .: 173-175 ° C. The purity corresponds to that of 2.AB DDR or the USPXXI.

Example 4

In 2000I mother liquor from Example 2, did already five times as a solvent for each 250 kg of raw nifedipine was used, another 250kg raw Nifedipio be registered. Furthermore, the procedure described in Example 1 is repeated. This gives a pure nifedipine of mp. 172.5-174 ⁰ C in the Quaiität described in Example 1.

Yield: 235 kg nifedipine = 94% of theory based on the crude product used. The quality corresponds to that of Example 3.

Examples

In 2000 l of isopropanol, 208 kg of dry crude nifedipine (0.6 kmol) are entered. To this mixture 12.2 kg benzoic acid (0.1 kmol) are added .. The suspension is heated up and goes into a clear solution at 55 ⁰ C. After filtration of this solution to remove mechanical impurities is cooled and the precipitated nifedipine is separated from the mother liquor, washed with isopropanol and distilled water and dried.

Yield: 178 kg nifedipine = 85.6% of theory, based on the crude product used. M.p .: 173-175 ⁰ C. The purity corresponds to that of the DDR 2.AB or USPXXI.

Examples

In 15001 toluene, 208 kg of dry crude nifedipine (0.6 kmol) and 20 kg of p-toluenesulfonic acid (0.12 kmol) are introduced. At 5O ⁰ C solution of the mixture enters. After removal of mechanical impurities by filtration at 60-65 ⁰ C is cooled and the precipitated nifedipine separated from the mother liquor, washed with methanol and dried.

Yield: 182 kg nifedipine = 87.5% of theory, based on the crude product. M.p .: 174-176 ⁰ C. The purity corresponds to that of Example. 5

Claims (11)

1. A process for the preparation of pure nifedipine from the crude product obtained in the synthesis by recrystallization, characterized in that the crude nifedipine obtained in the synthesis with solutions of organic, solid at room temperature acids in an inert organic solvent in which this organic solid acids are soluble at room temperature, recrystallized. 2. The method according to claim 1, characterized in that as an organic, solid at room temperature acids halogenated aliphatic monocarboxylic acids, aliphatic di- or tricarboxylic acids, which may optionally be substituted by hydroxy groups or aromatic carboxylic or sulfonic acids are used. 3. The method according to claim 1 and 2, characterized in that are used as halogenated aliphatic monocarboxylic acids mono-, di- or trichloroacetic acid. 4. The method according to claim 1 and 2, characterized in that as aliphatic di- or tricarboxylic acids which may optionally be substituted by hydroxy groups, oxalic acid, tartaric acid or citric acid are used. 5. The method according to claim 1 and 2, characterized in that are used as the aromatic carboxylic or sulfonic acids, benzoic acid or toluenesulfonic acid. 6. The method according to claim 1 to 5, characterized in that as inert organic solvents in which the solid at room temperature acids are sufficiently soluble at room temperature, lower aliphatic alcohols or optionally substituted aromatic hydrocarbons are used. 7. The method according to Aröpruch 1 to 6, characterized in that are used as lower aliphatic alcohols methanol or ^r ihanol. 8. The method according to claim 1 to 6, characterized in that are used as optionally substituted aromatic hydrocarbons toluene or chlorobenzene. 9. The method according to claim 1 to 8, characterized in that the ratio of crude nifedipine is 1: 0.1 to 1:10. 10. The method according to claim 1 to 9, characterized in that the recrystallization at temperatures between 50 and 9O ⁰ C, but preferably between 60 and 75 ° C, is performed. 11. The method according to claim 1 to 10, characterized in that the mother liquor is used several times for recrystallization.