DD274620A1 - PROCESS FOR PREPARING PURE 3-CYAN-6-METHYL-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRID-2-ON - Google Patents

Abstract

The invention relates to a process for the preparation of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one of the formula I in good yields and high purity. It can be technically easily prepared by reacting 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyan-penta-1,4-diene-5-carboxylic acid amide of the formula II in alcohols with a alkaline sodium compound is heated. II can be easily obtained by reacting 1-alkoxy-3- (pyrid-4-yl) -but-1-en-3-ones of formula IV with malononitrile.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of pure 3-cyano-6-methyl-5-pyrid-4-yl) -1,2-dihydro-pyrid-2-one of the formula I, which is used in medicine as Kardiotonikum (milrinone).

Characteristic of the known technical solutions

It is known to reflux 1- (pyrid-4-yl) -propan-2-one of the formula III with 2-cyano-3-ethoxy-prop-2-en-nitrile for 5 hours in ethanol and I in 65 to isolate to 67% yield (US-PS 3347363, Synthesis 1985, 479, ES-OS 8603708).

Another known process describes the reaction of III with dialkylformamide dialkyl acetals to form i-dialkylamino-2- (pyrid-4-yl) -but-1-en-3-ones of the general formula V in which the radicals Rj are a lower alkyl radical , which are further cyclized with cyanoacetamide in the presence of sodium alkoxides by refluxing in dimethylformamide. The dimethylformamide is then distilled off, added acetonitrile, the sodium salt isolated and released from it I.

Recrystallization from dimethylformamide / water gives I in 51% yield (US Pat. No. 4,313,951).

It is also known, 1-dimethylamino-2- (pyrid-4-yl) -but-1-en-3-one of the formula V (R ₂ = CH ₃ ) with cyanoacetamide under the conditions of phase transfer catalysis in React acetonitrile with Tetrabu'ylammoniumbromid as a catalyst and a large excess of potassium hydroxide and I after elaborate isolation in 82% yield to obtain (US-PS 4563528).

It is also known, 1-alkoxy-2- (pyrid-4-yl) -but-1-en-3-ones of the formula IV, wherein Ri is a lower alkyl radical having 1 to 4 carbon atoms, by condensation of 1- (pyrid-4-yl) -propan-2-one of formula III are obtained with Trialkylorthoformiaten be reacted with Malonsäuredinitril in alcohols to I.

In addition, it is known to react the compounds of formula IV with cyanoacetamide in alcohols in the presence of A cold and I precipitate by adjusting the reaction mixture to pH 6-7, with methanol / water auszurühren, dissolve in dilute sodium hydroxide solution and after activated carbon treatment of the Precipitate solution in a purified form.

Another Aufarbeitungsweise this production route is that distilled from the resulting reaction mixture of the alcohol, I precipitated by the addition of water and acidification and is purified by dropping. Sometimes, however, a further purification step by recrystallization from dimethylformamide was required.

The yields of purified product were using sodium methoxide 61% of theory and using sodium hydroxide solution 78% of theory (US Patent 4417054, EP-PS 95152).

As further purification methods for I, fractional crystallization and column chromatography are described (ES-OS 8603701,8603708,8603709 and 8603715).

Further Harstellungsmöglichkeiten for I consist in the implementation of 2- (pyrid-4-yl) -butane-1,3-dione with cyanoacetamide in the presence of alkali metal alkoxides (ES-OS 8603715), the dehydration of 6-methyl-5- (pyrid 4-yl) -1,2-dihydropyrid-2-one-3-carboxylic acid amide for example with thionyl chloride (ES-OS 8603615) and the diazotization of 2-amino-3-cyano-6-methyl-5- (pyrid-4-yl) yl) -pyridine and boiling of the diazonium salt to I.

For processes for the preparation of I, which do not start from III, the starting materials are relatively difficult to access or only available indirectly from the precursors of I. So they are not suitable for a technical application.

But even under the condensation of III and Dialkylformamiddialkylacetalen running syntheses have significant disadvantages. These consist in the accessibility, which is more difficult in comparison to the trialkyl orthoformates, and in their lower selectivity, which leads to the formation of isomeric products (US Pat. No. 4,417,054).

Disadvantages of the hitherto described synthetic routes proceeding with the reaction of the trialkyl orthoformates with III in the presence of alkalis are the extensive purification work. To produce pure products, it is necessary to carry out with methanol / water, dissolve again in caustic soda, treat with activated charcoal and precipitate again, and then recrystallize from dimothylformamide or dimethylformamide / water. Especially such Roinigungsoperationen bind considerable capacity by additional filtration operations and redistillation of solvents. Proven liquor acid consumption also requires increased resources to ensure environmental protection.

Object of the invention

The invention makes it possible to produce 3-cyano-6-methyl-5- (pyrld-4-yl) -1,2-dihydro-pyrid-2-one in a technically simple manner and in good yields on a new synthetic route.

Explanation of the essence of the invention The invention has the object, pure 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one in a technically simple manner in

produce good yields on a new synthetic route.

According to the present invention, this is achieved by reacting 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyanopentane

1,4-diene-5-carboxylic acid amide <'Jer. Formula II is heated with an alkaline sodium compound in an alcohol.

Alkaline sodium compounds for the purposes of the present invention are, for example, sodium hydroxide, sodium alkoxides

and sodium carbonate. Conveniently, they are used in a slight excess, for example up to 25 mol%.

For the purposes of the present invention, alcohols are, for example, those having 1 to 4 C atoms, but preferably methanol. Although egg warming is possible for the practice of the present invention over a wide temperature range,

However, an advantageous embodiment of the invention is that the reaction at temperatures of 50 to 120 ⁰ C, but preferably at the boiling temperature of the respective reaction mixtures, is performed.

The workup of the resulting reaction mixture to pure 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one can

done in different ways.

So you can acidify once the reaction is complete, the resulting reaction mixture, the failed 3-cyano-6-methyl-5

(Pyrid-4-yl) -1,2-dihydro-pyrid-2-one, dissolved in the appropriate amount of sodium hydroxide with heating to 40 to 100 ° C, preferably to about 60 ⁰ C, as the sodium salt, if desired, connect an activated carbon treatment and precipitate the pure 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one by acidification, wash with water and dry.

A particular embodiment of the invention, however, is that from the resulting reaction mixture

precipitating sodium salt of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one, this is wet or dry in

Suspended water, the suspension to 40 to 100 ⁰ C, preferably heated to about 6o ° C, optionally a little caustic soda

add to the complete dissolution of the suspension, if desired, followed by an activated carbon treatment and the pure 3-cyano-6-methyl-5 {pyrid-4-yl) -1,2-dihydropyrid-2-one precipitated by acidification, separated, washed with water and dries.

The yield is 72% of theory based on the compound of formula II. The 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-

dihydro-pyrid-2-one is obtained as a nearly colorless substance in a pharmaceutically acceptable quality.

The starting 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyanopenta-1,4-diene-5-carboxylic acid amide is a new one Connection. It can be prepared by reacting 1- (pyrid-4-yl) -propan-2-one with triethyl orthoformate in a mixture of glacial acetic acid

and acetic anhydride and reacting the thus obtained 1-ethoxy-2- (pyrid-4-yl) -but-1-en-3-one with malononitrile in methanol. For the production of this starting product no protection is claimed in the context of this application.

It is the subject of a patent application filed on the same day. At the same time as the starting product, the synthetic route is new. The course of the reaction according to the invention was not

Predictably. To the same extent that the CONH ₂ group was incorporated into the cycle to form I, this would have been achieved with the reactive CN group to give 6-methyl-5- (pyrid-4-yl) -1,2-dihydro- pyrid-2-one-3-carboxylic acid amide or 2-

Alkoxy-6-methyl-5- {pyrid-4-yl) pyridine-3-carboxamide can be done. embodiment In a 250 ml three-necked flask, 27.7 g of 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyanopenta-1,4-diene-5-carboxylic acid amide

110 ml of methanol were suspended and 6.5 g of sodium methylate were added. The mixture is stirred for 3 hours at reflux, cooled and stirred for 1 hour at 15 ⁰ C, it is filtered off with suction and washed three times with 30ml of methanol and dried.

The obtained sodium salt of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one is suspended in 200 ml of water and on

Heated to 60 ° C. If any remains undissolved, this is brought into solution by adding a little caustic soda. 2 g of charcoal are added, stirred for 15 minutes and filtered. To the filtrate is added dropwise about 7 ml of concentrated hydrochloric acid to a pH of 6-7, cooled to about 20 ° C, filtered off with suction, washed with water and t-rose.

Yield: 15.2 g of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydropyrid-2-one 72% of theory. Almost colorless crystals. Fp _v: 280-319 ⁰ C (decomposition).

The starting 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyan-p-inta-1-diene-S-carboxamide can be prepared as follows:

In a 500 ml three-necked flask with stirrer, internal thermometer and distillation head with Liebig condenser and template, 27.4 g of 1- (pyrid-4-yl) -propan-2-one (0.2 mol.), 32.6 g Triethylo'thoformiat (0, 22 mol.), 51 g. Acetic anhydride (0.5 mol.) And 54 ml. Acetic acid (0.9 mol.) Are stirred and allowed to stand overnight. It is then distilled off at about 4 kPa and an internal temperature of not more than 75 ⁰ C, 30 ml of methanol is added and distilled this again in vacuo under the same conditions. There are 200ml methanol and 23.8 g of malononitrile (0.36 mol.) Was added and the reaction mixture stirred for 3 hours bai 40 ⁰ C. It is then cooled to 20 ° C, filtered off with suction and washed three times with 20 ml of methanol. Yield: 39.3 g of 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tricyanopenta-1,4-diene-5-carboxylic acid amide 71% of theory

 Mp .: 240-317 ° C. Dark red crystals.

The mother liquor is concentrated to about 50 ml and cooled to 20 ° C. It is filtered off with suction and, after drying, 2.8 g of 2-methyl-3- (pyrid-4-ylidene) -1,1,5-tficyan-penta-1,4-diene-5-carboxylic acid amide & 4% of theory.

- H-

/ = \ CH = c ^

/ \ / ^ CONHr

HN) = ^C

C »

H ₃ C

r \.

CH ₉ - CO - CH, IIIII

ΛΛ

CO - CH IV

CH-N

CO - CH ₃

Claims (6)

1. A process for the preparation of pure 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one of the formula I, characterized in that 2-methyl-3 - (pyrid-4-ylidene) -1,1,5-tricyan-penta-1,4-diene-5-carboxamide of the formula II is heated with an alkaline sodium compound in an alcohol. 2. The method according to claim 1, characterized in that are used as the alkaline sodium compound sodium hydroxide, sodium or sodium carbonate. 3. Process according to claims 1 and 2, characterized in that are used as alcohols having 1 to 4 carbon atoms, preferably methanol. 4. Process according to claims 1 to 3, characterized in that the reaction at temperatures of 5O ⁰ C to 120 ⁰ C, but preferably at the boiling temperature of the reaction mixtures, is performed. 5. Process according to claims 1 to 4, characterized in that from the resulting reaction mixture, the 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one by Acid precipitates and cleans by dropping over its sodium salt. 6. Process according to claims 1 to 4, characterized in that from the resulting reaction mixture, the precipitated sodium salt of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydropyrid-2-one separates, this suspended in water, dissolves under heating and precipitated by acidification of the 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one.