HU205102B - Process for producing high purity isoflavones - Google Patents

Abstract

Hydroxy gp. substd. high purity isoflavones are prepd. by cyclising appropriate benzyl-phenyl-ketones, with ortho-formic-esters. - A novel catalyst system contg. magnesium salts, ammonium salts and organic bases, avoids alkylation of hydroxy gps. due to the influence of ortho-formates. The purity of the raw prod. is high enough that it can be used for the prepn. of medicinal 7-iso-propoxy-iso-flavone

Description

The present invention relates to a process for the preparation of high purity isoflavones of formula I wherein R is one or more hydroxy groups from phenylbenzyl ketones of formula H wherein R is as defined above, IH. by ring closure in solution and organic base catalyzed by ortho-formic acid esters of the formula wherein X is a lower alkyl group.

Isoflavones of formula I are known to be important intermediates for the preparation of substituted isoflavones in which R is an alkoxy group. so e.g. a medicine known as 7-isopropoxyisoflavone Ipriflavon.

The following process for the preparation of isoflavones of general formula I is described in the literature. The phenyl benzyl ketone of formula H is HT. orthobutyric acid ester of the formula (II) in the presence of a basic catalyst, preferably morpholine, in dimethylformamide. By boiling the reaction mixture, raising the temperature to 150 ° C and then reacting while distilling off the resulting alcohol, the compounds of formula I are obtained.

A major disadvantage of the method described in the literature is that the ortho-acetic acid ester not only participates in the ring closure reaction, but also reacts with the hydroxyl group on the aromatic ring to form the corresponding alkyl ether. For example, if a 7-hydroxyisoflavone is prepared from 2,4-dihydroxyphenylbenzyl ketone and ethyl ortho-acetic acid, the product is contaminated with 10% 7-ethoxyisoflavone as shown in the comparative example. This is very confusing because separation can only be achieved by recrystallization several times and is therefore possible at high losses. If, however, isopropylation is carried out without purification to Ipriflavone, the ethoxy compound contaminates the product and is virtually impossible to separate.

It is an object of the present invention to provide a process for the preparation of substituted isoflavones of Formula I which does not undergo such an alkylation side reaction and thus provides compounds of Formula I which are highly pure and can be converted into a pharmaceutical product without purification.

The process of the present invention is based on the surprising discovery that when the ortho-acetic acid ester ring closure reaction is carried out in the presence of magnesium compounds and unsubstituted or preferably 1-4 lower alkyl alkyl substituted ammonium chloride catalysts, there is no alkylation reaction, no ether-like, hardly separable by-product is formed. This recognition is unexpected in many ways. On the one hand, it is known that compounds of magnesium formed with inorganic acids form complexes with amines and could have been expected to neutralize the catabolic effect of organic amines. On the other hand, magnesium compounds, like Lewis acidic substances, are expected to catalyze the alkylation reaction of phenols with ortho-formic acid esters. Thus, when magnesium compounds were added to organic base catalysts, it was not expected that the reaction would proceed rapidly and selectively and that the phenolic hydroxyl groups would not be alkylated.

In the process of the invention, a. Compounds of formula I wherein R is one or more hydroxy groups are reacted in a solvent in the presence of an organic amine, a magnesium compound and an optionally substituted ammonium chloride catalyst. ortho formic acid ester of general formula (X) wherein X is lower alkyl. Organic amines include amines known in the art, preferably morpholine. As the magnesium compound, metal magnesium, magnesium salts such as magnesium chloride, oxychloride sulfate, oxide, carbonate, acetate, stearate or the like can be used. The amount of magnesium compound is 0.01-0.1 mole per mole of starting ketone.

Optionally substituted ammonium chloride catalysts include ammonium chloride, ethyl, diethyl, triethyl or tetraethylammonium chloride, and dodecyltrimethylammonium chloride.

In a preferred embodiment of the production process of the invention, 1 mol Π. The ketone of the formula (I) is reacted with 1 to 1.5 moles of ortho-formic acid ethyl ester in an amount of 0.1-0.5, preferably 0.2-0.4 moles of morpholine and 0.0 ΙΟ, 1 moles, preferably 0.02-0.04. moles of magnesium compound and 0.04-0.4 moles of optionally substituted ammonium salt.

The process according to the invention has the advantage of affording pure products of general formula I already in good yield as crude products. These products do not contain ether-type impurities which also correspond to formula I, but where R XO represents atomic groups

The process of the present invention is illustrated in detail by the following examples without limiting the scope of the invention to the process of the examples.

EXAMPLES

Example 1

To a mixture of dry dimethylformamide (29.2 g) and 2,4-dihydroxyphenylbenzyl ketone (40 g) were added ethyl ether (30 g), morpholine (4.2 g) and magnesium oxide (0.4 g) at 70 ° C, 2g ammonium chloride. The reaction mixture was distilled off from the resulting ethyl alcohol and heated at 150 ° C for 1 hour. After cooling, stirring with 120 g of methanol and crystallizing the product, 40 g of 7-hydroxyisoflavone is obtained which contains only 0.1% 7-ethoxyisoflavone by chromatography. 210-218 ° C.

Example 2

All proceed as in Example 1, but using 0.25 g of magnesium metal instead of magnesium oxide. 39.5 g of 7-hydroxyisoflavone are obtained, containing 0.1% of 7-ethoxyisoflavone.

Example 3

All proceed as in Example 1, but using 1.3 g of two crystallized aqueous magnesium chloride instead of magnesium oxide and ammonium chloride. 40 g of 7-hydroxyisoflavone of identical purity are obtained

Example 1.

HU 205 102 Β

Comparative example

To a mixture of 29.2 g of dry dimethylformamide and 40 g of 2,4-dihydroxyphenylbenzyl ketone are added 30 g of ortho-formic acid ethyl ester and 4.2 g of morpholine at 70 ° C. The resulting ethyl alcohol was distilled off from the reaction mixture and heated at 150 ° C for 1 hour. After cooling, the mixture was stirred with 120 g of methanol and crystallized. 38 g of 7-hydroxyisoflavone are obtained, which according to chromatography contains 10% of 7-ethoxyisoflavone. Melting point 200-210 ° C. For purification it must be recrystallized from methanol and chloroform.

Example 4

All proceed as in Example 1, but no morpholine is added to the reaction mixture. To a mixture of dry dimethylformamide (29.2 g) and 2,4-dihydroxyphenylbenzyl ketone (40 g) at room temperature at 70 ° C was added 30 g of ethyl ortho-acetic acid and 1.0 g of magnesium oxide and 3.0 g of ammonium chloride. . 32.5 g of 7-hydroxyisoflavone are obtained with a purity similar to that of Example 1.

Claims (4)

PATENT CLAIMS A process for the preparation of isoflavones of general formula I in high purity wherein R is one or more hydroxyl groups, as defined in Π. phenylbenzyl ketones of the general formula wherein R is as defined above, a. ortho formic acid esters of the formula wherein X is a C 1 -C 4 alkyl group, in solution, at a temperature of 60 to 180 ° C and organically catalyzed by ring closure, characterized in that the reaction is carried out under magnesium halide, in the presence of 0.01 to 0.2 moles of other magnesium compound providing the compound, and 0.04 to 0.4 moles of optionally substituted ammonium halide. A process according to claim 1, wherein magnesium oxide and ammonium chloride are used. 3. A process according to claim 1, wherein the metal magnesium and ammonium chloride are used. A process for the preparation of isoflavones of general formula I in high purity according to claim 1, in which R represents one or more hydroxyl groups, a. phenylbenzyl ketones of the general formula wherein R is as defined above, a. ortho-formic acid esters of the general formula wherein X is a C 1 -C 4 alkyl group, in solution by ring closure at a temperature between 60 ° C and 180 ° C, characterized in that the reaction is carried out in the presence of magnesium halide or optionally magnesium halide is added in the presence of 0.01-0.2 moles of the halide and optionally substituted ammonium halides.