Process for the preparation of substituted isoflavone derivative

Details Process for the preparation of substituted isoflavone derivative Process for the preparation of substituted isoflavone derivative

1991-12-05

1993-09-21

Chan, Nicky

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D31136

Patent

active

052471020

DESCRIPTION:

BRIEF SUMMARY
Cross Reference to Related Application

This application is a National Phase of PCT/HU90/00023 filed Apr. 6, 1990.


FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of substituted isoflavone derivatives of high purity, which are suitable for the preparation of pharmaceutical compositions, particularly for the preparation of ipriflavon (Osteochin.sup.R) which is the common name of 7-isopropoxy-isoflavone suitable for use against osteoporosis (HU-PS 162 377).
In the specification the substituents are defined as follows:
According to the invention pure isoflavone derivatives of the formula (I) ##STR3## can be prepared by reacting resorcinol-derivatives of the formula (III) ##STR4## and ethyl-ortho-formate the compounds of the formula (III) and (IV) are subjected to ring closure in the presence of an organic solvent, preferably dimethylformamide and/or isopropanol and/or in a 0.3-2-fold volume calculated to the volume of the resorcinol derivatives of the formula (III) and/or in the presence of excess ester of the formula (IV) at a temperature of 70.degree.-100.degree. C., whereupon the reaction mixture becomes supersaturated (20-70% by weight) related to the product of the formula (VII) ##STR5## and thus the product of the formula (VII) continuously precipitates from the reaction mixture in the course of the reaction. After cooling the reaction mixture the product of the formula (VII) is filtered without or with the addition of a solvent or an almost equivalent amount of anhydrous potassium carbonate is added and the crystallizing double salt of the formula (V) ##STR6## is isolated while the contaminant of the formula (VI) ##STR7## remains in the solution, or dissolves selectively, whereafter the product of the formula (V) or (VII) is reacted with isopropyl halide and the pure product containing up to 0.5% by weight of the contaminant of the formula (VI) is optionally separated.


BACKGROUND OF THE INVENTION

As is known, the appropriately substituted 7-hydroxy-isoflavone-derivatives are suitable intermediates in the synthesis of 7-alkoxy-isoflavones which are effective medicines in human and veterinary therapy. Thus, it is desirable to prepare the 7-hydroxy-isoflavone-derivative of the formula (VII) in such chemical purity that it should be suitable for the preparation of the 7-alkylated end-product in appropriate purity, that is, it is an important requirement to suppress the formation of the contaminating derivatives of the formula (VI).
The 7-hydroxy-derivative of the formula (VII) can be prepared in the industry by subjecting the resorcinol-derivative of the formula (III) and an orthoformic acid ester of the general formula (IV) to ring closure. The following methods are known for carrying out the above synthesis:
In a pyridine-piperidine mixture by boiling for 1 hour (CA. 56, 2408) with a yield of 80% with 70% perchloric acid or POCl.sub.3 -dimethyl-formamide (Zsurn. Chem. Khim. 1970 40/2459; CA 75. 201219), with a yield of 33% using HCl as a catalyst (CA. 83, 193010), with a yield of 70%. In an analogous process the mixture is boiled for 8 hours in pyridine/piperidine mixture and unsubstituted isoflavone is prepared with a yield of 60% starting from 2-hydroxy-phenyl-benzyl-ketone (US-PS 3 340 276).
The mentioned ring closures are all performed at 110.degree.-150.degree. C. in the presence of a mixture of a solvent boiling at a temperature above 100.degree. C. (pyridine homologs, dimethyl-formamide etc ) and a secondary amine (piperidine, morpholine, pyrrolidine) preferably at the boiling point of &he mixture. In some cases the formed alcohol is distilled off during reaction, presumably in order to improve conversion or in order to raise temperature.
When reproducing said processes we have found that in addition to 7 hydroxy-isoflavone derivatives of the formula (VII) a significant amount& (in some cases 2-10% by weight measured by HPLC) of 7-ethoxy-isoflavone-derivative of the formula (VI) is formed among to other side products. By reducing the molar exce

REFERENCES:
patent: 4644012 (1987-02-01), Tsuda et al.

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