PROCESS FOR PRODUCING FLAVONE DERIVATIVES WITH MEDICINAL ACTIVITY

Abstract: A process for producing flavone derivative of formula: in which R is hydrogen or a disaccharide radical, R₁ is -OH or -OCH₃; R₂ is H or -OH; starting from flavone-7-glucosides of formula by total acetylation with acetiv anhydride and pyridine, and selective dehydrogenation in the 2-3 position with SeO₂ in a molar excess of about 10:1, in isoamyl alcohol solution.

Description: "Process for producing flavone derivatives with medicinal activity". This inventions relates to a new process for producing flavone derivatives of formula: EMI1.1 in which R is H or a disaccharide radical; R1 is -OH or -OCH3; R2 is H or -OE. In particular, the new process relates to the production of diosmin of formula: EMI1.2 in which R is a rutinose residue, and of apigenin of formula t EMI1.3 Both diosmin and apigenin are products which have been known for a very long time, as they are products of natural origin obtainable by extraction from various types of plant. Small quantities have been prepared by various processes generally used for the production of flavones, in order to determine their structure and test their,acti- vity. In recent years both diosmin and apigenin have found various interesting pharmaceutical uses, which have posed the previously non-exi- stent problem of producing said produots industrially. In particular, it has been found that diosmin is a product which is excellent for the venous system and as a hepato-protector, whereas apigenin has good spasmolytio activity both on the smooth musculature in general and on the bronchial musculature, in addition to having a good anti-inflammatory and anti-shock activity. Both these products. have the great advantage if total lack of toxicity. The problem of industrially producing diosmin and apigenin has proved difficult to solve, both with regard to the economics of the process and with regard to the purity of the final product. In this respect, known processes generally use costly raw materials and always have very low yields. In addition, the products obtained contain small percentages of by-products related to the production process used, and are absolutely unacceptable in a pharmaceutical pro duct. A process has recently been proposed for diosmin which, in contrast to the previous processes, is considered an industrial process (German Pub. Appl.2,602,314 of 12.1.78). This process, which uses hesperidin as its starting substance, is characterised by the formation of the double bond in the 2-3 position by bromination and dehydrobromina tion. A new industrial process has now been founds and forms the subject matter of the present invention which enables compounds of formula (I), and in particular diosmin and apigenin, to be produced starting from low cost raw materials, with high yields and pharmaceutical purity. The new process comprises the following essential stages : 1) total acetylation of flavanone-7-glucoside of formula t EMI3.1 in which K is a disaccharide radical; R1 is -OH or -OCH3g R2 i8 H or -OH, by heating to 90- 1000C with acetic anhydride and pyri dine; 2) oxidation of the acetyl derivative of the flavanone-7-glucoside prepared in the preceding stage, using selenium dioxide in iso amyl alcohol, in order to form a double bond in the 2-3 position by selective dehydrogenation, to give s EMI3.2 in which R3 is a totally acetylated disaocharide radical ; R4 is -OAc or -OCH3, R5 is H or -OAc (Ac is an acetyl radioal). 3) alkaline hydrolysis with dilute inorganic bases at 1000C in order to eliminate all the acetyl groups and restore the hydroxyl funct ions, to give s EMI3.3 in which R, ] R1, K2 are as defined under point (1). 4) acid hydrolysis with dilute inorganic acids under reflux, in or der to separate the disaccharide radical R and form a hydroxide in position 7, to give t EMI4.1 This stage is obviosuly optional, and is carried out only if the required product is an aglycone and not a glucoside. If the process according to the present invention is applied to the production of diosmin, the starting substance is hesperidin or hespe retin-7-rhamnogluooside of formula t EMI4.2 in which R is a rutinoes radical. The octoacetyl derivative of hesperidin is prepared by heating with acetic anhydride and pyridine at 95 -100 C for 5-6 hours. The hesperidin octoacetyl is precipitated by adding H20 to the react ion mixture and then cooling, and is purified by crystallisation. It is then dissolved in isoamyl alcohol and treated with an approximately 1: 10 molar excess of SeO2 under reflux for 24 hours. The diosmin octoacetyl formed in this manner is hydrolysed with 15% NaOH by heating to 100 C for t-15 minutes. The diosmin of formula II precipitates on oooling and acidi4ing, and is purified by base-acid treatment. If the process according to the present invention is applied to the production of apigenin, the starting substance used is naringin or naringenin-7-rhamnogluooside of formula s EMI5.1 in which R is a rutinose radical. The naringin is totally acetylated by heating at 90-1000C for 5-6 hours with an excess of acetic anhydride and pyridine. The octoacetyl naringin which precipitates by adding H20 to the reao- tion mixture and then cooling, is dissolved in isoamyl alcohol and treated with an approximately @ 10 molar excess of SeO2 under reflux for 24 hours. The unsaturated 2-3 octoacetyl derivative of formula EMI5.2 is formed, in which R3 is a totally acetylated rufinose radical, and Ac is -COCH3, and this is treated with dilute alkalis, preferably with 15% NaOHs at 1000C for t-15 minutes. The apigenin-7-rhamnogluooside precipitates by cooling and acidifying with strong mineral acid, and is crystallised from methanol from which apigenin is obtained by hydrolysis with strong dilute acids, preferably 18% H2SO4, under reflux. Both the diosmin and apigenin obtained by the process according to the present invention are of pharmaceutical purity. The final overall yield both of diosmin and apigenin is about 60%. A further important aspect of the process according to the present invention is the faot that the raw starting materials used are gluoosides, in this case hesperidin and naringin, which are available in large quantity and low price in the discarded parts of oitrus fruits. Compared with the only known industrial process for preparing diosmin (the said German Pub. Appi. 2,602,314), the advantage of the new process is that the use of bromine is avoided, this being a reagent which at the industrial level creates great environmental hydiene and effluent pollution problems. Two actual preparation examples are given hereinafter, for non-limiting illustration purposes. only, in order to allow a more complete understan ding and easy reproduction of the process according to the present in- vention. ExAMPLE 1 Synthesis of diosmin from hesperidin. 1) The following are fed into a 2 litre flask : - 48 g of hesperidin (78.6 moles) - 600 ml of acetic anhydride. - 100 ml of pyridine. The mixture is stirred and heated to 95-100 C for 5 hours; The flair contents are then poured into 6 litres flask, they are cooled with ice, and 4500 ml of iced water are slowly added. The precipitate is filtered, washed with water, dried in an oven at 60-700C, and crystallised from hot benzene and hexane. 55.82 g of white crystalline acetate (58.95 m moles) precipitate, having a M.P. of 123-1250C (dec.). Yield with respect to the theoretical 75%. 2) The following are fed into a 2 litre flask : - 55.82 g of hesperidin ootoacetyl (58.95 m moles) - 65.5 g of SeO2 (590 m.moles) - 1000 ml of isoamyl alcohol. The mixture is heated under reflux for 24 hours, the metal Se which forms is then filtered off under hot conditions, and the solvent is evaporated. 3) 870 ml of 15% NaOH is added to the residue, and the mixture heated to 100 C for 10 minutes. It is cooled, 150 ml of concentrated hydrochlorio acid are slowly added, and the solution which is still alkaline is filtered. The aqueous solution is extracted repeatedly with ethyl acetate, and then again acidified with concentrated HCl until a pH of 3 is attained. A yellow solid precipitates, and this is purified by base-aoid treat ment and dried at 1200C. 28.4 g of diosmin are obtained having a M.P. of 278-280 C. Yield with respect to the theoretical 79. 1%. On chromatographic analysis, the product was found to be totally free of impurities. ExAMPLE 2 Synthesis of apigenin from naringin. 1) The following are fed into a.2 litre flasks - 48.25 g of naringin (83.11 m moles) - 600 ml'of acetic anhydride - 100 ml of. pyridine The mixture is heated to 95-100 C for 5 hours, and is then poured into a 6 litre flask, cooled with ice and 4500 ml of iced water are added. The precipitate is filtered off, washed several times with water, dried in an oven at 60-700C and crystallised by dissolving in 400 ml of hot benzene, followed by crystallisation from hexane. 56 g of naringin octoacetyl are obtained, having a M.P. of 119-1210C (dec.). Yield with respect to the theoretical 73.5%. 2) The following are fed into a 2 litre flasks - 56 g of naringin octoacetyl (16.08 m moles) - 77.8 g of SeO2 (701.15 m moles) - 1100 ml of isoamyl alcohol and the mixture heated under reflux for 24 hours. The metal Se which forms is filtered off under hot conditions, and the solvent is evaporated. 870 ml of 13% NaOR are added to the residue, and the mixture is heated to 1005C for 10 minutes. It is cooled, 150 ml of concentra, ted hydrochloric acid are slowly added, and the solution which is still alkaline is filtered. The aqueous solution is exotracted with 500 ml of ethyl acetate, and again with 300 ml of ethyl acetate. The aqueous solution is acidified with concentrated HCl until a pH of 3 is attained, and the solid precipitate is filtered off and dried at 1000C. The apigenin-7-rhamnoglucoside is dissolved in boiling methanol, and the solution left at ambient temperature for 24-36 hours until the product has completely reprecipitated. The solid precipitate is filtered off, is washed with ioned methanol and is dried at 100 C. 28.25 g (48.83 m moles) of product are obtained, having a M.P. of 1980-2000C. Yield with respect to the theoretical 80%. 3) The following are fed into a 3 litre flask : - 28.25 of apigenin-7-rdsmnoglucoside (48.83 m moles) - 1600 ml of 18% sulphuric acid and the mixture heated under reflux for 4-5 hours. On cooling, 13 g of a yellow crystalline product having a N.P. of 3450-3300C precipitate. Yield with respect to the theoretical 98.52%. On chromatographic analysis, the apigenin was found to be totally free from impurities of any kind.

Claims: C L A I M S 1. A process for producing flavone derivatives of formula EMI9.1 in which R is hydrogen or a disacoharide radical ; R1 is -OH or -OCH3 ; R2 is H or -OH. starting from flavanone-7-glucosides of formula 8 EMI9.2 in which R, R1, R2 are as heretofore defined, by means of : a) total acetylation of the flavanone-7-glucoside by heating to 90-100 C for about 5 hours with acetic anhydride and pyridine; b) selective dehydrogenation in the 2-3 position by means of SeO2 in a approximately 1 molar excess over the flavanone, in an isoamyl alcohol solution heated under reflux; c) total deacetylation by means of alkaline hydrolysis with dilu te inorganic bases under hot conditions; d) possible elimination of the glucoside radical by means of acid hydrolysis with strong dilute mineral acids under hot oondi tions. 2. A process as claimed in claim 1, wherein diosmin is prepared from hesperidin. 3. A process as claimed in claim 1, wherein apigenin is prepared from naringin. 4. A process as claimed in claim 1, wherein the deacetylation by alskline hydrolysis is carried out with 15% NaOH at 100 C for 10 minutes. 5. A process as claimed in claim 1, wherein the elimination of the glucoside radical by adid hydrolysis is carried out with 18% di lute sulphuric acid under reflux for 4-5 hours.

Inventors: REDAELLI, CLAUDIO
Applicants: BONOMELLI S.P.A.
Application year: 1981
Main classification: C07H17
IPC codes: C07D311, C07H17