FIELD OF THE INVENTION: The invention relates to the industrial process for the preparation of pure diosmin from hesperidin. The process also describes recovery and recycling of the reagents involved in the manufacturing process.

BACKGROUND OF THE INVENTION: Diosmin was first reported by O. A. Osterle and G. Wander in HeIv. Chim. Acta. 8, 519 - 536, 1925 and is a naturally occurring flavonoid glycoside that can be isolated from various plant sources, i.e from the peel of the citrus fruit or hesperidin. Diosmin is a protecting agent and is used for the treatment of chronic venous insufficiency, lymphedema, hemorrhoids and varicose veins. It has been also used for other therapeutic purposes such as cancer, premenstrual syndrome, colitis, and diabetes.

The several references are reported in the prior art for conversion of hesperidin to diosmin.

Zemplen and Bogner, in Ber. 76, 452, 1943 reported monobromination of acetylated flavanones by liquid bromine in chloroform solution in presence of ultraviolet radiation to obtain flavone derivative by following loss of hydrogen bromide and deacetylation with alcoholic alkali. The conversion of hesperidin to diosmin reported is 37%.

In the journal reference, J. Org. Chem., 16, 930 - 933, 1951, by N. B. Lorette et. al. N-bromosuccinimide was used for the bromination of acetylated hesperidin in chloroform and benzoyl peroxide was used as a catalyst. Diosmin yield was 44%.

Studies in Organic Chemistry (Amsterdam) (1982), Volume Date 1981, 11, 115-119 describes conversion of Hesperidin, neohesperidin and naringin to diosmin, neodiosmin, and rhoifolin respectively by dehydrogenation with iodine in pyridine. Tianran Chanwu Yabjiu Yu Kaif (2006), 18(6), 896-899 describes separation and purification of diosmin by macroporous resins, and reported 95% pure diosmin.

ES459076 describes the preparation of diosmin by bromination and debromination of hesperidin acetate in tetrahydrofuran with 2-carboxy ethyl triphenyl phosphonium bromide followed by saponification with potassium tertiary butoxide.

ES465156 describes diosmin preparation by reaction of hesperidin with aqueous sodium hydroxide, iodine and pyridine with 66% yield.

DE2740950 describes iodination-dehydroiodination of hesperidin in the presence of pyridine and iodine resulting 89% of diosmin.

EP52086 claims a process for the preparation of diosmin comprising of total acetylation of hesperidin or related flavone by heating it in acetic anhydride and pyridine followed by selective dehydrogenation or oxidation by means of SeO2 in isoamyl alcohol and then deprotection by means of alkaline hydrolysis with inorganic bases under hot condition. The isolated diosmin is purified by base acid treatment with overall reported yield is of 60%.

US4078137 describes a process for diosmin comprising of acetylation of hesperidin, thereby brominating it and the brominated product is hydrolysed to isolate diosmin with bromine content less then 0.1% with over all 65% yield.

In BE 904614, diosmin was prepared by iodination of hesperidin followed by elimination of HI. In the process, iodine in dimethylformamide and pyridine were successively added to hesperidin and the resulting mixture was heated at 100°C to give 96% pure diosmin.

EP 860443 describes the process that involves reaction of hesperidin with iodine in presence of pyridine at reflux temperature for 5 hours. The reaction mixture is cooled to 5°C and the isolated diosmin is purified using base acid treatment to get the quality of diosmin above 90% with 75 % yield.

FR2760015 provides industrial dehydrogenation of hesperidin with potassium iodide in DMSO in presence of cone. H2SO4 resulted in diosmin with 73% yield and pharmacopoeial quality.

WO2000011009 describes reaction of hesperidin with iodine in presence of pyridine and anhydrous alkaline earth metal base. The process involves purifying the reaction mass using morpholine followed by base acid treatment which resulted in diosmin with 80% yield and purity of diosmin meets with pharmacopoeial norms.

EP 1086953 discloses the process for purification of diosmin by reacting with pulverized zinc in aqueous solution followed by filtration and acidification.

Diosmin which is produced by many of the prior art processes is often found to contain impurities and is contaminated with various byproducts, for instance hesperidin, Isorhoifin, acetyl lisovanilone, 6-Iododiosmin, linarin, diosmetin and other organic volatile impurities. Some of the major impurities are resulted from hesperidin during extraction. The impurities of hesperidin have a major effect on the final assay of diosmin. The impurities vary depending upon the source of hesperidin. It is worthy to note that direct crystallization of crude diosmin with aqueous base acid solution does not necessarily improve the assay / purity of diosmin.

The process described in Studies in Organic Chemistry (Amsterdam) (1982), Volume Date 1981, 11, 115-119 is different from the present inventors process.

Although ES459076 teaches the preparation of diosmin by bromination and debromination of hesperidin acetate in tetrahydrofuran with 2-carboxy ethyl triphenyl phosphonium bromide, it does not teach about the final purity of diosmin with pharmaceutical quality as required.

ES465156 and DE2740950 although disclose method of preparation, does not teach a process that gives yields as are taught by present invention.

EP52086 and US4078137 uses acetic anhydride for acetylation of hesperidine with yields around 60%, which are phenomenally less as compared with yields of process described by present invention.

Sequence of addition of reactants in the process as taught by BE 904614 is different than the teachings of the present invention.

FR2760015 teaches use of different reactants under conditions that are different from the teachings of the present invention.

Invention disclosed in present application does not use morpholine as disclosed in WO2000011009.

Though there are reported several processes for preparation of diosmin in the prior art, present invention describes a novel systematic process for the preparation of diosmin by converting hesperidin to diosmin at optimum level i.e. % conversion, and keeping the impurities at minimum level which results in consistently pure diosmin with good yield and the desired quality. The process allows recovery and recycle of major contributing chemicals and solvents such as methanol, pyridine and iodine, without impact on quality, purity or yield of the process making the process more economical and ecofriendly. It is surprisingly found that quality diosmin output obtained is independent of hesperidin quality used.

OBJECTIVE OF THE INVENTION: The object of the present invention is to prepare pure diosmin complying with pharmacopoeial quality and to provide a process to prepare pure diosmin complying with pharmacopoeial quality.

Further object of the invention is to provide a process which results the diosmin with desired yield and assay, irrespective of impurities present in key raw material i.e. hesperidin.

Yet another object of the invention is to manufacture the diosmin with more than 99% assay using aqueous dimethylformamide mixture and to provide a process to manufacture the diosmin with more than 99% assay.

Another object of the invention is to provide a process for the preparation of diosmin wherein methanol is used and levels of impurities such as as isorhoifin and diosmetin in diosmin are reduced.

Another object of the invention is to provide a process that allows recovery and reuse of the pyridine to reduce the cost and to make the process economical.

Another object of the invention is to provide a process that facilitates recovery and recycle of costly ingredient such as iodine to make the process further economical.

SUMMARY OF THE INVENTION:

This particular invention relates to a process for the preparation of pure diosmin.

The invention also discloses the process for reducing the impurities by the treatment of crude diosmin with alcohol, particularly methanol and followed by crystallization using dimethylformamide: water mixture in the ratio 1 :1 to 9:1 followed by base acid treatment to further reduce the residual impurity level. DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a process for the optimum conversion of hesperidin to diosmin monitored by HPLC to get hesperidin content less than 1 %. The temperature selected for this process is 95 - 105°C with total time taken for the reaction is 9 - 10 hours. It has also been observed that at temperatures below 90°C, the conversion of diosmin is less and at higher temperatures i.e. above 105°C, the sublimation of iodine takes place which results in lesser conversion to diosmin, thus affecting the yield and quality of diosmin.

The present invention also describes the purification process using dimethylformamide: water mixture in the appropriate proportion to get diosmin assay more then 99% with impurity at minimum level, complying with pharmacopoeial limits.

The costly reagent used in the process such as iodine is recovered with assay more than 90 % and is recycled in the process. Therefore crystallized diosmin obtained by the process of the present invention is substantially free of iodine. The process therefore provides substantial cost reduction yet delivering diosmin that meets pharmacopoeial standards.

The process to prepare pure diosmin comprises: (a) reacting hesperidin with iodine in presence of base by recovering pyridine and then treating reaction mass with alcohol to reduce the impurities such as isorhoifin and diosmetin and treating the resulting solid from step (a) with sodium thiosulfate solution to isolate crude diosmin which is crystallized using dimethylformamide : water mixture with the specific proportion, followed by water distillation and base acid treatment to remove volatile impurities. The alcohols used in the process are C1-C4 alcohol, such as methanol, ethanol, isopropyl alcohol, n-propanol, isobutanol, most preferably methanol.

In case of base acid crystallization, base used are organic or inorganic base and acid used are organic or inorganic acid, preferably inorganic base and inorganic acid are used. Inorganic base used are sodium hydroxide, potassium hydroxide and inorganic acid used are sulfuric acid, hydrochloric acid.

Substantial purity of reactants recovered is to be understood as that quality of reactants that allows them to be recycled.

The process provides flexibility to use dimethylformamide: water mixture in various ratios and proportions such as 1: 1 to 9:1, preferably 2: 1 to 9: 1 and most preferable being 5:1.

Following examples illustrate particular aspects of the invention, however these illustrations do not limit the scope of the invention.

EXAMPLES:

Example - 1

100 gm of hesperidin , 700 ml of pyridine, 9.8 gm of sodium hydroxide and 45.6 gm of iodine were charged in 2 liter clean glass assembly, The resulting solution was heated to 95-105 ⁰ C for 9 - 10 hours. Reaction was monitored by HPLC to get hesperidin less than 1 %. The pyridine was recovered completely by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. Iodine was recovered from mother liquor, solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Yield : 80 - 86 gm. Recovery of iodine from above methanol mother liquor: Distilled methanol and pyridine mixture. The obtained residue was acidified with sulfuric acid. The resulting pH was less than 1. The brown precipitate formed was filtered. The resulting filtrate was oxidized with hydrogen peroxide at 0-10°C and filtered to obtain crude iodine having assay 50 - 60 %, which was steam distilled to obtain pure iodine with assay 95 %.

Example - 2

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting mass was heated to 90-95 ⁰ C to obtain clear solution. 200 ml of water was added at 90- 95 ⁰ C and maintained for 30 min. The reaction mass was cooled and filtered. The wet solid was collected.

Charged wet solid obtained in 3 liter clean glass assembly and charged 900 ml of water, 900 ml of 5% aqueous NaOH solution. Distilled out approximately 900 ml of water under vacuum below 5O ⁰ C. Charged 1000 ml of water and the resulting reaction mass was treated with charcoal and filtered through hyflow. pH 1.8-2.2 was adjusted using sulfuric acid. Stirred the mass for 30 min, filtered and washed it with water, hot water. Solid was dried. Yield : 80 - 85 gm. Assay : 99.9 %.

Example - 3

100 gm of crude diosmin as prepared in example 1, 1800 ml of dimethylformamide and 1800 ml of water was charged in 5 liter clean glass assembly. The resulting solution was heated to 90-95 ⁰ C to obtain slurry and maintained for 30 min. Cooled the reaction mass and filtered, washed with water and hot water. The obtained solid was dried. Yield: 90 - 95 gm. Assay : 97 %. Example - 4

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting solution was heated to 90-95 ⁰ C to obtain clear solution.charged 360 ml of water at 90-95 ⁰ C and maintained for 30 min. The reaction mass was filtered, washed with water and with hot water. Solid obtained was dried. Yield: 90 - 95 gm. Assay : 99.5 %.

Example - 5

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting solution was heated to 90-95 ⁰ C to obtain clear solution, charged 900 ml of water at 90-95 ⁰ C and maintained for 30 min. The reaction mass was filtered, washed with water and with hot water. Solid obtained was dried. Solid obtained was 90 — 95 gm. Assay obtained was 98.8 %.

Example - 6

100 gm of hesperidin , 700 ml of recovered pyridine, 9.8 gm of sodium hydroxide and 45.6 gm of iodine were charged in 2 liter clean glass assembly . The resulting solution was heated to 95-105 ⁰ C for 9 - 10 hrs. Reaction was monitored by HPLC. Pyridine was recovered completely by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. The solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Crude diosmin obtained was 80 - 86 gm. Purity was 98.6 %.

Example - 7

100 gm of hesperidin , 700 ml of recovered Pyridine, 9.8 gm of sodium hydroxide and 48 gm (assay 95 %) of recovered iodine were charged in 2 liter clean glass assembly.. The resulting solution was heated to 95-105 ⁰ C for 9 - 10 hours. Reaction was monitored by HPLC to get hesperidin less than 1 %. The pyridine was recovered by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. The solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Yield:80 - 86 gm. Purity : 95.3 %.