FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process for the industrial preparation of pure dosmin.
2. APPLICANT (S)
(a) NAME : ELDER PHARMACEUTICALS LTD.
(b) NATIONALITY : INDIAN
(c) ADDRESS : Elder House, Plot No. C/9, Dalia Indl. Estate,
Off. New Link Road. Andheri (W):
Mumbai-400 058, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

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 Hclv. 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 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 deacetyiation with alcoholic alkali. The conversion of hesperidin to diosmin reported is 37%.
N. B. Lorette et. al, In the journal reference, i.e. in J. Org. Chem., 16, 930 - 933, 1951. have used N-bromosuccinimide for the bromination of acetylated hesperidin in chloroform and benzoyl peroxide catalyst and diosmin obtained was in 44% yield.
Studies in Organic Chemistry (Amsterdam) (1982), Volume Date 1981. 11, 115-119 describes conversion of Hesperidin, neohesperidin and naringin to diosmin. ncodiosmin, and rhoifolin respectively by dehydrogenation with iodine in pyridine.
Tianran Chanwu Yabjiu Yu Kaif (2006), 18(6), 896-899 have separated and purified diosmin by macroporous resins, and reported 95% pure diosmin.
ES459076 has described the preparation of diosmin by bromination and
denomination 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-dehydroiodinalion of hesperidin in the presence of pyridine and iodine resulting 89% of diosmin.
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KP52086-A1 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 Se02 in isoamyl alcohol and then deprotection by means of alkaline hydrolysis with dil. inorganic bases under hot condition. The isolated diosmin is then 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 yield reported is about 65%.
In BE 904614. diosmin was prepared by iodinalion 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.
In HP 860443A1 describes the process that involves reaction of hesperidin with iodine in presence of pyridine at reiTux temperature far 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 the information about dehydrogenation of hesperidin with potassium Iodide in DMSO in presence of cone. H2S04, the resulted diosmin is of pharmacopoeial quality with yield obtained is around 73%.
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 to diosmin with 80%> yield and the purity of diosmin, meets with pharmacopoeia.
HP1086953 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 the prior an processes is always contaminated with various byproducts, for instance hesperidin, Isorhoifin,, acetyl lisovanilone. 6-lododiosmin, linarin. diosmetin and other organic volatile impurities and the major of these impurities resulted from hesperidin during extraction. These impurities of hesperidin have a major effect on the final assay of diosmin and also these impurities vary from consignment to consignment as hesperidin ts being extracted from the natural occurring source. It was also observed by the present inventor that direct crystallization of crude diosmin with aqueous base - acid solution does not improve the assay / purity of diosmin.
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Though there are several processes have been reported for diosmin in the prior art. however a sincere effort has been carried out to design systematic process for the preparation of diosmin by monitoring the reaction using the sophisticated instruments such as HPLC, there by converting hesperidin to diosmin at optimum level i.e. % conversion, thereby keeping the impurities at minimum level which results in consistently a pure diosmin with good yield and the desired quality. While designing a process an appropriate care has been taken with respect to recovery and recycle of major contributing chemicals and solvents such as methanol, pyridine and iodine, back in the process so to make the process more economical and ecofriendlv. The strength of process lies in getting a pure diosmin irrespective of quality hesperidin received.
OBJECTIVE OF THE INVENTION
The object of the present invention is to prepare pure diosmin complying with pharmacopoeia) quality.
Further object of the invention is to provide the consistent 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.
Another object of invention is to incorporate methanol in the process to reduce (be level of impurities such as isorhoifin and diosmetin in diosmin.
Another object of the invention is to recover the pyridine as part of process and reused in the process to reduce the cost further to make the process cost wise viable.
Another object of the process is to recover and recycle the costly ingredient of the process i.e. Iodine to make the process further economical.
SUMMARY OF THE INVENTION
This particular invention relates to process for the industrial preparation of pure diosmin.
The invention also discloses the reduction of impurities by the treatment of crude diosmin with alcohol, particularly methanol and then it is further crystallized using
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dimethylformamide water mixture in a specific proportion followed by acid base to reduce further the residual impurity level, i.e. volatile impurities.
DETAILED DESCRIPTION OF THE INVENTION:
In the present invention provides the detail information and process for optimum conversion to diosmin monitored by HPIX to get hesperidin content less than 1 %. The temperature selected for this process was 95 105°C with total time taken for the reaction is 9 - 10 hours. It has been also observed that temperature below 90°C. the conversion of diosmin is less and at higher temperature above 105°C, the sublimation of iodine takes place which results in less conversion to diosmin, thus affect 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 in the process such as iodine is recovered with assay more than 90 % and is recycled in the process.
The process to prepare pure diosmin comprises: (a) reacting hesperidin with iodine in presence of base there by recovering pyridine and then further reaction mass treated with alcohol to reduce substantially the impurities such as isorhoifin and diosmetin. (b) treating the further resulting solid with sodium thiosulfate solution there by isolated crude diosmin is further 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, 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.
The following examples illustrates the particular aspects of the Invention, however this illustration does not limit the scope of the invention.
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EXAMPLES:
bxample - 1
100 gm of hesperidin is pfaced in 2 /iter dean glass assembly, then 700 ml of pyridine. 9.8 gm ofsodium hydroxide and 45.6 gm of iodine is added. The resulting solution is heated to 95-105°C for 9-10 hours. Reaction is monitored by HPLC to get hesperidin less than 1 %. The pyridine is recovered completely by applying vacuum. Charge methanol to the resulting solid the reaction mass is heat to reflux and then filter at room temperature and solid obtained is treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. Adjust pH 2-4 with cone, sulfuric acid. Reaction mass is filter to obtain crude diosmin. Crude diosmin obtained is 80 - 86 gm.
Recovery of Iodine: After methanol filtration filtrate is distilled to recover methanol and pyridine mixture & residue. Residue is acidified with sulfuric acid. The resulting pH is below 1. The brown precipitate is formed which filtered. The resulting filtrate is oxidized with hydrogen peroxide at 0-10°C & filter to obtained crude iodine having assay 50 - 60 %. which is steam distilled to obtain pure iodine having assay above 90 %.
Example - 2
100 gm of crude diosmin is placed in 3 liter clean glass assembly, as prepared in example L then 1800 ml of dimcthylformamide. The resulting solution is heated to 90-95°C to obtain clear solution, then add 200 ml of water at 90-95llC & maintained for 30 min. and at the end cool the reaction mass and filter the material and collect wet solid.
Placed this wet solid in 3 liter clean glass assembly and then add 900 ml of water. 900 ml of 5% aqueous NaOH solution. Distilled out approximately 900 ml of water under vacuum below 50°C. Then add 1000 ml of water and the resulting reaction mass is treated with charcoal and filtered through hyflow. Adjust |>H 1.8-2.2 of resulting filtrate using sulfuric acid. Stir the mass for 30 min. filter and wash it with water and then with hot water. Solid obtained is dried. Solid obtained is 80 - 85 gm. Assay obtained is above 99 %.
Example - 3
1800 ml of dimcthylformamide is placed in 3 liter clean glass assembly, then 1800 ml of water & 100 gm of crude diosmin as prepared in example 1. The resulting solution is heated to 90-95°C to obtain slurry & maintained for 30 min. At the end
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cool the reaction mass and filter the material and wash with water and then with hot water to obtain solid which is dried. Solid obtained is 90 - 95 gm. Assay obtained is above 97 %.
Example - 4
100 gm of crude diosmin is placed in 3 liter clean glass assembly, as prepared in example 1, then 1800 ml of dimethylformamide. The resulting solution is healed to 90-95°C to obtain clear solution then add 200 ml of water at 90-95°C & maintained 30 min. at the end cool the reaction mass and filter the material and wash it with water and then with hot water. Solid obtained is dried. Solid obtained is 90 95 gm. Assay obtained is above 99 %.
Example - 5
100 gm of hesperidin is placed in 2 liter clean glass assembly, then 700 ml of recovered pyridine. 9.8 gm of sodium hydroxide and 45.6 gm of iodine are added. The resulting solution is heated to 95-105°C for 9-10 hrs. Reaction is monitored by HPLC to get hesperidin less than 1 %. The pyridine is recovered completely by applying vacuum. Charge methanol to the resulting solid the reaction mass is heat to reflux and then filter at room temperature and solid obtained is treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. Adjust pH 2-4 with cone, sulfuric acid. Reaction mass is filter to obtain crude diosmin. Crude diosmin obtained is 80 86 gm. Purity obtained is above 90 %.
Example - 6
100 gm of hesperidin is placed in 2 liter clean glass assembly, then 700 ml of recovered Pyridine. 9.8 gm of sodium hydroxide and 48 gm (assay 95 %) of recovered of iodine are added. The resulting solution is heated to 95-105°C for 9 10 hours. Reaction is monitored by HPLC to get hesperidin less than 1 %. The pyridine is recovered completely by applying vacuum. Charge methanol to the resulting solid the reaction mass is heal to reflux and then filter at room temperature and solid obtained is treated with sodium thiosulfaie solution and 900 ml, 5% aqueous NaOH solution. Adjust pH 2-4 with cone, sulfuric acid. Reaction mass is filtered to obtain crude diosmin. Crude diosmin obtained is 80 - 86 gm. Purity obtained is above 90 %.
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We claim.
1. A process for preparation of diosmin with assay above 99 % and with
recovery of process reagents having substantial purity comprising,
a. reacting hcsperidin with iodine and pyridine in presence of alkali at 95
- 105°C for 9-10 hours to gel product with hcsperidin content less
than 1 % as monitored,
b. recovering pyridine having purity above 99% leaving behind the
residue,
c. treating the residue with alcohol to isolate crude diosmin and to reduce
impurities such as Isorhoifin and diosmetin.
d. and recovering iodine above 90% assay from mother liquor of alcohol
washing,
e. treating isolated crude diosmin with sodium thiosulfate to get diosmin
substantially free of iodine.
f. crude diosmin is crystallized from aqueous dimethylformamide
followed by treatment with alkaline solution,
g. water distillation, and
h. isolation by acidification.
2. The process as claimed in claim lc, in which alcohol is selected from C1-C4 alcohol.
3. The process as claimed in claim lc, wherein alcohol is methanol.
4. The process as claimed in claim lb. in which pyridine having purity 99% is recovered and is recycled in the process.
5. The process as claimed in claim 1 and claim If, in which diosmin is recrystallized from dimethyl formamide: water, followed by treatment with alkaline solution, water distillation and isolation by acidification.
6. The process as claimed in claim 1 and claim 5, wherein dimelhylformamide: water is used in the ratio 1: 1 to 5:1, preferably 2: 1 to 5: 1, most preferably 5:1.
DATE AND SIGNATURE

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