Processes for the preparation of diosmin and flavonoid fractions.

Abstract

Invention details;

Description

[0001] PROCESS FOR THE PREPARATION OF DIOSMINE AND FLAVONOIC FRACTION

[0002] The present invention relates to a process for the preparation of diosmin. Diosmin is the compound of formula (I):

[0003] Diosmin is synthesized by oxidation of rhesperidin. Hesperidin is the compound of formula (II):

[0004] Hesperidin is obtained from natural substances (orange peels). The diversity of orange peels used leads to hesperidins of unequal purity, containing other flavonoids with varying contents. For example, rhesperidin can contain up to 4% isonaringin, which is converted into isorhoifolin by oxidation. Diosmin therefore generally contains other flavonoids, some of which come from the oxidation of the flavonoids present in the original rhesperidin, and others are secondary reaction products.

[0005] The specifications imposed by the European Pharmacopoeia for diosmin are as follows:

[0006] Diosmin Pharmacopoeia means a diosmin meeting the above specifications.

[0007] Diosmin is also the major component of the micronized purified flavonoid fraction, or MPFF (Daflon®).

[0008] A flavonoid fraction is an active ingredient comprising approximately 90% diosmin, mixed with hesperidin, diosmetin, linarin and isorhoifolin.

[0009] The flavonoid fraction according to the present invention preferably comprises from 86.0 to 95.0% of diosmin, from 2.5 to 6.0% of hesperidin, from 0.2 to 2% of diosmetin, from 0.8 to 3.5% of linarin and from 0.8 to 3.5% of isorhoifolin.

[0010] Furthermore, the flavonoid fraction according to the present invention may contain other flavonoids derived from hesperidin, the total content of which does not exceed 1.0%.

[0011] Diosmin Pharmacopoeia and the micronized purified flavonoid fraction are used in the treatment of venous diseases, such as chronic venous insufficiency or hemorrhoidal diseases.

[0012] Given their pharmaceutical interest, it is essential to obtain them with excellent yield and good purity, even starting from a hesperidin with a purity of around 90 to 95%.

[0013] In particular, it is essential that the diosmin obtained, whether in the form of Diosmin Pharmacopoeia or flavonoid fraction, contains less than 0.6% of 6-iododiosmin. Methods for preparing diosmin from hesperidin have been described in the literature.

[0014] Patent applications FR2311028 and WO2016 / 124585 describe the production of diosmin by acetylation of hesperidin, oxidation of acetylated hesperidin to acetylated diosmin and then deacetylation.

[0015] This process is not ideal, as the yield is only 65% ​​and 77% respectively. In addition, it involves several steps.

[0016] Patent applications EP3321273 and FR2782518 describe the production of diosmin by oxidation of hesperidin with iodine in a single step, in an amide solvent (EP3321273) or in pyridine (FR2782518).

[0017] However, the use of iodine in stoichiometric quantities is problematic on an industrial scale.

[0018] The problem of the present invention was to obtain Pharmacopoeia Diosmin or the flavonoid fraction from hesperidin in a single step before isolation (without going through the step of acetylation of hesperidin and deacetylation of acetylated diosmin), with an excellent yield, while minimizing the content of 6-iododiosmin in the product obtained.

[0019] More specifically, the present invention relates to a process for the preparation of Diosmin Pharmacopoeia or flavonoid fraction by oxidation of hesperidin to diosmin by an iodine-donating oxidizing couple, at a temperature of 80 to 120°C, in a mixture of polar aprotic solvent and acetic acid, followed by isolation by addition of water, filtration, rinsing and drying.

[0020] According to one embodiment of the present invention, diosmin is obtained in the form of Diosmin Pharmacopoeia.

[0021] According to another embodiment, diosmin is obtained in the form of a flavonoid fraction comprising from 86.0 to 95.0% diosmin, from 2.5 to 6.0% hesperidin, from 0.2 to 2% diosmetin, from 0.8 to 3.5% linarin and from 0.8 to 3.5% isorhoifolin.

[0022] Furthermore, the flavonoid fraction according to the present invention may contain other flavonoids derived from hesperidin, the total content of which does not exceed 1.0%.

[0023] The iodine-donating oxidizing couple is preferably chosen from Nal / FLCh, KI / H2O2, TBAI / H2O2 and Nal / h / H2O2. The quantity of iodine donor Nal, Kl or TBAI is preferably 0.4 to 0.8 molar equivalents relative to Thesperidine used.

[0024] The quantity of hydrogen peroxide is preferably 0.9 to 1.1 molar equivalents relative to thesperidin used.

[0025] When Nal / T / tLO is used, the Nal / L molar ratio is preferably about 9 / 1.

[0026] Among the polar aprotic solvents which can be used in the process according to the invention, mention may be made, by way of example, of dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide.

[0027] The preferred polar aprotic solvent is dimethyl sulfoxide.

[0028] When the polar aprotic solvent is dimethyl sulfoxide, S-methylated impurities may form during the process. It is important to minimize the content of these impurities.

[0029] According to one embodiment of the present invention, the crude diosmin obtained is purified by a base / acid treatment: passage into solution in water in the presence of a base such as sodium hydroxide, then precipitation by salification with an acid such as sulfuric acid, filtration, rinsing and drying.

[0030] According to another embodiment of the present invention, the crude diosmin is first re-pasted in an organic solvent such as dimethyl sulfoxide, N-butylpyrrolidone, pyridine, sulfolane, dimethyl carbonate or propylene carbonate, or in a mixture of organic solvent and water such as a mixture of pyridine and water, then filtered and rinsed with water, before undergoing a base / acid treatment.

[0031] According to another embodiment of the present invention, the diosmin obtained is purified by a base / acid treatment in the presence of hydrogen peroxide.

[0032] The following examples illustrate the invention.

[0033] The purity of Thesperidin used in the examples was 93.6%. Using a high purity Hesperidin makes it possible to obtain Diosmin Pharmacopoeia.

[0034] Abbreviations:

[0035] DMSO dimethyl sulfoxide eq. molar equivalents (relative to Thesperidin)

[0036] HPLC High Performance Liquid Chromatography (High Performance Liquid Chromatography) m / m ratio expressed as mass / mass

[0037] NBP N-Butyl-Pyrrolidone

[0038] ND Not Detected

[0039] TB AI Tetrabutyl ammonium iodide rpm revolutions per minute volume equivalent vol (expressed in L / kg of the flavonoid involved)

[0040] EXAMPLE 1: Crude Diosmin

[0041] In a 6L reactor, introduce hesperidin (800 g, 1.31 mol, 1.0 eq.) and sodium iodide (123.7 g, 0.82 mol, 0.63 eq.).

[0042] Then add the DMSO (3.1 vol, or 2.48 L) and the acetic acid (0.5 vol, or 0.40 L).

[0043] Stir at 250 rpm (anchor) then heat to 97°C (Tmass).

[0044] At 97°C, add 3.5M aqueous H2O2 solution (367 mL, 0.98 eq.).

[0045] At the end of the pouring, the heterogeneous reaction medium is left to stir at 97°C for 15 min then brought back to 25°C.

[0046] At 25°C, water (1.5 vol, or 1.2 L) is added (exotherm of 12°C), then the medium is filtered through a porosity 3 frit.

[0047] The cake is rinsed with water (2x 2.5 vol, or 2x 2.0 L)

[0048] The resulting cake is filtered. The crude diosmin thus obtained can be used directly in the next step.

[0049] Alternatively, it can be isolated and dried in a ventilated oven at 80°C overnight. Diosmin is then obtained with a yield of 94% and a 6-iodo-diosmin content of 0.52%.

[0050] EXAMPLE 2: Base / acid treatment and micronization

[0051] Transfer the undried crude diosmin obtained in Example 1 into a 6L reactor. Add water (5.0 vol relative to the hesperidin used in Example 1, i.e. 4.0 L) and sodium hydroxide (611 g, 4.58 mol, 3.5 eq.).

[0052] Stir at 25°C until completely dissolved (typically 1 hour).

[0053] Clarify the medium on a Clarcel® pad then transfer the filtrate into a 6L reactor. Cool the solution to 10°C then slowly add 37% sulfuric acid (typically 611 g, 2.30 mol) without exceeding 13°C (Tmass) and until pH=3 is obtained.

[0054] Stir for 45 minutes at 10°C to complete the precipitation.

[0055] Filter the medium through a porosity 3 frit.

[0056] Rinse the cake with water (2x 2.5 vol, or 2x 2.0 L).

[0057] The product is dried in a ventilated oven at 80°C overnight. The resulting product can be used for a reprocessing step in the presence of hydrogen peroxide.

[0058] Alternatively, the resulting solid can be micronized.

[0059] Diosmin is then obtained in the form of micronized flavonoid fraction with a yield of 92% from hesperidin and a 6-iodo-diosmin content of 0.5%.

[0060] EXAMPLE 3: Base / acid reprocessing in the presence of hydrogen peroxide

[0061] Base / acid reprocessing in the presence of hydrogen peroxide makes it possible to eliminate any S-methylated impurities.

[0062] In a 250 mL Erlenmeyer flask, introduce the diosmin obtained before micronization in Example 2 (10.0 g, 16.4 mmol).

[0063] Then add water (5.0 vol, or 50 mL) and sodium hydroxide (7.67 g, 3.5 eq.).

[0064] Shake until completely dissolved.

[0065] Add 35% hydrogen peroxide (0.1 or 0.2 eq.) in one portion then stir at room temperature for 30 min to 3 hours.

[0066] Cool to 10°C then add sulfuric acid (7.40 g, 1.7 eq.) until pH=3. Filter the medium through a porosity 3 frit.

[0067] The cake is rinsed with water (2x 2.0 vol, or 2x 10 mL).

[0068] The solid is then dried overnight at 80°C in a ventilated oven.

[0069] Diosmin is obtained in the form of flavonoid fraction.

[0070] EXAMPLE 4: Pyridine / water re-paste then base / acid treatment

[0071] The isolated and dried crude diosmin obtained in Example 1 was re-pasted in the binary system pyridine / LEO 6 / 1 (volume ratio), at 25°C, for 90 min. This re-pasting reduces the 6-iodo-diosmin content and eliminates any S-methylated impurities.

[0072] Transfer the crude diosmin (100g, dry weight, 164.3 mmol) obtained in Example 1 into an IL reactor.

[0073] Add water (1.0 vol, or 100 mL) and pyridine (6 vol, or 600 mL).

[0074] Stir at 25°C for 90 minutes.

[0075] Filter the medium through a porosity 3 frit.

[0076] Rinse the cake with water (2x 2.5 vol, or 2x 250 mL).

[0077] Drain the solid on a filter and transfer the product without additional drying into an IL reactor.

[0078] Add water (5.0 vol, or 500 mL) and sodium hydroxide (76.7 g, 575.1 mol, 3.5 eq.). Stir at 25°C until completely dissolved (typically 1 h).

[0079] Clarify the medium on a Clarcel® pad then transfer the filtrate into an IL reactor. Cool the solution to 10°C then slowly add 37% sulfuric acid (typically 76.7 g, 289.3 mmol) without exceeding 13°C (Tmass) and until pH=3 is obtained.

[0080] Stir for 45 minutes at 10°C to complete the precipitation.

[0081] Filter the medium through a porosity 3 frit.

[0082] Rinse the cake with water (2x 2.5 vol, or 2x 250 mL).

[0083] The product is dried in a ventilated oven at 80°C overnight.

[0084] Diosmin is obtained in the form of flavonoid fraction with a purity greater than 88%, a yield of 88% from hesperidin and a 6-iodo-diosmin content of 0.4%.

[0085] EXAMPLE 5: Re-pasting in other solvents.

[0086] The crude diosmin used was obtained under the conditions of Example 1.

[0087] DMSO re-pasting:

[0088] In a 100 mL three-necked flask, introduce diosmin (5.0 g) and DMSO (3 vol) then heat to 80°C until completely dissolved.

[0089] Allow to cool to 25°C then add water (3 vol). Filter through a porosity 3 frit, rinse the cake with water (2 x 2.5 vol) then dry in a ventilated oven overnight at 80°C.

[0090] Diosmin is obtained in the form of flavonoid fraction (4.9 g).

[0091] Sulfolane re-pasting:

[0092] In a 100 mL three-necked flask, introduce diosmin (5.0 g) and sulfolane (7 vol) then stir at room temperature for 1 hour.

[0093] Filter through a porosity 3 frit. Rinse the cake with water (2 x 2.5 vol) then dry in a ventilated oven overnight at 80°C.

[0094] Diosmin is obtained in the form of flavonoid fraction (5.0 g).

[0095] Dimethyl carbonate re-paste:

[0096] In a 100 mL three-necked flask, introduce diosmin (5.0 g) and dimethyl carbonate (7 vol) then stir at room temperature for 1 hour.

[0097] Filter through a sintered filter with porosity 3. Rinse the cake with water (2 x 2.5 vol) then dry in a ventilated oven for 2 days at 50°C.

[0098] Diosmin is obtained in the form of flavonoid fraction (4.9 g). Re-pasting propylene carbonate:

[0099] In a 100 mL three-necked flask, introduce diosmin (5.0 g) and propylene carbonate (7 vol) then stir at room temperature for 1 hour. Filter through a porosity 3 frit. Rinse the cake with water (2 x 2.5 vol) then dry in a ventilated oven for 2 days at 50°C.

[0100] Diosmin is obtained in the form of flavonoid fraction (4.8 g).

[0101] NBP re-pasting:

[0102] In a 100 mL three-necked flask, introduce diosmin (5.0 g) and N-butylpyrrolidone (7 vol) then stir at room temperature for 1 hour.

[0103] Filter through a porosity 3 frit. Rinse the cake with water (2 x 2.5 vol) then dry in a ventilated oven overnight at 80°C. Diosmin is obtained in the form of a flavonoid fraction (4.8 g).

Claims

DEPCT6719 / 03 / 25671. A process for the preparation of diosmin by oxidation of hesperidin through an iodine-donating oxidizing couple at 80 to 120 °C in a mixture of polaraprotic solvent and acetic acid, followed by isolation by added water, filtration, rinsing, and drying.

2. A process according to claim 1 in which the obtained diosmin is in the form of pharmacopoeiadiosmin. Containing diosmin from 90.0 to 102.0%, hesperidin less than 4.0%, diosmetin less than 2.0%, isorhoifolin less than 3.0%, linarin less than 3.0%, and 6-iododiosmin less than 0.6%.

3. The process according to claim 1 in which diosmin is obtained as a flavonoid fraction containing diosmin from 86.0 to 95.0%, hesperidin from 2.5 to 6.0%, diosmetin from 0.2 to 2%, linarin from 0.8 to 3.5%, and isorhoifolin from 0.8 to 3.5%.4.

5. The process under claim 1 or 3 where the obtained diosmin contains less than 0.6% 6-iododiosmin.

6. The process under claim 1 through 4 where the iodine-producing oxidizing pair is selected from NaI / H2O2, KI / H2O2, TBAI / H2O2, and NaI / I2 / H2O2.

7. The process under claim 5 where the iodine-producing oxidizing pair is NaI / H2O2.

8. The process under claim 6 where the amount of NaL is from 0.4 to 0.8 molar equivalent, taking into consideration that...

8. Any one of the processes under claims 5 through 7 where the amount of hydrogen peroxide is between 0.9 and 1.1 molar equivalent relative to the hesperidin used.

9. Any one of the processes under claims 1 through 8 where the polar aprotic solvent is dimethyl sulfoxide.

10. Any one of the processes under claims 1 through 9 where the obtained diosmin is purified by the action of a base / acid. 11.One of the processes under Reputations 1 through 9 in which the obtained crude diosmin is first reslurried in an organic solvent such as dimethyl sulfoxide, N-butylpyrrolidone, pyridine, sulfolane, dimethyl carbonate or propylene carbonate, or a mixture of organic solvent and water such as a mixture of pyridine and water, then filtered and leached with water before passing through the action of a base / acid.

12. One of the processes under Reputations 1 through 11 in which the obtained diosmin is purified by the action of a base / acid in the presence of hydrogen peroxide;