WO2000011009A2 - Method for industrial production of diosmin from hesperidin by reaction with iodine and pyridine - Google Patents
Method for industrial production of diosmin from hesperidin by reaction with iodine and pyridine Download PDFInfo
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- WO2000011009A2 WO2000011009A2 PCT/FR1999/002001 FR9902001W WO0011009A2 WO 2000011009 A2 WO2000011009 A2 WO 2000011009A2 FR 9902001 W FR9902001 W FR 9902001W WO 0011009 A2 WO0011009 A2 WO 0011009A2
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- pyridine
- iodine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
Definitions
- the present invention relates to a process for the industrial manufacture of diosmin from hesperidin.
- Diosmin is a bioflavonoid known in its natural state and is found for example in the peel of citrus fruits and is used for its venotonic and protective application of the liver. On an industrial level, the hemisynthesis of diosmin is carried out using the natural product hesperidin.
- the manufacturing processes known to date consist of reacting:
- the invention relates more precisely, among these methods, those in which hesperidin is reacted as main reagents with iodine and pyridine, in the presence of a mineral base.
- FR-A-2411 845 and FR-A-2402655 describe such processes, in which the starting reaction mixture is additionally added with an aqueous sodium hydroxide solution.
- the process of the invention which aims at the industrial manufacture of diosmin from hesperidin by reaction with iodine and pyridine, is a process of the general type taught by FR-A-2 411 845 and FR-A-2402 655 mentioned above, that is to say comprising the steps of: a) preparation of a reaction medium by mixing hesperidin, iodine, pyridine and an inorganic alkali metal base or alkaline earth; b) heating this reaction medium, to obtain a reaction product containing diosmin, and c) purifying the reaction product by elimination of the pyridine and iodine residues.
- the reaction medium prepared in step a) is essentially devoid of water, the mineral base being provided in solid form.
- the mineral base of an alkali or alkaline earth metal is in particular a base chosen from the group comprising sodium hydroxide, potassium hydroxide and calcium carbonate.
- the incorporation without addition of water of this mineral base of an alkali or alkaline-earth metal into the reaction medium for the formation of diosmin makes it possible, by its catalytic effect, to obtain the latter with very high purity in terms of residual iodine traces.
- the purification step can be improved by providing in step c) of purification a sub-step for the elimination of iodized residues by dissolving in a solvent comprising a secondary amine, in particular morpholine.
- the residual iodine content at the end of the operation is in a range much greater than 200 ppm, while in the conditions of the invention the residual iodine content is less than 200 ppm, typically of the order of 80 to 100 ppm.
- the Applicant has found that one could advantageously provide, in the purification step, a sub-step for the elimination of pyridine by addition of water and azeotropic water-pyridine distillation. Evaporation in situ of all of the pyridine by such distillation makes it possible to obtain a residual pyridine level of less than 50 ppm, which is not the case. not possible to obtain by conventional means of purification.
- the proportion of the mineral base of alkali or alkaline-earth metal relative to hesperidin is between 1 and 2, preferably approximately 1, 8, molar equivalents
- the heating of the reaction medium in step b) is operated at a temperature between 70 and 110 ° C, preferably about 90 ° C, for a period between 5 to 7 hours, preferably about 6 hours.
- the applicant has found that, by providing, according to the invention, the incorporation into a reaction medium of a mineral base of alkali or alkaline-earth metal, it was possible, owing to the catalytic effect obtained, substantially reduce the reaction time compared to conventional pyridine-iodine processes, typically a reduction of around 40%.
- Elimination of morpholine the product isolated on the filter is dissolved again in a 5% sodium hydroxide solution. The medium is neutralized with sulfuric acid. The suspension is filtered and washed with hot water at 60 ° C. After drying, the diosmin is obtained with a yield of 80% and a purity meeting the standards of the pharmacopoeia, in particular a residual iodine content of less than 200 ppm and a residual pyridine content of less than 50 ppm. The residual iodine level can even be less than 100 ppm.
Abstract
The invention concerns a method comprising the following steps: a) preparing a reaction medium by mixing hesperidin, iodine, pyridine and an alkaline or alkaline-earth metal base, said reaction medium being substantially water-free and the mineral base being brought in solid form; b) heating said reaction medium to obtain a reaction product containing diosmin; and c) purifying the reaction product by eliminating pyridine and iodine residues. The mineral base can be sodium hydroxide, potassium hydroxide or calcium carbonate. At the purifying step c) a further sub-step is provided for eliminating iodine-containing residues by solution in a solvent comprising a secondary amine such as morpholine. Said method ensures a residual iodine content less than 200 ppm.
Description
Procédé de fabrication industrielle de diosmine à partir de l'hespéridine par réaction avec de l'iode et de la pyridine Process for the industrial production of diosmin from hesperidin by reaction with iodine and pyridine
La présente invention concerne un procédé de fabrication industrielle de la diosmine à partir de l'hespéridine.The present invention relates to a process for the industrial manufacture of diosmin from hesperidin.
La diosmine est un bioflavonoïde connu à l'état naturel et se trouve par exemple dans l'écorce des agrumes et est utilisée pour son application veinotonique et protectrice du foie. À un niveau industriel l'hemisynthèse de la diosmine est réalisée à partir de l'hespéridine produit naturel. Les procédés de fabrication connus à ce jour consistent à faire réagir :Diosmin is a bioflavonoid known in its natural state and is found for example in the peel of citrus fruits and is used for its venotonic and protective application of the liver. On an industrial level, the hemisynthesis of diosmin is carried out using the natural product hesperidin. The manufacturing processes known to date consist of reacting:
- l'hespéridine avec de l'iode en présence de pyridine (Voigtlânder H W et coll., The Conversion of Flavanones to Flavones, Studies in Organic Chemistry, 1981 , vol. 11 , 115-119 et les brevets FR-A-2411 845 et FR- A-2402655), qui fournit la diosmine avec 89 % de rendement ; - l'hespéridine avec de la soude, de l'iodure de potassium et de l'iode en milieu aqueux (Voigtlânder H W et coll., The Conversion of Flavanones to Flavones, Studies in Organic Chemistry, 1981, vol. 11 , 115-119) qui fournit la diosmine avec un rendement de 50 %, après une étape supplémentaire de purification utilisant de la soude ; - l'hespéridine avec de l'anhydride acétique, de la pyridine et de l'oxyde de sélénium (brevet EP 0 052 086) qui fournit la diosmine avec 79 % de rendement ;- hesperidin with iodine in the presence of pyridine (Voigtlânder HW et al., The Conversion of Flavanones to Flavones, Studies in Organic Chemistry, 1981, vol. 11, 115-119 and patents FR-A-2411 845 and FR-A-2402655), which provides diosmin with 89% yield; - hesperidin with soda, potassium iodide and iodine in an aqueous medium (Voigtlânder HW et al., The Conversion of Flavanones to Flavones, Studies in Organic Chemistry, 1981, vol. 11, 115- 119) which provides the diosmin with a yield of 50%, after an additional purification step using sodium hydroxide; - hesperidin with acetic anhydride, pyridine and selenium oxide (patent EP 0 052 086) which provides diosmin with 79% yield;
- l'hespéridine avec de l'iode et de la pyridine dans le diméthylforma- mide (brevet belge 904 614) qui fournit la diosmine avec 75 % de ren- dément ;- hesperidin with iodine and pyridine in dimethylformamide (Belgian patent 904,614) which provides diosmin with 75% yield;
- l'hespéridine avec de l'iode et de la résine de poly-(4-vinylpyridine) dans le diméthylsulfoxyde (brevet belge 904 614) qui fournit la diosmine avec 78 % de rendement ;- hesperidin with iodine and poly- (4-vinylpyridine) resin in dimethylsulfoxide (Belgian patent 904 614) which provides diosmin with 78% yield;
- l'hespéridine avec de l'acétate de sodium, de l'iode dans du méthanol (brevet espagnol 537 183) qui fournit la diosmine avec 84 % de rendement et 96 % de pureté ;- hesperidin with sodium acetate, iodine in methanol (Spanish patent 537,183) which provides diosmin with 84% yield and 96% purity;
- l'hespéridine avec de l'anhydride acétique, de l'acétate de sodium, du brome et de la pyridine (brevet DE 26 02 314) qui fournit la diosmine avec 63 % de rendement contenant 0,09 % de dérivés bromes ; - l'hespéridine acétylée avec du N-bromosuccinimide ou du bromure de
pyridinium et des peroxydes de benzoyle (J. Org. Chem., 1951, 930) qui fournit la diosmine avec 44 % de rendement.- hesperidin with acetic anhydride, sodium acetate, bromine and pyridine (patent DE 26 02 314) which provides diosmin with 63% yield containing 0.09% bromine derivatives; - hesperidin acetylated with N-bromosuccinimide or bromide pyridinium and benzoyl peroxides (J. Org. Chem., 1951, 930) which provides diosmin with 44% yield.
De plus d'autres procédés de synthèse concernant la déshydrogénation des flavanones en flavones ont été étudiés et décrits dans la littérature comme la combinaison de l'iode avec de l'acide sulfurique dans le dimé- thylsulfoxyde {Chem. Ind. (London) 1979, 315).In addition, other synthetic methods relating to the dehydrogenation of flavanones to flavones have been studied and described in the literature as the combination of iodine with sulfuric acid in dimethyl sulfoxide (Chem. Ind. (London) 1979, 315).
L'invention concerne plus précisément, parmi ces procédés, ceux dans lesquels on fait réagir comme réactifs principaux l'hespéridine avec de l'iode et de la pyridine, en présence d'une base minérale. Les FR-A-2411 845 et FR-A-2402655 (précités) décrivent de tels procédés, où le mélange réactionnel de départ est en outre additionné d'une solution aqueuse de soude.The invention relates more precisely, among these methods, those in which hesperidin is reacted as main reagents with iodine and pyridine, in the presence of a mineral base. FR-A-2411 845 and FR-A-2402655 (cited above) describe such processes, in which the starting reaction mixture is additionally added with an aqueous sodium hydroxide solution.
Ces procédés procurent des résultats satisfaisants du point de vue industriel, mais un certain nombre d'inconvénients leur sont attachés. En premier lieu, du fait du chauffage des produits halogènes impliqués dans la réaction, on constate qu'un chauffage important (température élevée et/ou temps de réaction important) conduit à un bon rendement en produit final, mais avec une pureté médiocre ; au contraire, si l'on chauffe peu, la pureté est meilleure, mais le rendement décroît. En second lieu, et surtout, la teneur en iode résiduelle dans la diosmine se situe, avec les procédés connus, à un niveau de 1000 ppm, teneur juste compatible avec les normes actuelles de la pharmacopée (normes basées sur la quantité maximale d'iode susceptible d'être ingérée par jour). Il apparaît souhaitable de disposer d'un procédé permettant de réduire de façon importante cette teneur résiduelle en iode, afin notamment de pouvoir assurer une conformité du produit final obtenu avec de nouvelles normes, plus strictes, actuellement en cours d'élaboration.These methods give satisfactory results from the industrial point of view, but a certain number of drawbacks are attached to them. Firstly, due to the heating of the halogen products involved in the reaction, it is found that significant heating (high temperature and / or long reaction time) leads to a good yield of final product, but with poor purity; on the contrary, if one heats little, the purity is better, but the yield decreases. Secondly, and above all, the residual iodine content in diosmin is, with known methods, at a level of 1000 ppm, a content just compatible with current standards of the pharmacopoeia (standards based on the maximum amount of iodine likely to be ingested daily). It seems desirable to have a process which makes it possible to significantly reduce this residual iodine content, in particular in order to be able to ensure compliance of the final product obtained with new, more stringent standards, currently being developed.
Il en est de même pour la teneur résiduelle en pyridine, qu'il est indispensable de réduire au minimum dans le produit final. Or les procédés connus, précédemment décrits, ne permettent pas de répondre à de telles exigences.The same is true for the residual pyridine content, which must be reduced to a minimum in the final product. However, the known methods, previously described, do not make it possible to meet such requirements.
À la suite d'études approfondies en vue de mettre au point un procédé échappant aux inconvénients mentionnés ci-dessus, la demanderesse a trouvé que la synthèse de la diosmine à partir de l'hespéridine dans des condi- tions réactionnelles précises permettait de répondre à ces nouvelles exigen-
ces et d'obtenir la diosmine avec à la fois un bon rendement et une qualité élevée.Following in-depth studies with a view to developing a process which avoids the drawbacks mentioned above, the applicant has found that the synthesis of diosmin from hesperidin under precise reaction conditions makes it possible to respond to these new demands these and obtain diosmin with both good yield and high quality.
Le procédé de l'invention, qui vise à la fabrication industrielle de la diosmine à partir de l'hespéridine par réaction avec de l'iode et de la pyridine, est un procédé du type général enseigné par les FR-A-2 411 845 et FR-A- 2402 655 précités, c'est-à-dire comprenant les étapes de : a) préparation d'un milieu réactionnel par mélange d'hespéridine, d'iode, de pyridine et d'une base minérale de métal alcalin ou alcalino-terreux ; b) chauffage de ce milieu réactionnel, pour obtention d'un produit de réaction contenant de la diosmine, et c) purification du produit de réaction par élimination des résidus de pyridine et d'iode.The process of the invention, which aims at the industrial manufacture of diosmin from hesperidin by reaction with iodine and pyridine, is a process of the general type taught by FR-A-2 411 845 and FR-A-2402 655 mentioned above, that is to say comprising the steps of: a) preparation of a reaction medium by mixing hesperidin, iodine, pyridine and an inorganic alkali metal base or alkaline earth; b) heating this reaction medium, to obtain a reaction product containing diosmin, and c) purifying the reaction product by elimination of the pyridine and iodine residues.
De façon caractéristique de l'invention, le milieu réactionnel préparé à l'étape a) est essentiellement dépourvu d'eau, la base minérale étant apportée sous forme solide. La base minérale de métal alcalin ou alcalino-terreux est notamment une base choisie dans le groupe comprenant l'hydroxyde de sodium, l'hydroxyde de potassium et le carbonate de calcium.Characteristically of the invention, the reaction medium prepared in step a) is essentially devoid of water, the mineral base being provided in solid form. The mineral base of an alkali or alkaline earth metal is in particular a base chosen from the group comprising sodium hydroxide, potassium hydroxide and calcium carbonate.
L'incorporation sans addition d'eau de cette base minérale d'un métal alcalin ou alcalino-terreux dans le milieu réactionnel pour la formation de la diosmine permet, par son effet catalytique, d'obtenir celle-ci avec une très grande pureté en termes de traces résiduelles en iode. L'étape de purification peut être améliorée en prévoyant à l'étape c) de purification une sous-étape d'élimination des résidus iodés par mise en solution dans un solvant comprenant une aminé secondaire, notamment de la morpholine.The incorporation without addition of water of this mineral base of an alkali or alkaline-earth metal into the reaction medium for the formation of diosmin makes it possible, by its catalytic effect, to obtain the latter with very high purity in terms of residual iodine traces. The purification step can be improved by providing in step c) of purification a sub-step for the elimination of iodized residues by dissolving in a solvent comprising a secondary amine, in particular morpholine.
On constate en effet que, lorsque la réaction est conduite seulement en présence de pyridine, ou de soude et d'iode, le taux résiduel en iode en fin d'opération se situe dans une plage très supérieure à 200 ppm, tandis que dans les conditions de l'invention le taux résiduel en iode est inférieur à 200 ppm, typiquement de l'ordre de 80 à 100 ppm.It can be seen that, when the reaction is carried out only in the presence of pyridine, or sodium hydroxide and iodine, the residual iodine content at the end of the operation is in a range much greater than 200 ppm, while in the conditions of the invention the residual iodine content is less than 200 ppm, typically of the order of 80 to 100 ppm.
De plus, la demanderesse a constaté que l'on pouvait avantageusement prévoir, dans l'étape de purification, une sous-étape d'élimination de la pyridine par addition d'eau et distillation azéotropique eau-pyridine. L'évaporation in situ de la totalité de la pyridine par une telle distillation per- met d'obtenir un taux résiduel en pyridine inférieur à 50 ppm, ce qu'il n'est
pas possible d'obtenir par les moyens classiques de purification. Avantageusement, la proportion de la base minérale de métal alcalin ou alcalino-terreux par rapport à l'hespéridine est comprise entre 1 et 2, de préférence environ 1 ,8, équivalents molaires, et le chauffage du milieu ré- actionnel à l'étape b) est opéré à une température comprise entre 70 et 110 °C, de préférence environ 90 °C, pendant une durée comprise entre 5 à 7 heures, de préférence environ 6 heures.In addition, the Applicant has found that one could advantageously provide, in the purification step, a sub-step for the elimination of pyridine by addition of water and azeotropic water-pyridine distillation. Evaporation in situ of all of the pyridine by such distillation makes it possible to obtain a residual pyridine level of less than 50 ppm, which is not the case. not possible to obtain by conventional means of purification. Advantageously, the proportion of the mineral base of alkali or alkaline-earth metal relative to hesperidin is between 1 and 2, preferably approximately 1, 8, molar equivalents, and the heating of the reaction medium in step b) is operated at a temperature between 70 and 110 ° C, preferably about 90 ° C, for a period between 5 to 7 hours, preferably about 6 hours.
De plus, la demanderesse a trouvé qu'en prévoyant, selon l'invention, l'incorporation en milieu réactionnel d'une base minérale de métal alcalin ou alcali- no-terreux, on pouvait, du fait de l'effet catalytique obtenu, diminuer substantiellement le temps de réaction par rapport aux procédés classiques pyridine- iode, diminution typiquement de l'ordre de 40 %.In addition, the applicant has found that, by providing, according to the invention, the incorporation into a reaction medium of a mineral base of alkali or alkaline-earth metal, it was possible, owing to the catalytic effect obtained, substantially reduce the reaction time compared to conventional pyridine-iodine processes, typically a reduction of around 40%.
Ce gain de temps important diminue le risque de dégradation de la diosmine pendant la réaction, ce qui donne un rendement meilleur, facilite la purifica- tion et aboutit à un coût de fabrication moindre.This significant time saving reduces the risk of degradation of the diosmin during the reaction, which gives a better yield, facilitates the purification and results in a lower manufacturing cost.
On peut notamment prévoir des proportions respectives entre la base minérale d'alcalin ou d'alcalino-terreux, la pyridine et l'hespéridine de 1 : 37,62 : 7,68 en rapport massique, ce qui correspond à 5 litres de pyridine par kg d'hespéridine (proportion en elle-même classique) et 1,8 équivalents molai- res de base minérale d'alcalin ou d'alcalino-terreux par rapport à l'hespéridine. Le nombre d'équivalents molaires en iode est compris entre 1 et 1 ,1. On va maintenant décrire un exemple d'exécution de l'invention, mettant en œuvre les enseignements ci-dessus.We can in particular provide for respective proportions between the alkaline or alkaline earth mineral base, pyridine and hesperidin of 1: 37.62: 7.68 in mass ratio, which corresponds to 5 liters of pyridine per kg of hesperidin (proportion in itself conventional) and 1.8 molar equivalents of mineral base of alkali or alkaline earth compared to hesperidin. The number of molar iodine equivalents is between 1 and 1, 1. We will now describe an embodiment of the invention, implementing the above teachings.
ExempleExample
Synthèse du produit : dans un micro-réacteur de 5 I équipé d'un réfrigérant, on place 500 g d'hespéridine (pureté 90 à 95 %), puis 2,5 I de pyridine, 59 g de soude anhydre et 228,7 g d'iode. La solution est portée à 90 °C pendant 6 h. En fin de réaction la suspension est concentrée par évaporation de 70 % de la pyridine sous vide à 50 °C. Élimination de la pyridine : la suspension est ensuite dispersée dans 2 I d'eau et 13 g de thiosulfate de sodium. L'azéotrope eau-pyridine est évaporé à 50 °C sous vide. La suspension obtenue est filtrée et lavée à l'eau.
Élimination de l'iode (lavage à la morpholine) : le produit isolé sur le filtre est remis en suspension dans 2,650 I de morpholine et le reste d'eau est évaporé à 80 °C sous vide. Puis le milieu réactionnel est chauffé à 127 °C sur une courte période et 1 ,650 I de morpholine est évaporée sous pres- sion réduite. Après refroidissement et ajout de 0,75 I d'eau, la suspension est filtrée et lavée avec de l'eau à 60 °C.Synthesis of the product: in a 5 I micro-reactor equipped with a condenser, 500 g of hesperidin (90 to 95% purity) are placed, then 2.5 I of pyridine, 59 g of anhydrous soda and 228.7 g of iodine. The solution is brought to 90 ° C for 6 h. At the end of the reaction, the suspension is concentrated by evaporation of 70% of the pyridine in vacuo at 50 ° C. Elimination of pyridine: the suspension is then dispersed in 2 l of water and 13 g of sodium thiosulfate. The water-pyridine azeotrope is evaporated at 50 ° C. under vacuum. The suspension obtained is filtered and washed with water. Elimination of iodine (washing with morpholine): the product isolated on the filter is resuspended in 2.650 I of morpholine and the rest of the water is evaporated at 80 ° C. under vacuum. The reaction medium is then heated to 127 ° C. over a short period and 1.650 l of morpholine is evaporated under reduced pressure. After cooling and adding 0.75 I of water, the suspension is filtered and washed with water at 60 ° C.
Élimination de la morpholine : le produit isolé sur le filtre est dissous à nouveau dans une solution à 5 % en soude. Le milieu est neutralisé avec de l'acide sulfurique. La suspension est filtrée et lavée à l'eau chaude à 60 °C. Après séchage, la diosmine est obtenue avec un rendement de 80 % et une pureté répondant aux normes de la pharmacopée, en particulier un taux résiduel en iode inférieur à 200 ppm et un taux résiduel en pyridine inférieur à 50 ppm. Le taux résiduel en iode peut même être inférieur à 100 ppm.
Elimination of morpholine: the product isolated on the filter is dissolved again in a 5% sodium hydroxide solution. The medium is neutralized with sulfuric acid. The suspension is filtered and washed with hot water at 60 ° C. After drying, the diosmin is obtained with a yield of 80% and a purity meeting the standards of the pharmacopoeia, in particular a residual iodine content of less than 200 ppm and a residual pyridine content of less than 50 ppm. The residual iodine level can even be less than 100 ppm.
Claims
1. Un procédé de fabrication industrielle de diosmine à partir de l'hespéridine par réaction avec de l'iode et de la pyridine, comprenant les étapes suivantes : a) préparation d'un milieu réactionnel par mélange d'hespéridine, d'iode, de pyridine et d'une base minérale de métal alcalin ou alcalino-terreux, b) chauffage de ce milieu réactionnel, pour obtention d'un produit de réaction contenant de la diosmine, et c) purification du produit de réaction par élimination des résidus de pyridine et d'iode, caractérisé en ce que le milieu réactionnel préparé à l'étape a) est essentiellement dépourvu d'eau, la base minérale étant apportée sous forme solide.1. A process for the industrial manufacture of diosmin from hesperidin by reaction with iodine and pyridine, comprising the following steps: a) preparation of a reaction medium by mixing hesperidin, iodine, of pyridine and of an inorganic base of an alkali or alkaline earth metal, b) heating of this reaction medium, to obtain a reaction product containing diosmin, and c) purification of the reaction product by elimination of the residues of pyridine and iodine, characterized in that the reaction medium prepared in step a) is essentially devoid of water, the mineral base being provided in solid form.
2. Le procédé de la revendication 1 , dans lequel la base minérale de métal alcalin ou alcalino-terreux est choisie dans le groupe comprenant l'hydroxyde de sodium, l'hydroxyde de potassium et le carbonate de calcium.2. The process of claim 1, wherein the mineral base of an alkali or alkaline earth metal is selected from the group comprising sodium hydroxide, potassium hydroxide and calcium carbonate.
3. Le procédé de la revendication 1 , dans lequel l'étape c) de purification comprend une sous-étape d'élimination des résidus iodés par mise en solution dans un solvant comprenant une aminé secondaire.3. The method of claim 1, wherein step c) of purification comprises a sub-step of elimination of iodized residues by dissolving in a solvent comprising a secondary amine.
4. Le procédé de la revendication 3, dans lequel l'aminé secondaire est la morpholine.4. The process of claim 3, wherein the secondary amine is morpholine.
5. Le procédé de la revendication 1 , dans lequel l'étape c) de purification comprend une sous-étape d'élimination de la pyridine par addition d'eau et distillation azéotropique eau-pyridine.5. The method of claim 1, wherein step c) of purification comprises a sub-step of removing pyridine by adding water and azeotropic water-pyridine distillation.
6. Le procédé de la revendication 1 , dans lequel la proportion de la base minérale de métal alcalin ou alcalino-terreux par rapport à l'hespéridine est comprise entre 1 et 2, de préférence environ 1 ,8, équivalents molaires.
6. The method of claim 1, wherein the proportion of the mineral base of alkali or alkaline earth metal relative to hesperidin is between 1 and 2, preferably about 1.8, molar equivalents.
7. Le procédé de la revendication 1 , dans lequel le chauffage du milieu réactionnel à l'étape b) est opéré à une température comprise entre 70 et 110°C, de préférence environ 90 °C, pendant une durée comprise entre 5 à 7 heures, de préférence environ 6 heures.
7. The method of claim 1, wherein the heating of the reaction medium in step b) is carried out at a temperature between 70 and 110 ° C, preferably about 90 ° C, for a period between 5 to 7 hours, preferably around 6 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99936746A EP1105402A1 (en) | 1998-08-19 | 1999-08-17 | Method for industrial production of diosmin from hesperidin by reaction with iodine and pyridine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9810544A FR2782518A1 (en) | 1998-08-19 | 1998-08-19 | Preparation of vasotropic diosmin from hesperidin by anhydrous reaction with iodine and pyridine with solid mineral base |
| FR98/10544 | 1998-08-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000011009A2 true WO2000011009A2 (en) | 2000-03-02 |
| WO2000011009A3 WO2000011009A3 (en) | 2000-06-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR1999/002001 WO2000011009A2 (en) | 1998-08-19 | 1999-08-17 | Method for industrial production of diosmin from hesperidin by reaction with iodine and pyridine |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1105402A1 (en) |
| FR (1) | FR2782518A1 (en) |
| WO (1) | WO2000011009A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN103012524A (en) * | 2012-12-31 | 2013-04-03 | 浙江大学 | Semisynthetic method for preparing rhoifolin |
| EP3053930A1 (en) | 2015-02-03 | 2016-08-10 | Interquim, S.A. | Process for the preparation of diosmin |
| CN112979603A (en) * | 2021-03-08 | 2021-06-18 | 宜宾西华大学研究院 | Continuous flow micro-channel synthesis process of flavonoid compound |
| CN114306363A (en) * | 2022-01-05 | 2022-04-12 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435666B (en) * | 2013-07-30 | 2016-03-16 | 李玉山 | A kind of production new technology of diosmin |
| AR122887A1 (en) * | 2020-07-09 | 2022-10-12 | Servier Lab | DIOSMIN PREPARATION PROCEDURE |
| AR126366A1 (en) | 2021-07-06 | 2023-10-11 | Servier Lab | PROCEDURE FOR THE PREPARATION OF DIOSMIN AND THE FLAVON FRACTION |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2402655A1 (en) * | 1977-09-10 | 1979-04-06 | Merck Patent Gmbh | FLAVON PREPARATION PROCESS |
| FR2411845A1 (en) * | 1977-12-16 | 1979-07-13 | Merck Patent Gmbh | PROCESS FOR THE PREPARATION OF FLAVONE GLUCOSIDES |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1191620B (en) * | 1985-05-30 | 1988-03-23 | Edmond Pharma Srl | PROCEDURE FOR THE PREPARATION OF DIOSMINE |
-
1998
- 1998-08-19 FR FR9810544A patent/FR2782518A1/en active Pending
-
1999
- 1999-08-17 WO PCT/FR1999/002001 patent/WO2000011009A2/en not_active Application Discontinuation
- 1999-08-17 EP EP99936746A patent/EP1105402A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2402655A1 (en) * | 1977-09-10 | 1979-04-06 | Merck Patent Gmbh | FLAVON PREPARATION PROCESS |
| FR2411845A1 (en) * | 1977-12-16 | 1979-07-13 | Merck Patent Gmbh | PROCESS FOR THE PREPARATION OF FLAVONE GLUCOSIDES |
Non-Patent Citations (2)
| Title |
|---|
| VOIGTLAENDER H -W ET AL: "THE CONVERSION OF FLAVANONES TO FLAVONES" STUDIES IN ORGANIC CHEMISTRY, vol. 11, no. 11, 6 septembre 1981 (1981-09-06), pages 115-119, XP002048479 cité dans la demande * |
| VOIGTLAENDER, HANS WALTER ET AL: "A simple method for the conversion of flavanones into flavones" ARCH. PHARM. (WEINHEIM, GER.) (1983), 316(3), 219-22, XP002102341 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| WO2010092592A3 (en) * | 2009-02-11 | 2011-09-09 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN103012524A (en) * | 2012-12-31 | 2013-04-03 | 浙江大学 | Semisynthetic method for preparing rhoifolin |
| US10287310B2 (en) | 2015-02-03 | 2019-05-14 | Interquim, S.A. | Process for the preparation of diosmin |
| WO2016124585A1 (en) * | 2015-02-03 | 2016-08-11 | Interquim, S.A. | Process for the preparation of diosmin |
| KR20170108005A (en) * | 2015-02-03 | 2017-09-26 | 인터퀴임, 에스.에이. | How to make Diosmin |
| EP3053930A1 (en) | 2015-02-03 | 2016-08-10 | Interquim, S.A. | Process for the preparation of diosmin |
| EA032402B1 (en) * | 2015-02-03 | 2019-05-31 | Интерким, С.А. | Process for the preparation of diosmin |
| US10711025B2 (en) | 2015-02-03 | 2020-07-14 | Interquim, S.A. | Process for the preparation of diosmin |
| KR20200131334A (en) * | 2015-02-03 | 2020-11-23 | 인터퀴임, 에스.에이. | Process for the preparation of diosmin |
| KR102216702B1 (en) | 2015-02-03 | 2021-02-18 | 헬스테크 바이오 액티브스 에스.엘.유. | Diosmin preparation method |
| KR102309525B1 (en) | 2015-02-03 | 2021-10-07 | 헬스테크 바이오 액티브스 에스.엘.유. | Process for the preparation of diosmin |
| CN112979603A (en) * | 2021-03-08 | 2021-06-18 | 宜宾西华大学研究院 | Continuous flow micro-channel synthesis process of flavonoid compound |
| CN114306363A (en) * | 2022-01-05 | 2022-04-12 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
| CN114306363B (en) * | 2022-01-05 | 2022-11-08 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1105402A1 (en) | 2001-06-13 |
| FR2782518A1 (en) | 2000-02-25 |
| WO2000011009A3 (en) | 2000-06-29 |
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