CA1039717A - PROCESS OF PREPARING MONO-O-.beta.-HYDROXY-ETHYL-7 RUTOSIDE - Google Patents

Abstract

A Process of Preparing mono-O-.beta.-hydroxyehtyl--7 rutoside Abstract of the Disclosure Mono-O-.beta.-hydroxyethyl-7 rutoside is prepared by reacting ethylene oxide in an aqueous, partially aqueous or organic polar solvent with a rutoside complex whose ortho-diphenyl group of the B ring is blocked by a complexing agent, e.g, boron or boric acid. The reaction temperature is preferably from 30 to 40° C, The OH
phenolic complexes are then freed by hydrolysis.
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Description

~ 97~7 The invention concerns a new industrially applicable process of selectively preparing mono-O~
hydroxyethyl-7 rutoside (designated in the specification by ~ ;
Mono-7-HER) in which ethylene oxide is reacted in a solvent with a rutoside complex whose ortho_diphenyl group of the B
ring is blocked by a complexing agent. The solvent is preferably aqueous, or partially` aqueous or organic polar. The complexing agent is preferably borax or boric acid, the ratter in the presence of a weak base such as sodium acetateO After the reaction, the O}J-phenolic complexes are freed in a known manner, preferably by hydrolysis, in particular in an acid solution .
The known hydroxyethyration of ~rutoside for example by means of ethylene chlorhydrin and employing stoichiometric quantities of alkali, or by means of a great excess of ethylene oxide in the presence of alkali always leads to a more or less complex mixture of O~ -hydroxyethyl derivatives of rutoside from whioh one or other of the components cannot be isolated on an industrial scale, Only ethylene oxide as hydroxyethylation agent enables production of the 7_mono-etherified derivative of rutoside in the practically pure state according to a known process teaching the use of hydro-alcoholic solvents or water_dioxane mixtures to slow the speed of hydroxyethylation.
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In this known process, the duration of the reaction leads to the formation of dif~ercnt hydroxyethyl derivatives

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which successively pass from the mono-derivatives to di- and tri- derivatives and then tetra-substitutes. It was thus necessary to permanently control the reaction and to be able to interrupt it upon the formation of mono-7-HER, this being a delicate operation. The process according to the invention does not have this drawback, as the reaction cannot continue beyond mono_etherification and because of this the yield obtained is superior.
According to the known process, the temperature of the reaction was relatively high, namely above 50C:: and preferably between ~0 and 90C, whereas in the process according to the present invention, the reaction temperature preferably remains below 50C.
Acoording to the process of the invention, the consumption of ethylene oxide is reduced and it is used in safer conditions.
According to the known process, several successive .
¢rystallisations are required Ac¢ording to the new process, the quantitative hydroxyethyla1;ion of rutoside is controlled and there is formed, beside the mono-7-HER, traces of di-O~
hydroxyethyl_5, 7 rutoside and tri-O_hydroxyethyl-7 ~ 3 ~, 41 rutoside, the two latter substances being soluble in water and hen¢e easy to eliminate by a single crystallisation which leaves the chromatographically pure mono-7_HER.
, ;~ - The soluble rutoside complex used in the prscess of the invention may be obtained by reacting preferably ,~

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- lQ;~17 practically stoichiometric quantities of complexing agents and rutoside in the reaction solvent. The complexing agent is preferably borax or boric acid, salified or not. The reaction solvent may be aqueous, partially aqueous or polar organic~
The complex may be directly prepared before hydroxyethylation -and need not necessarily be isolated from the reaction medium before proceeding to the process of the invention. For . . ~ .
example, in water, formation of the borax-rutoside complex may be controlled by visible spectrography ( rutoside absorbs at 359nm and the rutoside_borax complex at 379nm~ or by ultraviolet spectrography ( rutoside absorbs at 255 nm with a shoulder at 260nm whereas the rutoside-borax complex absorbs at 268 nm with a shoulder at 330nm) .In partially aqueous or organic polar media, these rutoside_boric acid complexes may ~, ~
for example be detected by ultraviolet/visible spectrography.
` ~ ~ Hydroxyethylation is carried out directly on the complex by means of a measured quantity of ethylene oxide, preferably 2.5 moles or more per m~le of rutoside; it is favourized in aqueous media by a slight excess of borax, and in organic polar media by a weak base such as sodium acetate.
The process according to the invention may be carried out in the laboratory in an autoclave and industrially in ~ ~ a reactor, for example of the Grignard type able to be 1~ hermetically closed.
The etherification reaction takes place at a relatively low temperature, below S0C, preferably between d ~

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30 and 40C, ~t higher temperatures, there is a risk of decomposition of the complex, which would lead to a non-sought mixture of O-~-hydroxyethyl derivatives of rutoside. The reaction can take place in relatively concentrated solutions of rutine, for example above 30% by weight.
Progression of the reaction can be controlled chromatographically on a thin film of cellulose by means of a butanol-n-methanol_water mixture (10:1:3 by volume). The ' reaction is finished upon the quantitative disappearance of rutoside. Then, while cooling to ambient temperature, the residual ethylene oxide is removed, for example by passing an inert gas such as nitrogen into the reactor; this drives off the residual ethylene oxide which can be taken up by bubbling it in an, aqueous solution of 6N hydrochloric acid. The solution is then acidified, preferably to a pH comprised between 1 and 3, for example by means of a concentrated acid solution, preferably a mineral aeid such as 20% hydrochloric '! acid. This a¢idity frees the p~eviously formed phenolic OH ', ' complexes. Isolation of the sought_after substance may for example be obtained as follows : in water, the mono-7-H E R
derivative precipitates whereas in partially aqueous and organic ¦' , polar react;ons, the reaction solvent ls replaced by water and the pH of the solution is controlled to be brought to between ~ ', 1 and 3, which enables precipitation of the mono_7-HE~.
At this stage, the yield of practically pure ,"' mon$~7_HER in purely aqueous reaction media is of the order _ S _ t ~ I
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of 97_98%, iO e O far superior to the known process, Moreover, it is possible to easily remove the impurities whlch are soluble in water.
A simple recrystallisation in water leads to chrc ma-~ographically pure mono_7_HERO
The purity of the product can be controlled chromatographically on a thin layer of polyamide by using as solvent a butanol-n-methanol-water mixture (10:1:3 by volume) or by chromatographing its aglucon ( obtained by acid hydrolysis ) on S+S 2034 bmgl paper by means of formic acid-water solvent ( 7: 3 by volume ) according to the descending technique .
The product is also confirmed by mass spectro-graphy in the presence of various reactants such as sodium acetate, sodium methylate, sodium acetate/boric acid mixture, aluminium chloride with or without hydrochloric acid.
The product considered, mono-7-HER, notably has - the following pharmacological properties: normalisation of the capillary permeability, increase of the capillary resistance, a¢tion on the metaboiism of the conjunctive tissue, action on 20 the energetic metabolism of the vascular~wall and an anti-_inflammatory action. It has multiple medical applications: the treatment of circulatory troubles in particular troubles in the veins and capillaries, and of certain troubles of the metabolism of the conjunctive tissues. It is possible to incorporate it in various pharmaceutical presentations, in determined and fixed proportions, 103g7~7 ~
~ n one aspect o~ this invention there is provided a process of preparing mono-O-~-hydroxyethyl~7 rutoside, com-- prising reacting ethylene oxide in a solvent with a rutoside complex whose ortho-diphenyl group of the B-ring is blocked by a boron derivative as a complexing agent, and then freeing the OH phenolic complexes.

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Several examples of the process according to the invention will now be described~
Ex~ample 1 209g i. e. 0.55 mole of borax Na2B4O7.10 H2O is dissolved in 1150ml of distilled or demineralised water, and 310g i. e. 0.51 mole of rutoside is added and progressively passes into solution to form the rutoside_borax complex. The solution is stirred and held at 40C in an autoclave. By pumping out ambient air, the autoclave is piaced under slight vacuum, and 6205ml i. e. 56g or 1.275 mole of ethylene oxide is added by injection with nitrogen under slight pressure, and normal pressure is re_established with nitrogen. Stirring is continued -.
at the temperature of 40 C during 24 hours, the time required for entire disappearance of the rutoside~ Heating is stopped, and a stream of nitrogen passed during 2 hours to drive off the residual ethylene oxide which is trapped by passing the stn3~un ` ~ of gas through a washing bottle containing 1 litre oP 6N
hydrochlori¢ acid.
After transfer to a 2-litre erlenmeyer flask the reaction solution is brought to pH 2.0 by adding 180ml of 20%
` hydrochlori¢ acid (5.5N HCI): the precipitation of mono-7-HER
begins during acidification. The solution is left at 4C over~
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night then the precipitate is separated by filtration, and washed with cold water.

¦ ~ ~ The dried substance weighs about 320g, namely a - a yield of 97%.

- 10~7 This substance can be recrystallised in water.
Example 2 40g i. e. 0.0656 mole of rutoside is placed in - solution in 800ml of methanol in the presence of 16.4g i . e~
0.265mole of boric acid H3BO3 and 21.4g i.e. 0.0262 mole of sodium acetate CH3COONa, and the mixure stirred at 35C
in an autoclave. 72g i. e. 1.64 mole of ethylene oxide in liquid form are added, in a single time. The stirring is continued at the same temperature during 228 hours. 132ml of 2N hydro- ;
chloric acid is then added and evaporated to dryness in a IlRotavaporll(Trade Mark ) apparatus under vacuum without exceeding 50 C . The residue is taken up with 200ml of water ~ .
¦ ~ and the pH brought to 2.5 with 2N HCI. After dilution to 250ml (16% solution) with water, the mixuture is filtered and left at 4 C at rest during 3 1/2 hours . The precipitate is filtered with a IlBu¢hnerll and dried under~'vacuum: it is ~ . .
mono-7-HER. The yield is 20 to 22g, namely 46.5 to 51.5%.

~am~le 3 As example 2, but replaoing the methanol by 200ml 20 o~ a methanol/dioxane mixture (1: 1 by volume ) . The rea¢tion time is in 1;his ¢ase about 350 hours, and the yield of mono-_7_HER of the order of 50%.
.:; ' Exam~le 4 ~ s example 2, but replacing the methanol by 400ml of a water-dioxane mixture (1: 1 by volume ) . The reaction time is of the order of 24 hours, and the yield of mono-7-HER of the order of 55%.

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process of preparing mono-O-.beta.-hydroxyethyl-7 rutoside, comprising reacting ethylene oxide in a solvent with a rutoside complex whose ortho-diphenyl group of the B-ring is blocked by a boron derivative as a complexing agent, and then freeing the OH phenolic complexes.

2. A process according to claim 1, in which the solvent is water.

3. A process according to claim 1, in which the solvent is a partially aqueous medium.

4. A process according to claim 1, in which the solvent is a polar organic medium, preferably an at least partially alcoholic medium.

5. A process according to claim 2, in which the complex-ing agent is borax.

6. A process according to claim 3, in which the complexing agent is boric acid salt.

7. A process according to claim 4, in which the complexing agent is boric acid.

8. A process according to claim 1, in which the reaction is carried out in the presence of a catalyst.

9. A process according to claim 5, in which the borax acts as a catalyst.

10. A process according to claim 6, in which the reaction is carried out in the presence of sodium acetate as a catalyst.

11. A process according to claim 1, in which the reaction temperature is less than 50°C.

12. A process according to claim 1, in which the reaction temperature is between 30 and 40°C.

13. A process according to claim 1, in which the product obtained is crystallised in strongly acidic aqueous medium.

14. The process according to claim 13, in which the pH
of the strongly acidic aqueous medium ranges between 1 and 3.