DE1668923C3 - 2 \ 4 ', 6', 3 tetrahydroxy 4 n per poxydihydrochalcone 4 'beta neohespendosid, its production and its use for the production of a sweetener composition - Google Patents

Description

2. Process for the production of 2 ', 4', 6 ', 3-tetrahydroxy - 4 - η - propoxydihydrochalcone - 4' - β - neohesperidoside, characterized in that phloracetophenone - 4 '- β - neohesperidoside and 3-hydroxy 4-n-propoxybenzaldehyde in a molar ratio of the benzaldehyde compound to the phloracetophenone ^ '- zi-neohesperidoside in the range of about 0.5: 1 to 5: 1 in a solvent which is at least about 30 percent by weight of an alkali metal hydroxide based on the total weight of solvent and alkali metal hydroxide, and consists of water or a mixture of water and methyl alcohol or 2s ethyl alcohol with a maximum of about 95% of the alcohol, ^{condensed at a temperature in the range of about 20 to 160 0} C, the condensation product is separated from the reaction mixture and in the dihydrochalconform transferred.

3. The method according to claim 2, characterized in that one carries out the condensation at about 60 to 160 ⁰ C.

4. The method according to claim 2 or 3, characterized in that the condensation at about 70 to 120 ° C

5. The method according to any one of claims 2 to 4, characterized in that the condensate by extracting the reaction mixture with ethyl acetate, isopropyl acetate, n-propyl acetate or Ethyl propionate is obtained from this

6. Use of 2 ', 4', 6 ', 3-tetrahydroxy 4-n-propoxydihydrochalcone-4' - /? - neohesperidoside for the manufacture of a composition containing this compound as a sweetener in an amount in the range contains from about 0.0001 to about 1 weight percent

Neohesperidosyl-O

The invention relates to the compound 2 ', 4', 6 ', 3-tetrahydroxy - 4 - η - propoxydihydrochalcone - 4' - β - neohesperidoside of the formula

OCH ₂ CH ₂ CH ₃

a process for their manufacture and their use as a synthetic sweetener. The "neohesperidosyl" residue has the following structure

HO OH

Normally, natural substances from the large class of substances known as "sugar" are used as sweeteners. Although the use of sugars achieves a pleasant sweetness, they are often undesirable as sweeteners because of their caloric value and are even unsuitable for metabolic disorders such as diabetes. There is therefore a constant search for substances that are free from such disadvantages and that are suitable as sugar substitute sweeteners. One of the important sugar substitutes is neo hesperidine dihydrochalcone. It has been found that this compound is characterized by a sweetness which, based on weight, is about three orders of magnitude higher than the sweetness of sucrose. However, it has not been possible to achieve technically acceptable yields with the previously proposed processes for the preparation of neohesperidin dihydrochalcone. One method that has been proposed for making dihydrochalcones is described in U.S. Patent 3,087,821. According to this method, certain flavanone glycosides are treated with an aqueous alkali solution in order to open the heterocyclic ring and to produce the corresponding chalcone as an intermediate product. This intermediate product is obtained by acidifying the reaction system to precipitate the chalcone. The dihydrochalcone is then produced by hydrogenating the ethylenic double bond of the chalcone. According to this process, neohesperidin dihydrochalcone, which according to the information in US Pat. No. 3,087,821 is 20 times as sweet as saccharin, can be produced from neohesperidin. The disadvantage is neohesperidin, which is used as the starting material for the production of neohesperidin dihydrochalcone

after this procedure is needed only in extraordinarily available in small quantities.

According to the method of US Pat. No. 3,087,821, naringine dihydochalcone can also be obtained from Naringin can be produced. In this process, the accessibility of starting materials is not an issue Limitation because naringin is the main flavanoid ingredient of grapefruit or grapefruit as well A common ingredient in other citrus fruits is naringine dihydrochalcone, but it is only about the same Sweetness like saccharin (based on poppy genes) and is therefore not as desirable as a product far sweeter neohesperidin dihydrochalcone.

Surprisingly, it has now been found that 2 ', 4', 6 ', 3 · teirahydroxy-4-n-propoxydihydrochalcone-4' - / <- neohesperidoside is a stable, water-soluble substance with an intense sweetness. It is more than 2000 times like that sweet like sucrose. In contrast to closely related compounds, 2 \ 4 ', 6', 3-tetrahydroxy-4-n-propoxydihydrocbalcon-4 '- / J-ncohesperidoside not characterized by an unpleasant aftertaste. It has also been found that when used this compound in concentrations at which an aftertaste can be detected, the sensation perceived by a person, not a bitter or metallic taste, it is a pleasant cooling sensation. Furthermore, it contains 2 ', 4', 6 ', 3-tetrahydroxy-4-n-propoxydihydrochalcone-4' - / i-neohesperidoside a “sugar” residue in the molecule, but because of its intense sweetness it can be used as a sweetener for edible preparations be used in relatively small amounts (0.0001 to 1 percent by weight) so that the Addition of the compound to only a practically negligible amount to the caloric value of the finished product Preparation contributes.

2 \ 4 ', 6', 3 - tetrahydroxy - 4 - η - propoxydihydrochalcone-4 '- / i-neohesperidoside is produced according to the invention by adding phioracetophenone-4'-0-neohesperidoside and 3-hydroxy-4-n-propoxybenzaldehyde in a molar ratio of the benzaldehyde compound to the phloracetophenone-4 '- / i-neohesperidoside in the range of about 0.5: 1 to 5: 1 in a solvent that contains at least about 30 percent by weight of an alkali metal hydroxide, based on the total weight of the solvent and alkali metal hydroxide, and consists of water or a mixture of water and methyl alcohol or ethyl alcohol with a maximum of about 95% of the alcohol, ^{condenses at a temperature in the range from about 20 to 160 0} C, separates the condensation product from the reaction mixture and converts it into the dihydrochalcone form.

The condensation product is in the chalcone or flavanone form, depending on the conditions used obtained, and converted into the dihydrochalcone form by hydrogenation.

The overall reaction is shown in the following scheme

Neohesperidosyl-O-f

T
OH

OH

C-CH,

Alc.

+ HC- <X-OCH ₂ CH ₂ CH ₃

11 \

-H ₂ O

Neohesperidosyl-O

-C-CH = CH- ^ f "V-OCH ₂ CHCH ₃

Neohesperidosyl - O

H ₂ / cat.

Neohesperidoayl - O

OH

JC- CH ₂ - CH, - / ~ V- OCH ₂ CH ₂ CH ₃

In the condensation according to the process according to the invention, considerable conversions of the benzaldehyde compound with phloracetophenone-4 '- /? - neohesperidoside to give the chalcone are achieved quickly, effectively and economically. In particular, the condensation according to the invention offers the surprising advantage that the chalcone can be produced in relatively high yields, but in very short reaction times, with regard to the known disadvantages of other condensations of aldehydes and ketones which contain sugar residues or hydroxyl groups. Another advantage is that easily accessible starting materials, namely 3-hydroxy-4-n-propoxybenzaldehyde and phloracetophen one - 4 '- β - neohesperidoside, are used. The latter is obtained by alkaline degradation of naringin (Tetrahedron 19, pp. 773 to 782).

The ratio of the reactants in the condensation carried out first can be proportionate vary over a wide range. Generally, the reactants will be used in amounts applied, which is a molar ratio of the benzaldehyde compound to the Phloracetonphenonderivat im Range from about 0.5: 1 to about 5; 1 correspond. The benzaldehyde compound is preferably used in a slight stoichiometric excess. An M oil ratio of the ben / aldehyde compound to the phloracetophenone derivative in the range of about 1.1: 1 to about 3: 1 is particularly preferred.

The benzaldehyde compound and the phloracetophenone derivative are used in water alone or in admixture reacted with methanol or ethanol as reaction media. When a reaction medium is out Water and alcohol is used, there may be a larger proportion of the alcohol, e.g. B. up to about 95 weight pi ozent, preferably up to about 90 percent by weight alcohol. The preferred reaction medium is water. The two reactants can work together in the same solvent or individually in separate portions of the same and different solvents that make up the reaction medium exists, are dissolved, whereupon the solvents are combined.

In preparing the reaction mixture, the amount of reaction medium used is not critical; in general, it is sufficient to completely dissolve the reactants and the alkali as well to achieve a mixture that can be easily stirred. The solvent is generally used in such amounts are used that there is a ratio of the amount by weight of the reactants to Volume of the solvent (g / ml) in the range <*> from about 0.01: 1 to about 0.5: 1, preferably from about 0.1: 1 to about 0.25: 1 for each reactant results.

Sodium hydroxide or potassium hydroxide or a mixture thereof is usually used as the alkali & 5 turns. Other alkali hydroxides, e.g., lithium hydroxide, can also be used. The Alkali is used in such an amount that the

desired condensation to the chalcon takes place. The effective amount of alkali is at least about 30 percent by weight, based on the total weight of solvent plus alkali (in contrast to the Total weight of the reaction mixture). An alkali concentration of at least about 35 weight percent and especially an alkali concentration of at least about 40% is preferred. The upper The limit for the alkali concentration is apparently critical, and the solution can reach the saturation value for the alkali, but usually the concentration is about 70 weight percent, preferably about 60 percent by weight

Reaktionslemperaturen are suitable in the range of about 20 to 160 ⁰ C, which is about the reflux temperature of the Reaktionsmiüchung and even higher. The reaction mixture is usually maintained at an elevated temperature of from about 60 to 160 ° C. The preferred reaction temperature is about 70 to 120 ° C., except when solid reactants are added to the reaction medium, as will be explained below. In general, reaction temperatures in the preferred range will increase the yield and decrease the time required to complete the reaction. achieved compared to reaction temperatures outside the preferred range. Satisfactory yields are obtained if the reaction mixture is kept at about 60 to 160 ° C. for about 1 to 30 minutes, preferably for about 2 to 15 minutes. As an example for a typical condensation, 2,4,6,3-tetrahydroxy-4 -11-propoxychalcone-4 '-, (- neohesperidoside is produced by adding ~ ian Phli) i; uctorhcnon-4' - / i-neohesperidoside and 3 -Hydr »■ xy-4-n-propoxybenzaldehyde to an aqueous solution containing 30 to 35 percent by weight of sodium or potassium hydroxide, and a reaction temperature of about 115 to 120 C for a time at ambient pressure, for. B. 5 minutes, which is sufficient to achieve the desired chalcone product. That high yields of chalcones are achieved in such a short time is in view of the relatively long time. ie generally at least 1 day required by similar procedures of known type. so that a considerable part of the implementation takes place, very surprising. To achieve maximum yields, however, reaction times of more than 30 minutes can be used.

The condensation is most conveniently carried out at ambient pressure. If so desired however, the reaction can also be carried out in a vessel which is at a suitable pressure is adjusted to keep the reaction and the entire reaction mixture in a liquid state. Pressures up to about 3 atmospheres are generally used in such fills. You can Implementation in a normal atmosphere or in the presence of an inert atmosphere, e.g. B. from nitrogen, Methane and / or other gases that are inert under the reaction conditions.

It will be apparent to those skilled in the art that numerous modifications can be made in the preparation of the reaction mixtures are possible, which are used for the process according to the invention. Numerous amendments are possible because of the above, the chloroacetophenone derivative and the benzaldehyde reactant and the alkali in the same amount of water or a combination from water and alcohol or in separate proportions of the solvents that form the reaction medium, can be dissolved, whereupon the resulting solutions are combined. According to one embodiment the reactants are dissolved separately in a relatively dilute alkali solution, which then is added to a more concentrated alkali solution. According to another embodiment solves the reactants are in alcohol and the resulting solution is added to a concentrated alkali solution. In the same way, solid alkali can be diluted to form solutions of the reactants in a Add alkali-containing reaction medium In the embodiments described above the solution containing the two reactants can be obtained by dissolving the reactants in separate portions of the same or different solvents and then combined of the solutions. One or more of the solutions may be hot at the time of addition or they can be cold and heated to the desired reaction temperature.

Good yields are also achieved if solid reactants are added to the reaction medium. In these cases, however, it is preferred to adjust the solution to an elevated temperature of about 60 to 160 ° C., preferably about 70 to 120 ° C., before adding the solid reactants, and to maintain this increased temperature during the reaction. The mixing of the reactants and / or the addition of one solution to another can take place all at once or in portions, it being possible in the latter case to work continuously or semicontinuously. The addition of a reactant solution to an alkaline solution is preferably carried out when the reactants have practically the same temperature as the alkaline solution. Usually heated, the solvent for the reactants to a temperature of about 80 to 100 ⁰ C, the dissolution of the Reaktionsteilnehmcrs or Reaktionstcilnchmer which are added to support and gibi the resulting solution to the alkaline solution is preferably in the The elevated reaction temperature indicated above is located. In the embodiments in which the reactants are dissolved in methanol or ethanol, the resulting solutions are generally added slowly to the hot alkali solution in order to reduce possible difficulties due to evaporation of the alcohol.

The condensation product can be obtained either in the flavanone or in the chalcone form, depending on the way in which the reaction mixture is treated after the reaction has ended. A method for obtaining the reaction product in the chalcone form is to cool the reaction mixture by external cooling or by adding ice to below room temperature, e.g. B. preferably to about - 1 1/2 to cool down toilet. The chalcone is caused to separate by setting the cooled reaction mixture to a pH of from about 1 to 9, preferably from about 3 to 8. A pH of about 7 is particularly preferred in order to achieve maximum yields of a relatively pure product. At a pH of about 10, a precipitate forms, which, however, goes back into solution when further acid is added. This precipitate was properly isolated and analyzed. The Chalcon

ίο does not generally precipitate immediately, but separates out if the reaction mixture is left to stand for at least a few hours, or more quickly if it is stirred. Mineral acids ,? .. B. dilute sulfuric acid and hydrochloric acid are suitable for this purpose.

The deposited chalcone is recovered by filtration or centrifugation. When the separated If chalcone is not obtained, but left in the mother liquor, it can turn into the flavanone forra cyclize.

Alternatively, the product can be obtained in the flavanone form if the reaction mixture is adjusted to a pH in the range from about 3 to 10 with a suitable mineral acid and the reaction mixture at an elevated temperature, for example between about 60 and 120 ^° C. and preferably holds between about 70 and 85 ° C. In this embodiment, a pH of about 4 to 9, and in particular a pH of about 5 to 8, is preferred. The flavanone form of the product forms as a precipitate and is removed by any convenient method, e.g. B. Filtration obtained. The flavanone can be obtained by mixing with an alkali solution, e.g. B. an aqueous solution with a sodium hydroxide or potassium hydroxide concentration of at least about 5% easily convert back into the chalcone form.

Even if the product is obtained in the form of the chalcone, it can be converted into the flavanone form. For example, the chalcone-containing precipitate is in its mother liquor in water or in a suitable organic solvent such as a low molecular weight ketone, e.g. B. acetone or an alcohol, e.g. B. methyl alcohol. Ethyl alcohol or isopropyl alcohol is heated to the above-mentioned elevated temperature of about 60 to 120 ° C., preferably about 70 to 85 ^° C., in order to convert the product into the flavanone form.

Regardless of the method used to obtain the product, it is generally possible further amounts of the flavanone or chalcone product from the filtrate by further crystallization and or to gain cooling.

It was also found that the Chalcon from the dei aqueous reaction mixture or obtained from the Filtra by a solvent extraction process den can,! n the first stage of extraction wm the aqueous reaction mixture or the filtrate with a water-immiscible organir.chei Treated solvent that is a solvent for

f »Excess reactants and other contaminants, e.g. B. for the aldehyde or for Zet is settlement products, but without extracting the chalcone 7. Benzene, toluene, cyclohexane and carbon chloride are suitable for this purpose

6s solvent. The aqueous phase, which contains the chalco, is then separated from the organic solvent phase and a low molecular weight aliphatic with a lower alkyl

here. Typical esters found suitable for this purpose include, for example Ethyl acetate, isopropyl acetate, n-propyl acetate and ethyl propionate. The chalcone is made by the ester extracted and can be recovered or appropriately treated for later recovery v / earth.

Finally, the chalcone (or flavanone) is converted into the dihydrochalcone form by hydrogenation using known methods convicted. One method that has proven particularly successful is to that chalcone product in a caustic solution, e.g. B. a sodium hydroxide solution, in the presence a hydrogenation catalyst, e.g. B. nickel to hydrogenate. The resulting dihydrochalcone is then made the reaction mixture obtained by conventional methods, initially in a filtration for removal residual catalyst and other solid impurities, acidification of the filtrate a pH value of about 3 to 6 for the deposition of the dihydrochalcone and isolation of the dihydrochalcon precipitate, z. B. by filtration, can exist.

The dihydrochalcone product obtained can be obtained by recrystallization from a suitable solvent, z. B. water. Acetone and methanol, are further purified.

Naringin, for example, can also be converted directly into the dihydrochalcone by the method according to the invention. According to such a process, naringin is first refluxed in an aqueous alkaline solution, for example in a potassium hydroxide solution, in order to break it down to phloracetophenone-4'-ß-neohesperidoside. Then 3-hydroxy-4-n-propoxybenzaldehyde is introduced into the reaction mixture together with enough alkali that the alkali concentration is increased to at least 30 percent by weight. The benzaldehyde compound is preferably added in such an amount that the molar ratio given above of the benzaldehyde compound and the phloracetophenone derivative is present at the beginning. The resulting mixture is then held for a suitable period of time, e.g. B. up to z \ i about 30 minutes under reflux conditions, acidified with a mineral acid to a pH of about 3 to 6 while maintaining a temperature of about 60 to 120 ⁰ C, so that a chalcon-containing precipitate forms, and wins the precipitate either as chalcone cyclized to flavanone or hydrogenated to dihydrochalcone.

The compound 2 .4 \ 6 ', 3-tetrahydroxy-4-n-propoxydihydrochalcon ^' - ^ - is neohesperidoside excellent for use as a sweetener in any material or composition used for human consumption, in terms of its intense sweetness. Water solubility, stability, low caloric value when used in amounts desired to achieve effective sweetness and the absence of undesirable aftertaste when used in such amounts are appropriate. Representative examples of edible substances, ie substances which are used for consumption or at least come into contact with the mouth of the end user, include, for example, fruits, vegetables, meat, moisture, flour and dessert additives, chewing gum, toothpaste, mouthwash and tobacco products.

The actual amount of 2 ', 4', 6 ', 3-tetrahydroxy-4-η-propoxydihydrocha'.con -4' -ß- neohesperidoside that is used as a sweetener for a particular use depends mainly on the type of material to be sweetened and the degree of sweetening desired. There are no special critical conditions for use

ίο after a certain amount of the new sweetener of this invention. As a result of the intense sweetness of 2 ', 4', 6 ', 3-tetrahydroxy-4-n-propoxydihydrochalcone-4'-j? -Neohesperidoside the amount of which is used is less than about 1 percent by weight of the Preparation to be sweetened by adding it, and often the amount of the sweetener is less than about 0.5 weight percent and ranges from about 0.0001 to about 0.1% of the weight of the edible Preparation that is the basic material.

It can be seen that the sweetener of the invention alone or in conjunction with a non-toxic Carrier as a diluent when incorporated into a material that is ultimately sweetened by it can be used. Such diluents can advantageously be inorganic or organic liquids, solids or semi-solids. Individual examples of suitable diluents are water, ethanol, glycerine, salt, sugar, gelatin, sorbitol, citric acid, cyclamate, Saccharin, flour and mixtures of such diluents.

example

7.5 g (0.016 mol) of phloracetophenone ^ '- ^ - neohesperidoside were added to a solution of about 10.3 g of potassium hydroxide in 20 ml of water at 110 to 115 ° C. The resulting hot clear solution was admixed with 3.75 g (0.022 mol) of 3-hydroxy-4-n-propoxybenzaldehyde (propylisovanilline). The solution was kept at 115 to 120 ^° C. for 5 minutes and then poured onto 150 g of ice. The solution was acidified to a pH of 6.5 at a temperature below 10 ^° C. with cold, dilute hydrochloric acid. The UV spectroscopic examination of the cold acidified solution showed an intense absorption at about 370πΐμ, which is characteristic of the chalcone structure.

The cyclization of the chalcone to the flavanone

so was done by heating the solution to 80 to WC for half an hour. The heated solution was then cooled to below 40 ^° C. (the boiling point of methylene chloride) and extracted twice with 100 ml of methylene chloride each time, whereupon

SS 1.5 g of unreacted 3-hydroxy-4-n-propoxybenz aldehyde were obtained. The precipitate wurdi of the cold aqueous phase was collected by filtration The crude product Siert twice from 100 ml of water umkristalli and nitrided at 30 ° C, then triturated twice with 35 m of water and filtered at 8O ⁰ C to yield 1.3 (13% yield, based on the phloracetophenor 3 \ 5,7 - trihydroxy - 4 '- η - propoxyflavanone - 7 - β - nee hesperidostd with a temperature of 222 to 224 ° C was obtained.

^6s analysis for C ₃₀ H ₁₈ O _1,:

free drinks, alcoholic drinks, desserts, Sweets, frozen and non-frozen desserts Calculated

C 56.42, H 4.99%; C 56.13, H 6.40%.

A solution of 1.2 g of purified 3 ', 5,7-trihydroxy-4' - η-propoxyflavanone -7-ß- neohesperidoside in 50 ml of 20% potassium hydroxide was in a shaker according to Parr in the presence of 0.5 g of 5 % Palladium-on-carbon hydrogenated. The solution would be acidified to pH 5.5 with cold dilute hydrochloric acid at a temperature below 10 ° C. The solution was freed from the catalyst and sodium chloride was added. The gummy product was separated from the cold solution. The crude product was recrystallized four times with 50 ml of water, giving 0.6 g (50% yield) 12

2 ', 4', 6 ', 3-tetrahydroxy-4-n-propoxydihydrochalci 4'-ß-neohesperidoside, mp 142 to 144 ° C obtained w the.

Analysis for C ₃₀ H ₄₀ O ₁₅ :

Calculated ... C 56.21, H 6.29%; found .... C 55.70, H 6.49%.

Analysis for C ₃₀ H ₄₀ O ₁₅ · V ₂ H ₂ O:

Calculated ... C 55.47, H 6.36%; found .... C 55.58, H 6.32%.

Claims (1)

Claims: 1. 2 ', 4', 6 ', 3-tetrahydroxy-4-n-propoxydihydrochalcone-4' - /? - neohesperidoside of the formula Neohesperidosy 1-0 -OH OH C- Il ο CH ₂ - <f CH, OK -OCH ₂ CH ₂ CH ₃